Clinicopathological and molecular differences between right-sided and left-sided colorectal cancer in Japanese patients

Clinicopathological and molecular differences between right-sided and left-sided colorectal... Abstract Background The aim of this study was to clarify clinicopathological features, frequencies of molecular biomarkers, and prognoses in Japanese colorectal cancer patients and compare them with right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC). Methods We consecutively selected 575 colorectal cancer patients who underwent surgical resection from 2008 to 2011. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum. Frequencies of KRAS gene mutation, BRAF gene mutation, microsatellite instability (MSI), l18qLOH and CpG island methylator phenotype (CIMP) were statistically analyzed between groups. Results Tumors were located in the RCC in 26.3% of patients and in the LCRC in 73.7%. Elderly patients, females and advanced diseases were significantly more frequent in the RCC group than in the LCRC group. However, venous invasion was significantly more frequent in LCRC than in RCC. Between groups, BRAF mutant type, KRAS mutant type, MSI and CIMP+ were significantly more frequent in RCC, whereas 18qLOH was significantly more frequent in LCRC. In overall survival, RCC demonstrated poor prognosis compared with LCRC; however, age, gender, stage, lymphatic invasion, KRAS status and BRAF status rather than tumor location were independent prognostic factors. In addition, the independent prognostic factors in RCC were different from those in LCRC in each stage. However, the consistency between OS and DFS was not observed in this study, excluding lymphatic invasion in LCRC. Conclusion Comparing RCC with LCRC, RCC is different from LCRC in clinicopathological features, molecular biomarkers and prognostic factors in Japanese colorectal cancer patients. Since the proportions of molecular biomarkers of CRC in this study are different from Western CRCs, further studies are required to clarify the clinicopathological differences between Japanese CRCs and Western CRCs. BRAF, CpG island methylator phenotype, colorectal cancer, loss of heterozygosity, microsatellite instability Introduction Over the past two decades, molecular biomarkers of colorectal cancer (CRC) have been studied in detail. Among them, the following three biomarkers have been proposed as global genomic/epigenomic status: microsatellite instability (MSI), 18q loss of heterozygosity (18qLOH) and CpG island methylator phenotype (CIMP) (1). An MSI tumor develops by the accumulation of frameshift mutations of target genes due to a mismatch repair system failure (2), whereas the typical development of microsatellite stable (MSS) tumor proceeds stepwise by the accumulation of inactivated tumor suppressor genes and activated oncogenes (3,4). 18qLOH commonly presents in CRC with chromosomal instability (CIN) and is associated with global hypomethylation in tumor cells. CIN and MSI tend to be exclusive of each other in CRC (5). CIMP with aberrant hypermethylation of promoter regions of various genes is a different epigenetic phenotype in CRC (6), which is associated with MSI (7). In addition to these three biomarkers, KRAS and BRAF genes also play important roles as biomarkers in CRC. Both genes frequently mutate in CRC, and their mutations influence chemo-sensitivity and prognosis. The large bowel is divided into two anatomical categories, i.e., the colon and rectum. However, from the oncological point of view, two anatomical categories of CRC have been proposed according to the tumor location with respect to the right side or left side of the splenic flexure, and clinicopathological differences between right-sided colon cancer (RCC) and left-sided CRC (LCRC) have been observed (8,9). To date, reports on the differences between RCC and LCRC with respect to the status of molecular biomarkers are mostly from Western countries, and few reports have been published from Japan. Thus, it is important to clarify these molecular characteristics in RCC and LCRC from Japanese patients. The aim of this study was to clarify the clinicopathological features and frequencies of molecular biomarkers in Japanese patients with CRC, comparing RCC and LCRC. Materials and methods Patients We consecutively selected 953 CRC patients who underwent surgical resection at the Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital from January 2008 to March 2011 after obtaining informed consent. Patients with inflammatory bowel disease or a known history of familial adenomatous polyposis were excluded. Finally, 575 CRC patients were available for analysis in this study (Fig. 1). If a patient had two or more colorectal tumors resected, the more advanced tumor was selected for analysis. Clinical information was collected either from medical records or directly from patients. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum. The study was approved by the institutional review board of our hospital (approval number: 612, 1202, 1433 and 2001). Figure 1. View largeDownload slide CONSORT diagram. Figure 1. View largeDownload slide CONSORT diagram. MSI and 18qLOH analysis Colorectal cancers and corresponding normal tissues, obtained after informed consent, were stored –80°C immediately after resection. Genomic DNA samples from them were extracted using the QIAamp DNA mini kit (QIAGEN, Valencia, CA). Microsatellite status was determined using two microsatellite markers (BAT25 and BAT26). Polymerase chain reaction (PCR) was performed to amplify cancer and corresponding normal DNAs. The reaction mixture (25 μl) contained 50 ng of genomic DNA, 0.4 μM of each primer, 0.2 μM concentrations of each four deoxynucleotide triphosphate, 1 × PCR buffer, and Taq polymerase. PCR was performed as follows: 5 min at 95°C once; 1 min at 94°C, 1 min at 50°C, and 1 min at 72°C for 35 cycles; and 10 min at 72°C once. Amplified PCR products were diluted with formamide, and run on an Applied Biosystems 3100xl automated capillary electrophoresis DNA sequencer. Allelic sizes for each of the markers were estimated using GeneMapper Software ver.4.0 (Applied Biosystems, Foster City, CA). Microsatellite instability status was defined as MSI (≥ one marker unstable of the informative markers), and MSS (no unstable markers) as described by the National Cancer Institute guidelines for MSI testing (10). For 18qLOH analysis, we excluded MSI tumors, because 18qLOH is rare in MSI tumors, and interpretation of 18qLOH is difficult in MSI tumors (11). LOH analysis was performed for three 18q markers (D18S56 at 18q12.1, D18S474 at 18q21.2, and D18S55 at 18q22.1) to exclude allele dropouts of one of two alleles using GeneMapper Software ver.4.0. LOH at each locus was defined as <0.67 or >1.35 of one of two allele peak heights in tumor DNA relative to corresponding normal tissue DNA. LOH positivity (18qLOH+) was defined as the presence of LOH in any of the 18q markers. LOH negativity (18qLOH–) was strictly defined as the presence of at least two informative markers and the absence of LOH (12). BRAF and KRAS genes mutation analysis In the mutation analysis, all samples were analyzed BRAF (V600E) and KRAS (codons 12 and 13) through direct sequencing. The PCR reaction mixture (10 μl) contained 200 ng of genomic DNA, 0.4 μM of each primer, 5 μl of the AmpliTaq Gold Fast PCR Master Mix (Applied Biosystems). Cycling steps were: initial Taq activation (97°C) for 5 min, 35 cycles as follows: denature for 95°C 1 s, annealing for 1 min at 60°C for BRAF and 60°C for KRAS, extend for 72°C 1 min and final extension 72°C 10 min. Primers are shown in the Supplementary Table 1. The PCR products were purified using the ExoSAP-IT (General Electric Company, Fairfield, CT). Amplified fragments went through a PCR sequencing amplification. Briefly, the PCR product was amplified using the BigDye Terminator v1.1 Cycle Sequencing Kit, (Applied Biosystems). The resulting PCR product was purified with the BigDye XTerminator Purification kit (Applied Biosystems). The cleaned product was loaded into a 3130xl Genetic Analyzer (Applied Biosystems). Sequence histograms were analyzed searching for heterozygous and homozygous substitutions using Sequencing Analysis Software ver.3.7 (Applied Biosystems). CIMP The bisulfite conversion and recovery of bisulfite-converted DNA steps were perfumed using the Zymo EZ DNA methylation kit (Zymo Research, CA, USA) according to the manufacturer’s instructions. Polymerase chain reaction (PCR) primers and probes for the CpG island loci (MLH1, CDKN2A, CRABP1, NEUROG1, CACNA1G) were used as described previously. DNA methylation analysis was performed by MethyLight as described previously. Briefly, the 20 μl MethyLight reaction mixture contained 10 μl 2 × EpiTect MethyLight Master Mix (Qiagen, Valencia, CA, USA), 0.4 μmol/l of each primer, 0.2 μmol/l probe, and 50 ng template. A LightCycler 480 system II (Roche Diagnostics, Indianapolis, IN, USA) was used to conduct the PCR reactions using the following thermal conditions: 5 min at 95°C once, followed by 45 cycles of 15 s at 95°C and 1 min at 60°C. The differences in the amounts of input genomic DNA were normalized by the COL2A1 gene. Duplicate tubes were used for each sample. The percentage methylated of reference (PMR) was calculated by dividing the GENE:COL2A1 ratio of a sample by the GENE:COL2A1 ratio of CpGenome Human Methylated DNA Standard (Millipore, Billerica, MA, USA) and multiplying by 100. The methylation status of each sample was determined to be positive when PMR > 4, a cut-off value based on validated data (13). We used the five-marker CIMP panel, including CACNA1G, CDKN2A, CRABP1, MLH1 and NEUROG1. The CIMP status was defined as CIMP+ (more than four markers positive of the five markers used) and CIMP– (less than three markers positive of the five markers used) (14). Statistical analysis Fisher’s exact test was used to evaluate the relationship between two discrete and dichotomous variables. In the survival analysis, the survival period was calculated from the time of initial resection of the primary colorectal tumor. Disease-free survival was defined as the time from the date of initial operation to the date of the first evidence of tumor recurrence. Overall survival was defined as the time from the date of initial operation to the date of death or last follow-up. Statistical comparisons of potentially predictive factors were first performed using the log-lank analysis for univariate analysis. The Cox proportional hazards model multivariate analysis was performed by only variables with a P value less than 0.10 at in univariate analysis. Statistical significance was defined as P < 0.05. All statistical analyses were performed with EZR, which is a graphical user interface for R (15). This interface is a modified version of R commander and includes statistical functions that are frequently used in biostatistics. Results Clinicopathological characteristics and molecular alterations in RCC and LCRC Among the 575 patients with CRC, the ascertainment rates were 100% in MSI status, 100% in KRAS status, 100% in BRAF status, 95.8% in 18qLOH status, and 97.0% in CIMP status. The summary of baseline characteristics according to the tumor location is shown in Table 1. With respect to the tumor location, 26.3% (95% CI: 22.7–30.1%) were RCC and 73.7% (95% CI: 69.9–77.3%) were LCRC. In RCC, elderly patients (P < 0.001), females (P = 0.007) and advanced diseases (P = 0.036) were significantly more frequent than in LCRC. However, venous invasion was significantly more frequent in LCRC than in RCC (P = 0.013). Table 1. Clinicopathological characteristics     Total  RCC  LCRC  P value      N = 575  N = 151 (26.3%)  N = 424 (73.7%)  (RCC vs. LCRC)  Age  Median (range)  66.1 (32–93)  70.1 (34–93)  64.7 (32–92)  <0.0001*  Gender  Male: female  332:243  73:78  259:165  0.007**  Stage (UICC)  I: II: III: IV  65:209:198:103  13:63:41:34  52:146:157:69  0.036**  T  T1: T2: T3: T4  14:69:375:116  4:11:93:42  10:58:282:74  0.009**  N  N0: N1: N2  294:164:117  80:40:31  212:124:86  0.81**  M  M0: M1  472:103  117:34  355:69  0.11**  Histology  Differentiated type: non-differentiated type  532:41  135:15  397:26  0.14**  Lymphatic invasion  (+): (−)  299:274  80:71  220:203  0.85**  Venous invasion  (+): (−)  472:102  114:37  358:65  0.013**  Curability  A: B: C  466:35:74  115:9:27  351:26:47  0.10**  MSI status  MSI: MSS  34:541  19:132  15:409  <0.0001**  KRAS status  Mutant type: wild type  150:425  53:98  97:327  0.005**  BRAF status  Mutant type: wild type  24:551  17:134  7:417  <0.0001**  18qLOH status  18qLOH+: 18qLOH-  394:157  86:59  308:98  <0.0001**  CIMP status  (+): (−)  42:527  31:115  11:412  <0.0001**  In Stage II/III            Site of recurrence  Recurrence (+): (−)  100:306  18:86  82:220  0.048**    Liver (+): (−)  33:373  9:95  24:278  0.84**    Lung (+): (−)  34:372  4:100  30:272  0.064**    Peritoneum (+): (−)  12:394  7:97  5:297  0.015**    Lymph node (+): (−)  14:392  0:104  14:288  0.025**    Bone (+): (−)  5:401  0:104  5:297  0.34**    Brain (+): (−)  4:402  1:103  3:299  1.0**    Ova (+): (−)  2:404  2:102  0:302  0.065**    Other (+): (−)  5:401  2:102  3:299  0.61**    Local recurrence (+): (−)  25:381  1:103  24:278  0.008**  In Stage IV            Site of metastasis  Liver (+): (−)  72:31  18:16  54:15  0.012**    Lung (+): (−)  14:89  2:32  12:57  0.14**    Peritoneum (+): (−)  29:74  15:19  14:55  0.019**    Lymph node (+): (−)  16:87  6:28  10:59  0.77**    Bone (+): (−)  1:102  0:34  1:68  1.0**    Ovary (+): (−)  1:102  0:34  1:68  1.0**    Other (+): (−)  3:100  0:34  3:66  0.55**      Total  RCC  LCRC  P value      N = 575  N = 151 (26.3%)  N = 424 (73.7%)  (RCC vs. LCRC)  Age  Median (range)  66.1 (32–93)  70.1 (34–93)  64.7 (32–92)  <0.0001*  Gender  Male: female  332:243  73:78  259:165  0.007**  Stage (UICC)  I: II: III: IV  65:209:198:103  13:63:41:34  52:146:157:69  0.036**  T  T1: T2: T3: T4  14:69:375:116  4:11:93:42  10:58:282:74  0.009**  N  N0: N1: N2  294:164:117  80:40:31  212:124:86  0.81**  M  M0: M1  472:103  117:34  355:69  0.11**  Histology  Differentiated type: non-differentiated type  532:41  135:15  397:26  0.14**  Lymphatic invasion  (+): (−)  299:274  80:71  220:203  0.85**  Venous invasion  (+): (−)  472:102  114:37  358:65  0.013**  Curability  A: B: C  466:35:74  115:9:27  351:26:47  0.10**  MSI status  MSI: MSS  34:541  19:132  15:409  <0.0001**  KRAS status  Mutant type: wild type  150:425  53:98  97:327  0.005**  BRAF status  Mutant type: wild type  24:551  17:134  7:417  <0.0001**  18qLOH status  18qLOH+: 18qLOH-  394:157  86:59  308:98  <0.0001**  CIMP status  (+): (−)  42:527  31:115  11:412  <0.0001**  In Stage II/III            Site of recurrence  Recurrence (+): (−)  100:306  18:86  82:220  0.048**    Liver (+): (−)  33:373  9:95  24:278  0.84**    Lung (+): (−)  34:372  4:100  30:272  0.064**    Peritoneum (+): (−)  12:394  7:97  5:297  0.015**    Lymph node (+): (−)  14:392  0:104  14:288  0.025**    Bone (+): (−)  5:401  0:104  5:297  0.34**    Brain (+): (−)  4:402  1:103  3:299  1.0**    Ova (+): (−)  2:404  2:102  0:302  0.065**    Other (+): (−)  5:401  2:102  3:299  0.61**    Local recurrence (+): (−)  25:381  1:103  24:278  0.008**  In Stage IV            Site of metastasis  Liver (+): (−)  72:31  18:16  54:15  0.012**    Lung (+): (−)  14:89  2:32  12:57  0.14**    Peritoneum (+): (−)  29:74  15:19  14:55  0.019**    Lymph node (+): (−)  16:87  6:28  10:59  0.77**    Bone (+): (−)  1:102  0:34  1:68  1.0**    Ovary (+): (−)  1:102  0:34  1:68  1.0**    Other (+): (−)  3:100  0:34  3:66  0.55**  Differentiated type, well differentiated adenocarcinoma and moderately differentiated adenocarcinoma; non-differentiated, poorly differentiated adenocarcinoma and mucinous carcinoma; MSI, microsatellite instability; MSS, microsatellite stable; LOH, loss of heterozygosity; *, Mann–Whitney’s U test; **, Fisher’s exact test. Table 1. Clinicopathological characteristics     Total  RCC  LCRC  P value      N = 575  N = 151 (26.3%)  N = 424 (73.7%)  (RCC vs. LCRC)  Age  Median (range)  66.1 (32–93)  70.1 (34–93)  64.7 (32–92)  <0.0001*  Gender  Male: female  332:243  73:78  259:165  0.007**  Stage (UICC)  I: II: III: IV  65:209:198:103  13:63:41:34  52:146:157:69  0.036**  T  T1: T2: T3: T4  14:69:375:116  4:11:93:42  10:58:282:74  0.009**  N  N0: N1: N2  294:164:117  80:40:31  212:124:86  0.81**  M  M0: M1  472:103  117:34  355:69  0.11**  Histology  Differentiated type: non-differentiated type  532:41  135:15  397:26  0.14**  Lymphatic invasion  (+): (−)  299:274  80:71  220:203  0.85**  Venous invasion  (+): (−)  472:102  114:37  358:65  0.013**  Curability  A: B: C  466:35:74  115:9:27  351:26:47  0.10**  MSI status  MSI: MSS  34:541  19:132  15:409  <0.0001**  KRAS status  Mutant type: wild type  150:425  53:98  97:327  0.005**  BRAF status  Mutant type: wild type  24:551  17:134  7:417  <0.0001**  18qLOH status  18qLOH+: 18qLOH-  394:157  86:59  308:98  <0.0001**  CIMP status  (+): (−)  42:527  31:115  11:412  <0.0001**  In Stage II/III            Site of recurrence  Recurrence (+): (−)  100:306  18:86  82:220  0.048**    Liver (+): (−)  33:373  9:95  24:278  0.84**    Lung (+): (−)  34:372  4:100  30:272  0.064**    Peritoneum (+): (−)  12:394  7:97  5:297  0.015**    Lymph node (+): (−)  14:392  0:104  14:288  0.025**    Bone (+): (−)  5:401  0:104  5:297  0.34**    Brain (+): (−)  4:402  1:103  3:299  1.0**    Ova (+): (−)  2:404  2:102  0:302  0.065**    Other (+): (−)  5:401  2:102  3:299  0.61**    Local recurrence (+): (−)  25:381  1:103  24:278  0.008**  In Stage IV            Site of metastasis  Liver (+): (−)  72:31  18:16  54:15  0.012**    Lung (+): (−)  14:89  2:32  12:57  0.14**    Peritoneum (+): (−)  29:74  15:19  14:55  0.019**    Lymph node (+): (−)  16:87  6:28  10:59  0.77**    Bone (+): (−)  1:102  0:34  1:68  1.0**    Ovary (+): (−)  1:102  0:34  1:68  1.0**    Other (+): (−)  3:100  0:34  3:66  0.55**      Total  RCC  LCRC  P value      N = 575  N = 151 (26.3%)  N = 424 (73.7%)  (RCC vs. LCRC)  Age  Median (range)  66.1 (32–93)  70.1 (34–93)  64.7 (32–92)  <0.0001*  Gender  Male: female  332:243  73:78  259:165  0.007**  Stage (UICC)  I: II: III: IV  65:209:198:103  13:63:41:34  52:146:157:69  0.036**  T  T1: T2: T3: T4  14:69:375:116  4:11:93:42  10:58:282:74  0.009**  N  N0: N1: N2  294:164:117  80:40:31  212:124:86  0.81**  M  M0: M1  472:103  117:34  355:69  0.11**  Histology  Differentiated type: non-differentiated type  532:41  135:15  397:26  0.14**  Lymphatic invasion  (+): (−)  299:274  80:71  220:203  0.85**  Venous invasion  (+): (−)  472:102  114:37  358:65  0.013**  Curability  A: B: C  466:35:74  115:9:27  351:26:47  0.10**  MSI status  MSI: MSS  34:541  19:132  15:409  <0.0001**  KRAS status  Mutant type: wild type  150:425  53:98  97:327  0.005**  BRAF status  Mutant type: wild type  24:551  17:134  7:417  <0.0001**  18qLOH status  18qLOH+: 18qLOH-  394:157  86:59  308:98  <0.0001**  CIMP status  (+): (−)  42:527  31:115  11:412  <0.0001**  In Stage II/III            Site of recurrence  Recurrence (+): (−)  100:306  18:86  82:220  0.048**    Liver (+): (−)  33:373  9:95  24:278  0.84**    Lung (+): (−)  34:372  4:100  30:272  0.064**    Peritoneum (+): (−)  12:394  7:97  5:297  0.015**    Lymph node (+): (−)  14:392  0:104  14:288  0.025**    Bone (+): (−)  5:401  0:104  5:297  0.34**    Brain (+): (−)  4:402  1:103  3:299  1.0**    Ova (+): (−)  2:404  2:102  0:302  0.065**    Other (+): (−)  5:401  2:102  3:299  0.61**    Local recurrence (+): (−)  25:381  1:103  24:278  0.008**  In Stage IV            Site of metastasis  Liver (+): (−)  72:31  18:16  54:15  0.012**    Lung (+): (−)  14:89  2:32  12:57  0.14**    Peritoneum (+): (−)  29:74  15:19  14:55  0.019**    Lymph node (+): (−)  16:87  6:28  10:59  0.77**    Bone (+): (−)  1:102  0:34  1:68  1.0**    Ovary (+): (−)  1:102  0:34  1:68  1.0**    Other (+): (−)  3:100  0:34  3:66  0.55**  Differentiated type, well differentiated adenocarcinoma and moderately differentiated adenocarcinoma; non-differentiated, poorly differentiated adenocarcinoma and mucinous carcinoma; MSI, microsatellite instability; MSS, microsatellite stable; LOH, loss of heterozygosity; *, Mann–Whitney’s U test; **, Fisher’s exact test. In Stage IV cases, liver metastasis was significantly more frequent in LCRC than in RCC (P = 0.012), while peritoneal dissemination was significantly more frequent in RCC than in LCRC (P = 0.019). In Stage II/III cases, lymph node recurrence (P = 0.025) and local recurrence (P = 0.008) were significantly more frequent in LCRC than in RCC, while peritoneal dissemination was significantly more frequent in RCC than in LCRC (P = 0.015). The frequencies of molecular biomarkers were 5.9% (95% CI: 4.1–8.2%) for MSI, 26.1% (95% CI: 22.5–29.9%) for KRAS mutant type, 4.2% (95% CI: 2.7–6.1%) for BRAF mutant type, 71.5% (95% CI: 67.7–75.4%) for 18qLOH+, and 7.4% (95% CI: 5.4–9.8%) for CIMP+. When RCC and LCRC were compared, MSI (P = 0.002), KRAS mutant type (P = 0.005), and BRAF mutant type (P < 0.001) were significantly more frequent in RCC, whereas 18qLOH was significantly more frequent in LCRC (P < 0.001). Overall survival In overall survival analyses (Table 2), patients with RCC had significantly poorer prognosis than patients with LCRC (P < 0.0001). MSS predicted significantly poorer prognosis than MSI in LCRC (P = 0.038); however, there was no prognostic difference of MSI status in RCC (P = 0.64). KRAS mutant type was associated with significantly poorer prognosis than KRAS wild type (P = 0.041), and KRAS mutant type was poorer prognosis in LCRC (P = 0.035). BRAF mutant type was associated with significantly poorer prognosis than BRAF wild type (P < 0.0001), and the prognostic differences were observed in both RCC (P = 0.021) and LCRC (P = 0.0097). The presence of CIMP+ predicted significantly poorer prognosis than CIMP– (P = 0.0034). Between RCC and LCRC, RCC was associated with significantly poorer prognosis than LCRC with MSI (P = 0.019), MSS (P = 0.0010), KRAS wild type (P = 0.0020), BRAF wild type (P = 0.0040), 18qLOH– (P = 0.0010), and CIMP– (P = 0.0050). Table 2. Univariate analyses of tumor location associated with overall survivals by molecular biomarker in colorectal cancer patientsa   All (5-year survival rate)  Stage II (5-year survival rate)  Stage III (5-year survival rate)  Stage IV (MST, months)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  71.9%  61.1%  75.5%  <0.0001  86.2%  77.7%  89.9%  0.0077  74.7%  65.6%  77.0%  0.24  28.6  21.0  35.2  0.13  N = 575  N = 151  N = 424  N = 207  N = 63  N = 144  N = 198  N = 41  N = 157  N = 102  N = 34  N = 68  MSI  81.2%  66.7%  100%  0.019  89.9%  80.0%  100%  0.19  71.4%  80.0%  100%  0.070  22.8  22.8  NA  NA  N = 34  N = 19  N = 15  N = 20  N = 11  N = 9  N = 7  N = 3  N = 4  N = 2  N = 2  N = 0  MSS  71.2%  70.4%  74.7%  0.0010  86.1%  77.3%  89.3%  0.0082  74.7%  77.3%  76.4%  0.45  26.7  21.0  37.4  0.14  N = 541  N = 132  N = 409  N = 187  N = 52  N = 135  N = 191  N = 38  N = 153  N = 100  N = 32  N = 32   P value  0.21  0.64  0.038    0.62  0.71  0.32    0.82  0.71  0.31    0.36  0.53  NA    KRAS MT  65.5%  60.4%  68.1%  0.30  84.3%  81.4%  85.4%  0.28  84.3%  68.8%  69.5%  0.73  22.8  21.2  30.6  0.26  N = 150  N = 53  N = 97  N = 55  N = 20  N = 35  N = 49  N = 16  N = 33  N = 29  N = 12  N = 17  KRAS WT  73.9%  61.4%  77.9%  0.0020  87.1%  76.2%  91.3%  0.017  87.1%  64.0%  78.7%  0.15  26.9  20.8  35.2  0.25  N = 425  N = 98  N = 327  N = 152  N = 43  N = 109  N = 149  N = 25  N = 124  N = 73  N = 22  N = 51  P value  0.041  0.93  0.035    0.58  0.94  0.46    0.58  0.74  0.065    0.64  0.87  0.80    BRAF MT  41.2%  40.3%  42.9%  0.88  71.4%  83.3%  NA  0.17  50.0%  20.0%  100%  0.053  13.2  17.4  10.8  0.25    N = 24  N = 17  N = 7  N = 7  N = 6  N = 1  N = 8  N = 5  N = 3  N = 8  N = 5  N = 3  BRAF WT  73.1%  63.7%  76.1%  0.0040  86.9%  77.0%  90.6%  0.0027  75.6%  71.9%  76.5%  0.79  32.8888  21.3  37.4  0.21  N = 551  N = 134  N = 417  N = 200  N = 57  N = 143  N = 190  N = 36  N = 154  N = 94  N = 29  N = 65  P value  <0.0001  0.021  0.0097    0.25  0.63  <0.0001    0.10  0.0034  0.33    <0.0001  0.019  <0.0001    18qLOH+  71.3%  62.7%  73.7%  0.069  86.3%  76.9%  89.6%  0.056  76.7%  67.2%  78.9%  0.31  26.1  21.1  32.8  0.68  N = 394  N = 86  N = 308  N = 136  N = 36  N = 100  N = 147  N = 28  N = 119  N = 74  N = 19  N = 55  18qLOH−  72.9%  58.9%  81.2%  0.0010  87.1%  79.2%  92.1%  0.029  71.4%  63.6%  74.2%  0.50  28.5  20.9  44.7  0.024  N = 157  N = 59  N = 98  N = 65  N = 26  N = 39  N = 42  N = 11  N = 31  N = 25  N = 13  N = 12  P value  0.69  0.53  0.10    0.93  0.93  0.55    0.48  0.71  0.62    0.52  0.21  0.49    CIMP+  54.4%  51.4%  63.6%  0.69  72.7%  70.0%  NA  0.56  61.9%  54.5%  80.0%  0.44  18.4  19.4  13.7  0.62  N = 42  N = 31  N = 11  N = 11  N = 10  N = 1  N = 16  N = 11  N = 5  N = 10  N = 7  N = 3  CIMP−  73.1%  63.2%  75.8%  0.0050  87.0%  78.5%  89.8%  0.0085  75.5%  68.4%  76.9%  0.54  34.3  21.0  37.4  0.31  N = 527  N = 115  N = 412  N = 192  N = 50  N = 142  N = 181  N = 29  N = 151  N = 91  N = 26  N = 65  P value  0.0034  0.19  0.20    0.22  0.73  0.76    0.19  0.30  0.97    0.0034  0.14  0.031      All (5-year survival rate)  Stage II (5-year survival rate)  Stage III (5-year survival rate)  Stage IV (MST, months)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  71.9%  61.1%  75.5%  <0.0001  86.2%  77.7%  89.9%  0.0077  74.7%  65.6%  77.0%  0.24  28.6  21.0  35.2  0.13  N = 575  N = 151  N = 424  N = 207  N = 63  N = 144  N = 198  N = 41  N = 157  N = 102  N = 34  N = 68  MSI  81.2%  66.7%  100%  0.019  89.9%  80.0%  100%  0.19  71.4%  80.0%  100%  0.070  22.8  22.8  NA  NA  N = 34  N = 19  N = 15  N = 20  N = 11  N = 9  N = 7  N = 3  N = 4  N = 2  N = 2  N = 0  MSS  71.2%  70.4%  74.7%  0.0010  86.1%  77.3%  89.3%  0.0082  74.7%  77.3%  76.4%  0.45  26.7  21.0  37.4  0.14  N = 541  N = 132  N = 409  N = 187  N = 52  N = 135  N = 191  N = 38  N = 153  N = 100  N = 32  N = 32   P value  0.21  0.64  0.038    0.62  0.71  0.32    0.82  0.71  0.31    0.36  0.53  NA    KRAS MT  65.5%  60.4%  68.1%  0.30  84.3%  81.4%  85.4%  0.28  84.3%  68.8%  69.5%  0.73  22.8  21.2  30.6  0.26  N = 150  N = 53  N = 97  N = 55  N = 20  N = 35  N = 49  N = 16  N = 33  N = 29  N = 12  N = 17  KRAS WT  73.9%  61.4%  77.9%  0.0020  87.1%  76.2%  91.3%  0.017  87.1%  64.0%  78.7%  0.15  26.9  20.8  35.2  0.25  N = 425  N = 98  N = 327  N = 152  N = 43  N = 109  N = 149  N = 25  N = 124  N = 73  N = 22  N = 51  P value  0.041  0.93  0.035    0.58  0.94  0.46    0.58  0.74  0.065    0.64  0.87  0.80    BRAF MT  41.2%  40.3%  42.9%  0.88  71.4%  83.3%  NA  0.17  50.0%  20.0%  100%  0.053  13.2  17.4  10.8  0.25    N = 24  N = 17  N = 7  N = 7  N = 6  N = 1  N = 8  N = 5  N = 3  N = 8  N = 5  N = 3  BRAF WT  73.1%  63.7%  76.1%  0.0040  86.9%  77.0%  90.6%  0.0027  75.6%  71.9%  76.5%  0.79  32.8888  21.3  37.4  0.21  N = 551  N = 134  N = 417  N = 200  N = 57  N = 143  N = 190  N = 36  N = 154  N = 94  N = 29  N = 65  P value  <0.0001  0.021  0.0097    0.25  0.63  <0.0001    0.10  0.0034  0.33    <0.0001  0.019  <0.0001    18qLOH+  71.3%  62.7%  73.7%  0.069  86.3%  76.9%  89.6%  0.056  76.7%  67.2%  78.9%  0.31  26.1  21.1  32.8  0.68  N = 394  N = 86  N = 308  N = 136  N = 36  N = 100  N = 147  N = 28  N = 119  N = 74  N = 19  N = 55  18qLOH−  72.9%  58.9%  81.2%  0.0010  87.1%  79.2%  92.1%  0.029  71.4%  63.6%  74.2%  0.50  28.5  20.9  44.7  0.024  N = 157  N = 59  N = 98  N = 65  N = 26  N = 39  N = 42  N = 11  N = 31  N = 25  N = 13  N = 12  P value  0.69  0.53  0.10    0.93  0.93  0.55    0.48  0.71  0.62    0.52  0.21  0.49    CIMP+  54.4%  51.4%  63.6%  0.69  72.7%  70.0%  NA  0.56  61.9%  54.5%  80.0%  0.44  18.4  19.4  13.7  0.62  N = 42  N = 31  N = 11  N = 11  N = 10  N = 1  N = 16  N = 11  N = 5  N = 10  N = 7  N = 3  CIMP−  73.1%  63.2%  75.8%  0.0050  87.0%  78.5%  89.8%  0.0085  75.5%  68.4%  76.9%  0.54  34.3  21.0  37.4  0.31  N = 527  N = 115  N = 412  N = 192  N = 50  N = 142  N = 181  N = 29  N = 151  N = 91  N = 26  N = 65  P value  0.0034  0.19  0.20    0.22  0.73  0.76    0.19  0.30  0.97    0.0034  0.14  0.031    aAnalyzed with Fisher’s exact test; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients; NA, not available. Table 2. Univariate analyses of tumor location associated with overall survivals by molecular biomarker in colorectal cancer patientsa   All (5-year survival rate)  Stage II (5-year survival rate)  Stage III (5-year survival rate)  Stage IV (MST, months)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  71.9%  61.1%  75.5%  <0.0001  86.2%  77.7%  89.9%  0.0077  74.7%  65.6%  77.0%  0.24  28.6  21.0  35.2  0.13  N = 575  N = 151  N = 424  N = 207  N = 63  N = 144  N = 198  N = 41  N = 157  N = 102  N = 34  N = 68  MSI  81.2%  66.7%  100%  0.019  89.9%  80.0%  100%  0.19  71.4%  80.0%  100%  0.070  22.8  22.8  NA  NA  N = 34  N = 19  N = 15  N = 20  N = 11  N = 9  N = 7  N = 3  N = 4  N = 2  N = 2  N = 0  MSS  71.2%  70.4%  74.7%  0.0010  86.1%  77.3%  89.3%  0.0082  74.7%  77.3%  76.4%  0.45  26.7  21.0  37.4  0.14  N = 541  N = 132  N = 409  N = 187  N = 52  N = 135  N = 191  N = 38  N = 153  N = 100  N = 32  N = 32   P value  0.21  0.64  0.038    0.62  0.71  0.32    0.82  0.71  0.31    0.36  0.53  NA    KRAS MT  65.5%  60.4%  68.1%  0.30  84.3%  81.4%  85.4%  0.28  84.3%  68.8%  69.5%  0.73  22.8  21.2  30.6  0.26  N = 150  N = 53  N = 97  N = 55  N = 20  N = 35  N = 49  N = 16  N = 33  N = 29  N = 12  N = 17  KRAS WT  73.9%  61.4%  77.9%  0.0020  87.1%  76.2%  91.3%  0.017  87.1%  64.0%  78.7%  0.15  26.9  20.8  35.2  0.25  N = 425  N = 98  N = 327  N = 152  N = 43  N = 109  N = 149  N = 25  N = 124  N = 73  N = 22  N = 51  P value  0.041  0.93  0.035    0.58  0.94  0.46    0.58  0.74  0.065    0.64  0.87  0.80    BRAF MT  41.2%  40.3%  42.9%  0.88  71.4%  83.3%  NA  0.17  50.0%  20.0%  100%  0.053  13.2  17.4  10.8  0.25    N = 24  N = 17  N = 7  N = 7  N = 6  N = 1  N = 8  N = 5  N = 3  N = 8  N = 5  N = 3  BRAF WT  73.1%  63.7%  76.1%  0.0040  86.9%  77.0%  90.6%  0.0027  75.6%  71.9%  76.5%  0.79  32.8888  21.3  37.4  0.21  N = 551  N = 134  N = 417  N = 200  N = 57  N = 143  N = 190  N = 36  N = 154  N = 94  N = 29  N = 65  P value  <0.0001  0.021  0.0097    0.25  0.63  <0.0001    0.10  0.0034  0.33    <0.0001  0.019  <0.0001    18qLOH+  71.3%  62.7%  73.7%  0.069  86.3%  76.9%  89.6%  0.056  76.7%  67.2%  78.9%  0.31  26.1  21.1  32.8  0.68  N = 394  N = 86  N = 308  N = 136  N = 36  N = 100  N = 147  N = 28  N = 119  N = 74  N = 19  N = 55  18qLOH−  72.9%  58.9%  81.2%  0.0010  87.1%  79.2%  92.1%  0.029  71.4%  63.6%  74.2%  0.50  28.5  20.9  44.7  0.024  N = 157  N = 59  N = 98  N = 65  N = 26  N = 39  N = 42  N = 11  N = 31  N = 25  N = 13  N = 12  P value  0.69  0.53  0.10    0.93  0.93  0.55    0.48  0.71  0.62    0.52  0.21  0.49    CIMP+  54.4%  51.4%  63.6%  0.69  72.7%  70.0%  NA  0.56  61.9%  54.5%  80.0%  0.44  18.4  19.4  13.7  0.62  N = 42  N = 31  N = 11  N = 11  N = 10  N = 1  N = 16  N = 11  N = 5  N = 10  N = 7  N = 3  CIMP−  73.1%  63.2%  75.8%  0.0050  87.0%  78.5%  89.8%  0.0085  75.5%  68.4%  76.9%  0.54  34.3  21.0  37.4  0.31  N = 527  N = 115  N = 412  N = 192  N = 50  N = 142  N = 181  N = 29  N = 151  N = 91  N = 26  N = 65  P value  0.0034  0.19  0.20    0.22  0.73  0.76    0.19  0.30  0.97    0.0034  0.14  0.031      All (5-year survival rate)  Stage II (5-year survival rate)  Stage III (5-year survival rate)  Stage IV (MST, months)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  71.9%  61.1%  75.5%  <0.0001  86.2%  77.7%  89.9%  0.0077  74.7%  65.6%  77.0%  0.24  28.6  21.0  35.2  0.13  N = 575  N = 151  N = 424  N = 207  N = 63  N = 144  N = 198  N = 41  N = 157  N = 102  N = 34  N = 68  MSI  81.2%  66.7%  100%  0.019  89.9%  80.0%  100%  0.19  71.4%  80.0%  100%  0.070  22.8  22.8  NA  NA  N = 34  N = 19  N = 15  N = 20  N = 11  N = 9  N = 7  N = 3  N = 4  N = 2  N = 2  N = 0  MSS  71.2%  70.4%  74.7%  0.0010  86.1%  77.3%  89.3%  0.0082  74.7%  77.3%  76.4%  0.45  26.7  21.0  37.4  0.14  N = 541  N = 132  N = 409  N = 187  N = 52  N = 135  N = 191  N = 38  N = 153  N = 100  N = 32  N = 32   P value  0.21  0.64  0.038    0.62  0.71  0.32    0.82  0.71  0.31    0.36  0.53  NA    KRAS MT  65.5%  60.4%  68.1%  0.30  84.3%  81.4%  85.4%  0.28  84.3%  68.8%  69.5%  0.73  22.8  21.2  30.6  0.26  N = 150  N = 53  N = 97  N = 55  N = 20  N = 35  N = 49  N = 16  N = 33  N = 29  N = 12  N = 17  KRAS WT  73.9%  61.4%  77.9%  0.0020  87.1%  76.2%  91.3%  0.017  87.1%  64.0%  78.7%  0.15  26.9  20.8  35.2  0.25  N = 425  N = 98  N = 327  N = 152  N = 43  N = 109  N = 149  N = 25  N = 124  N = 73  N = 22  N = 51  P value  0.041  0.93  0.035    0.58  0.94  0.46    0.58  0.74  0.065    0.64  0.87  0.80    BRAF MT  41.2%  40.3%  42.9%  0.88  71.4%  83.3%  NA  0.17  50.0%  20.0%  100%  0.053  13.2  17.4  10.8  0.25    N = 24  N = 17  N = 7  N = 7  N = 6  N = 1  N = 8  N = 5  N = 3  N = 8  N = 5  N = 3  BRAF WT  73.1%  63.7%  76.1%  0.0040  86.9%  77.0%  90.6%  0.0027  75.6%  71.9%  76.5%  0.79  32.8888  21.3  37.4  0.21  N = 551  N = 134  N = 417  N = 200  N = 57  N = 143  N = 190  N = 36  N = 154  N = 94  N = 29  N = 65  P value  <0.0001  0.021  0.0097    0.25  0.63  <0.0001    0.10  0.0034  0.33    <0.0001  0.019  <0.0001    18qLOH+  71.3%  62.7%  73.7%  0.069  86.3%  76.9%  89.6%  0.056  76.7%  67.2%  78.9%  0.31  26.1  21.1  32.8  0.68  N = 394  N = 86  N = 308  N = 136  N = 36  N = 100  N = 147  N = 28  N = 119  N = 74  N = 19  N = 55  18qLOH−  72.9%  58.9%  81.2%  0.0010  87.1%  79.2%  92.1%  0.029  71.4%  63.6%  74.2%  0.50  28.5  20.9  44.7  0.024  N = 157  N = 59  N = 98  N = 65  N = 26  N = 39  N = 42  N = 11  N = 31  N = 25  N = 13  N = 12  P value  0.69  0.53  0.10    0.93  0.93  0.55    0.48  0.71  0.62    0.52  0.21  0.49    CIMP+  54.4%  51.4%  63.6%  0.69  72.7%  70.0%  NA  0.56  61.9%  54.5%  80.0%  0.44  18.4  19.4  13.7  0.62  N = 42  N = 31  N = 11  N = 11  N = 10  N = 1  N = 16  N = 11  N = 5  N = 10  N = 7  N = 3  CIMP−  73.1%  63.2%  75.8%  0.0050  87.0%  78.5%  89.8%  0.0085  75.5%  68.4%  76.9%  0.54  34.3  21.0  37.4  0.31  N = 527  N = 115  N = 412  N = 192  N = 50  N = 142  N = 181  N = 29  N = 151  N = 91  N = 26  N = 65  P value  0.0034  0.19  0.20    0.22  0.73  0.76    0.19  0.30  0.97    0.0034  0.14  0.031    aAnalyzed with Fisher’s exact test; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients; NA, not available. In Stage II, survival was significantly worse in RCC compared with that in LCRC (P = 0.0077). However, no significant difference of prognosis was observed according to the molecular biomarker status. Compared with RCC and LCRC, RCC was associated with a significantly poorer prognosis than LCRC with MSS (P = 0.0082), and KRAS wild type (P = 0.017), BRAF wild type (P = 0.0027), 18qLOH– (P = 0.029), CIMP– (P = 0.0085). In Stage III, no significant difference of prognosis was observed according to the location. BRAF mutant type was associated with significantly poorer prognosis than BRAF wild type in RCC (P = 0.0034). Compared with RCC and LCRC, RCC tend to have poorer prognosis than LCRC with MSI (P = 0.070) and BRAF mutant type (P = 0.053); however, no significant difference of prognosis was observed according to the molecular biomarker status. In Stage IV, BRAF mutant type was associated with significantly poorer prognosis than BRAF wild type (P < 0.0001). CIMP+ was associated with a significantly poorer prognosis than CIMP– (P = 0.0034). Between RCC and LCRC, RCC had a significantly poorer prognosis than LCRC in 18qLOH– (P = 0.024). In multivariate analysis for overall survival (Table 3), age, gender, stage, lymphatic invasion, KRAS status and BRAF status were independent prognostic factors in colorectal cancer. Gender, stage and BRAF status were independent prognostic factors in RCC, and age, gender, stage, lymphatic invasion, KRAS status and BRAF status were independent prognostic factors in LCRC. Age, gender and lymphatic invasion in Stage II, histology in Stage III, and BRAF status in Stage IV were independent prognostic factors in colorectal cancer (Supplemental Tables 1–3). In RCC, gender in Stage II, and BRAF status in Stage III and Stage IV were independent prognostic factors. In LCRC, age and lymphatic invasion in Stage II, histology and KRAS status in Stage III, and age, venous invasion and BRAF status in Stage IV were independent prognostic factors. Table 3. Univariate and multivariate analyses of factors associated with overall survivals in colorectal cancer patientsa Variables  All  Right-sided colon cancer  Left-sided colorectal cancer  Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           >=65  68.3  0.0074  1.88 (1.32–2.66)  0.0004  61.4  0.63      71.6  0.023  2.18 (1.45–3.30)  0.0002   <65  77.2    1.0    60.8        80.5    1.0    Gender                           Male  68.1  0.017  1.92 (1.37–2.68)  0.0001  54.7  0.042  1.94 (1.12–3.37)  0.018  71.9  0.050  1.70 (1.11–2.59)  0.014   Female  76.8    1.0    67.1    1.0    81.1    1.0    Location                           Right  61.1  0.0005  1.21 (0.84–1.74)  0.30                   Left  75.5    1.0                    Stage                           I or II or III  81.4  <0.0001  1.0    73.6  <0.0001  1.0    83.9  <0.0001  1.0     IV  26.9    6.27 (4.47–8.79)  <0.0001  19.6    5.98 (3.29–10.9)  <0.0001  30.8    6.46 (4.27–9.78)  <0.0001  Histology                           Differentiated type  73.5  <0.0001  0.81 (0.48–1.36)  0.43  63.3  0.052  0.92 (0.40–2.10)  0.83  76.9  0.013  0.58 (0.30–1.09)  0.089   Non-differentiated type  53.3    1.0    46.7    1.0    57.2    1.0    Lymphatic invasion                           −  82.7  <0.0001  1.0    70.7  0.034  0.91 (0.48–1.72)  0.76  86.7  <0.0001  1.0     +  62.1    1.83 (1.28–2.60)  0.0008  52.7    1.0    65.6    2.32 (1.51–3.58)  0.0001  Venous invasion                           −  85.0  0.0027  1.0    75.4  0.024  1.0    90.1  0.010  1.0     +  69.0    1.21 (0.71–2.07)  0.48  56.2    1.74 (0.80–3.79)  0.76  73.1    1.25 (0.59–2.65)  0.56  MSI status                           MSI  81.2  0.21      66.7  0.64      100.0  0.038  1.0     MSS  71.2        70.4        74.7    1.44e+7 (0.00-Inf)  0.99  KRAS status                           Mutant type  65.5  0.041  1.0    60.4  0.93      68.1  0.035  1.0     Wild type  73.9    0.60 (0.42–0.84)  0.0037  61.4        77.9    0.58 (0.37–0886)  0.012  BRAF status                           Mutant type  41.2  <0.0001  1.0    40.3  0.021  1.0    42.9  0.0097  1.0     Wild type  73.1    0.44 (0.20–0.96)  0.040  63.7    0.32 (0.14–0.72)  0.0058  76.1    0.22 (0.078–0.61)  0.011  18qLOH status                           18qLOH+  71.3  0.69      62.7  0.53      73.7  0.10       18qLOH−  72.9        58.9        81.2        CIMP status                           (+)  54.4  0.0034  1.0    51.4  0.19      63.6  0.20       (−)  73.1    1.30 (0.66–2.57)  0.45  63.2        75.8        Variables  All  Right-sided colon cancer  Left-sided colorectal cancer  Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           >=65  68.3  0.0074  1.88 (1.32–2.66)  0.0004  61.4  0.63      71.6  0.023  2.18 (1.45–3.30)  0.0002   <65  77.2    1.0    60.8        80.5    1.0    Gender                           Male  68.1  0.017  1.92 (1.37–2.68)  0.0001  54.7  0.042  1.94 (1.12–3.37)  0.018  71.9  0.050  1.70 (1.11–2.59)  0.014   Female  76.8    1.0    67.1    1.0    81.1    1.0    Location                           Right  61.1  0.0005  1.21 (0.84–1.74)  0.30                   Left  75.5    1.0                    Stage                           I or II or III  81.4  <0.0001  1.0    73.6  <0.0001  1.0    83.9  <0.0001  1.0     IV  26.9    6.27 (4.47–8.79)  <0.0001  19.6    5.98 (3.29–10.9)  <0.0001  30.8    6.46 (4.27–9.78)  <0.0001  Histology                           Differentiated type  73.5  <0.0001  0.81 (0.48–1.36)  0.43  63.3  0.052  0.92 (0.40–2.10)  0.83  76.9  0.013  0.58 (0.30–1.09)  0.089   Non-differentiated type  53.3    1.0    46.7    1.0    57.2    1.0    Lymphatic invasion                           −  82.7  <0.0001  1.0    70.7  0.034  0.91 (0.48–1.72)  0.76  86.7  <0.0001  1.0     +  62.1    1.83 (1.28–2.60)  0.0008  52.7    1.0    65.6    2.32 (1.51–3.58)  0.0001  Venous invasion                           −  85.0  0.0027  1.0    75.4  0.024  1.0    90.1  0.010  1.0     +  69.0    1.21 (0.71–2.07)  0.48  56.2    1.74 (0.80–3.79)  0.76  73.1    1.25 (0.59–2.65)  0.56  MSI status                           MSI  81.2  0.21      66.7  0.64      100.0  0.038  1.0     MSS  71.2        70.4        74.7    1.44e+7 (0.00-Inf)  0.99  KRAS status                           Mutant type  65.5  0.041  1.0    60.4  0.93      68.1  0.035  1.0     Wild type  73.9    0.60 (0.42–0.84)  0.0037  61.4        77.9    0.58 (0.37–0886)  0.012  BRAF status                           Mutant type  41.2  <0.0001  1.0    40.3  0.021  1.0    42.9  0.0097  1.0     Wild type  73.1    0.44 (0.20–0.96)  0.040  63.7    0.32 (0.14–0.72)  0.0058  76.1    0.22 (0.078–0.61)  0.011  18qLOH status                           18qLOH+  71.3  0.69      62.7  0.53      73.7  0.10       18qLOH−  72.9        58.9        81.2        CIMP status                           (+)  54.4  0.0034  1.0    51.4  0.19      63.6  0.20       (−)  73.1    1.30 (0.66–2.57)  0.45  63.2        75.8        aAnalyzed with the Cox proportional hazards model; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients; NA, not available. Table 3. Univariate and multivariate analyses of factors associated with overall survivals in colorectal cancer patientsa Variables  All  Right-sided colon cancer  Left-sided colorectal cancer  Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           >=65  68.3  0.0074  1.88 (1.32–2.66)  0.0004  61.4  0.63      71.6  0.023  2.18 (1.45–3.30)  0.0002   <65  77.2    1.0    60.8        80.5    1.0    Gender                           Male  68.1  0.017  1.92 (1.37–2.68)  0.0001  54.7  0.042  1.94 (1.12–3.37)  0.018  71.9  0.050  1.70 (1.11–2.59)  0.014   Female  76.8    1.0    67.1    1.0    81.1    1.0    Location                           Right  61.1  0.0005  1.21 (0.84–1.74)  0.30                   Left  75.5    1.0                    Stage                           I or II or III  81.4  <0.0001  1.0    73.6  <0.0001  1.0    83.9  <0.0001  1.0     IV  26.9    6.27 (4.47–8.79)  <0.0001  19.6    5.98 (3.29–10.9)  <0.0001  30.8    6.46 (4.27–9.78)  <0.0001  Histology                           Differentiated type  73.5  <0.0001  0.81 (0.48–1.36)  0.43  63.3  0.052  0.92 (0.40–2.10)  0.83  76.9  0.013  0.58 (0.30–1.09)  0.089   Non-differentiated type  53.3    1.0    46.7    1.0    57.2    1.0    Lymphatic invasion                           −  82.7  <0.0001  1.0    70.7  0.034  0.91 (0.48–1.72)  0.76  86.7  <0.0001  1.0     +  62.1    1.83 (1.28–2.60)  0.0008  52.7    1.0    65.6    2.32 (1.51–3.58)  0.0001  Venous invasion                           −  85.0  0.0027  1.0    75.4  0.024  1.0    90.1  0.010  1.0     +  69.0    1.21 (0.71–2.07)  0.48  56.2    1.74 (0.80–3.79)  0.76  73.1    1.25 (0.59–2.65)  0.56  MSI status                           MSI  81.2  0.21      66.7  0.64      100.0  0.038  1.0     MSS  71.2        70.4        74.7    1.44e+7 (0.00-Inf)  0.99  KRAS status                           Mutant type  65.5  0.041  1.0    60.4  0.93      68.1  0.035  1.0     Wild type  73.9    0.60 (0.42–0.84)  0.0037  61.4        77.9    0.58 (0.37–0886)  0.012  BRAF status                           Mutant type  41.2  <0.0001  1.0    40.3  0.021  1.0    42.9  0.0097  1.0     Wild type  73.1    0.44 (0.20–0.96)  0.040  63.7    0.32 (0.14–0.72)  0.0058  76.1    0.22 (0.078–0.61)  0.011  18qLOH status                           18qLOH+  71.3  0.69      62.7  0.53      73.7  0.10       18qLOH−  72.9        58.9        81.2        CIMP status                           (+)  54.4  0.0034  1.0    51.4  0.19      63.6  0.20       (−)  73.1    1.30 (0.66–2.57)  0.45  63.2        75.8        Variables  All  Right-sided colon cancer  Left-sided colorectal cancer  Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           >=65  68.3  0.0074  1.88 (1.32–2.66)  0.0004  61.4  0.63      71.6  0.023  2.18 (1.45–3.30)  0.0002   <65  77.2    1.0    60.8        80.5    1.0    Gender                           Male  68.1  0.017  1.92 (1.37–2.68)  0.0001  54.7  0.042  1.94 (1.12–3.37)  0.018  71.9  0.050  1.70 (1.11–2.59)  0.014   Female  76.8    1.0    67.1    1.0    81.1    1.0    Location                           Right  61.1  0.0005  1.21 (0.84–1.74)  0.30                   Left  75.5    1.0                    Stage                           I or II or III  81.4  <0.0001  1.0    73.6  <0.0001  1.0    83.9  <0.0001  1.0     IV  26.9    6.27 (4.47–8.79)  <0.0001  19.6    5.98 (3.29–10.9)  <0.0001  30.8    6.46 (4.27–9.78)  <0.0001  Histology                           Differentiated type  73.5  <0.0001  0.81 (0.48–1.36)  0.43  63.3  0.052  0.92 (0.40–2.10)  0.83  76.9  0.013  0.58 (0.30–1.09)  0.089   Non-differentiated type  53.3    1.0    46.7    1.0    57.2    1.0    Lymphatic invasion                           −  82.7  <0.0001  1.0    70.7  0.034  0.91 (0.48–1.72)  0.76  86.7  <0.0001  1.0     +  62.1    1.83 (1.28–2.60)  0.0008  52.7    1.0    65.6    2.32 (1.51–3.58)  0.0001  Venous invasion                           −  85.0  0.0027  1.0    75.4  0.024  1.0    90.1  0.010  1.0     +  69.0    1.21 (0.71–2.07)  0.48  56.2    1.74 (0.80–3.79)  0.76  73.1    1.25 (0.59–2.65)  0.56  MSI status                           MSI  81.2  0.21      66.7  0.64      100.0  0.038  1.0     MSS  71.2        70.4        74.7    1.44e+7 (0.00-Inf)  0.99  KRAS status                           Mutant type  65.5  0.041  1.0    60.4  0.93      68.1  0.035  1.0     Wild type  73.9    0.60 (0.42–0.84)  0.0037  61.4        77.9    0.58 (0.37–0886)  0.012  BRAF status                           Mutant type  41.2  <0.0001  1.0    40.3  0.021  1.0    42.9  0.0097  1.0     Wild type  73.1    0.44 (0.20–0.96)  0.040  63.7    0.32 (0.14–0.72)  0.0058  76.1    0.22 (0.078–0.61)  0.011  18qLOH status                           18qLOH+  71.3  0.69      62.7  0.53      73.7  0.10       18qLOH−  72.9        58.9        81.2        CIMP status                           (+)  54.4  0.0034  1.0    51.4  0.19      63.6  0.20       (−)  73.1    1.30 (0.66–2.57)  0.45  63.2        75.8        aAnalyzed with the Cox proportional hazards model; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients; NA, not available. Disease-free survival In disease-free survival analysis (Table 4), MSS was associated with a significantly poorer prognosis than MSI in Stage II of RCC (P = 0.035). BRAF mutant type was associated with a significantly poorer prognosis than BRAF wild type in Stage II/III of LCRC (P = 0.027) and in Stage II of LRCR (P < 0.0001). CIMP+ was associated with a significantly poorer prognosis than CIMP– in Stage II of LCRC (P < 0.0001). Between RCC and LCRC, RCC had a significantly poorer prognosis than LCRC in Stage II of MSS (P = 0.027) and in Stage II of 18qLOH+ (P = 0.012). However, LCRC had a significantly poorer prognosis than RCC in Stage II with BRAF mutant type (P = 0.025). Table 4. Five-year disease free survival rate according to tumor locationa DFS  Stage II/III (5-year DFS rate)  Stage II (5-year DFS rate)  Stage III (5-year DFS rate)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  69.0%  60.9%  71.5%  0.18  76.5%  80.3%  66.9%  0.084  61.5%  51.7%  63.8%  0.40  N = 322  N = 79  N = 243  N = 164  N = 50  N = 114  N = 158  N = 29  N = 129  MSI  90.5%  63.7%  66.6%  0.56  100%  100%  100%  0.29  66.7%  50.0%  75.0%  0.70    N = 23  N = 11  N = 12    N = 17  N = 9  N = 8    N = 6  N = 2  N = 4    MSS  67.4%  59.7%  73.1%  0.078  74.0%  60.2%  79.0%  0.027  61.3%  51.9%  63.4%  0.44  N = 299  N = 68  N = 231  N = 147  N = 41  N = 106  N = 152  N = 27  N = 125   P value  0.031  0.72  0.19    0.029  0.035  0.19    0.77  0.91  0.71    KRAS MT  65.6%  62.5%  66.6%  0.90  75.9%  74.1%  76.5%  0.80  55.0%  53.8%  55.6%  0.68  N = 86  N = 28  N = 58  N = 45  N = 15  N = 30  N = 41  N = 13  N = 28  KRAS WT  70.2%  60.9%  73.1%  0.16  76.7%  64.6%  81.7%  0.10  63.7%  50.0%  66.0%  0.33  N = 236  N = 51  N = 185  N = 119  N = 35  N = 84  N = 117  N = 16  N = 101   P value  0.31  0.64  0.19    0.95  0.43  0.60    0.13  0.94  0.096    BRAF MT  54.5%  53.8%  33.3%  0.17  66.7%  65.4%  NA  0.025  40.0%  33.3%  50.0%  0.98  N = 11  N = 8  N = 3  N = 6  N = 5  N = 1  N = 5  N = 3  N = 2  BRAF WT  69.5%  75.0%  72.0%  0.18  76.9%  80.0%  81.1%  0.065  62.2%  53.8%  64.0%  0.49  N = 311  N = 71  N = 240  N = 158  N = 45  N = 113  N = 153  N = 26  N = 127   P value  0.41  0.083  0.027    0.63  0.39  <0.0001    0.44  0.84  0.55    18qLOH+  68.3%  53.3%  72.2%  0.052  74.5%  55.6%  81.6%  0.012  62.9%  52.6%  65.0%  0.43  N = 223  N = 47  N = 176  N = 105  N = 28  N = 77  N = 118  N = 19  N = 99  18qLOH−  73.8%  60.9%  73.2%  0.86  80.0%  84.2%  77.4%  0.66  64.4%  55.6%  67.8%  0.59  N = 87  N = 30  N = 57  N = 53  N = 21  N = 32  N = 34  N = 9  N = 25   P value  0.26  0.61  0.70    0.42  0.047  0.73    0.68  0.80  0.67    CIMP+  51.9%  51.4%  50.0%  0.55  60.0%  66.7%  NA  0.070  43.6%  33.3%  60.0%  0.74  N = 21  N = 15  N = 6  N = 10  N = 9  N = 1  N = 11  N = 6  N = 5  CIMP−  69.8%  69.8%  72.0%  0.203  77.1%  65.3%  80.9%  0.068  62.5%  54.5%  63.9%  0.59  N = 296  N = 60  N = 233  N = 150  N = 38  N = 112  N = 146  N = 22  N = 124   P value  0.083  0.19  0.091    0.19  0.95  <0.0001    0.25  0.45  0.69    DFS  Stage II/III (5-year DFS rate)  Stage II (5-year DFS rate)  Stage III (5-year DFS rate)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  69.0%  60.9%  71.5%  0.18  76.5%  80.3%  66.9%  0.084  61.5%  51.7%  63.8%  0.40  N = 322  N = 79  N = 243  N = 164  N = 50  N = 114  N = 158  N = 29  N = 129  MSI  90.5%  63.7%  66.6%  0.56  100%  100%  100%  0.29  66.7%  50.0%  75.0%  0.70    N = 23  N = 11  N = 12    N = 17  N = 9  N = 8    N = 6  N = 2  N = 4    MSS  67.4%  59.7%  73.1%  0.078  74.0%  60.2%  79.0%  0.027  61.3%  51.9%  63.4%  0.44  N = 299  N = 68  N = 231  N = 147  N = 41  N = 106  N = 152  N = 27  N = 125   P value  0.031  0.72  0.19    0.029  0.035  0.19    0.77  0.91  0.71    KRAS MT  65.6%  62.5%  66.6%  0.90  75.9%  74.1%  76.5%  0.80  55.0%  53.8%  55.6%  0.68  N = 86  N = 28  N = 58  N = 45  N = 15  N = 30  N = 41  N = 13  N = 28  KRAS WT  70.2%  60.9%  73.1%  0.16  76.7%  64.6%  81.7%  0.10  63.7%  50.0%  66.0%  0.33  N = 236  N = 51  N = 185  N = 119  N = 35  N = 84  N = 117  N = 16  N = 101   P value  0.31  0.64  0.19    0.95  0.43  0.60    0.13  0.94  0.096    BRAF MT  54.5%  53.8%  33.3%  0.17  66.7%  65.4%  NA  0.025  40.0%  33.3%  50.0%  0.98  N = 11  N = 8  N = 3  N = 6  N = 5  N = 1  N = 5  N = 3  N = 2  BRAF WT  69.5%  75.0%  72.0%  0.18  76.9%  80.0%  81.1%  0.065  62.2%  53.8%  64.0%  0.49  N = 311  N = 71  N = 240  N = 158  N = 45  N = 113  N = 153  N = 26  N = 127   P value  0.41  0.083  0.027    0.63  0.39  <0.0001    0.44  0.84  0.55    18qLOH+  68.3%  53.3%  72.2%  0.052  74.5%  55.6%  81.6%  0.012  62.9%  52.6%  65.0%  0.43  N = 223  N = 47  N = 176  N = 105  N = 28  N = 77  N = 118  N = 19  N = 99  18qLOH−  73.8%  60.9%  73.2%  0.86  80.0%  84.2%  77.4%  0.66  64.4%  55.6%  67.8%  0.59  N = 87  N = 30  N = 57  N = 53  N = 21  N = 32  N = 34  N = 9  N = 25   P value  0.26  0.61  0.70    0.42  0.047  0.73    0.68  0.80  0.67    CIMP+  51.9%  51.4%  50.0%  0.55  60.0%  66.7%  NA  0.070  43.6%  33.3%  60.0%  0.74  N = 21  N = 15  N = 6  N = 10  N = 9  N = 1  N = 11  N = 6  N = 5  CIMP−  69.8%  69.8%  72.0%  0.203  77.1%  65.3%  80.9%  0.068  62.5%  54.5%  63.9%  0.59  N = 296  N = 60  N = 233  N = 150  N = 38  N = 112  N = 146  N = 22  N = 124   P value  0.083  0.19  0.091    0.19  0.95  <0.0001    0.25  0.45  0.69    aAnalyzed with Fisher’s exact test; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients. Table 4. Five-year disease free survival rate according to tumor locationa DFS  Stage II/III (5-year DFS rate)  Stage II (5-year DFS rate)  Stage III (5-year DFS rate)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  69.0%  60.9%  71.5%  0.18  76.5%  80.3%  66.9%  0.084  61.5%  51.7%  63.8%  0.40  N = 322  N = 79  N = 243  N = 164  N = 50  N = 114  N = 158  N = 29  N = 129  MSI  90.5%  63.7%  66.6%  0.56  100%  100%  100%  0.29  66.7%  50.0%  75.0%  0.70    N = 23  N = 11  N = 12    N = 17  N = 9  N = 8    N = 6  N = 2  N = 4    MSS  67.4%  59.7%  73.1%  0.078  74.0%  60.2%  79.0%  0.027  61.3%  51.9%  63.4%  0.44  N = 299  N = 68  N = 231  N = 147  N = 41  N = 106  N = 152  N = 27  N = 125   P value  0.031  0.72  0.19    0.029  0.035  0.19    0.77  0.91  0.71    KRAS MT  65.6%  62.5%  66.6%  0.90  75.9%  74.1%  76.5%  0.80  55.0%  53.8%  55.6%  0.68  N = 86  N = 28  N = 58  N = 45  N = 15  N = 30  N = 41  N = 13  N = 28  KRAS WT  70.2%  60.9%  73.1%  0.16  76.7%  64.6%  81.7%  0.10  63.7%  50.0%  66.0%  0.33  N = 236  N = 51  N = 185  N = 119  N = 35  N = 84  N = 117  N = 16  N = 101   P value  0.31  0.64  0.19    0.95  0.43  0.60    0.13  0.94  0.096    BRAF MT  54.5%  53.8%  33.3%  0.17  66.7%  65.4%  NA  0.025  40.0%  33.3%  50.0%  0.98  N = 11  N = 8  N = 3  N = 6  N = 5  N = 1  N = 5  N = 3  N = 2  BRAF WT  69.5%  75.0%  72.0%  0.18  76.9%  80.0%  81.1%  0.065  62.2%  53.8%  64.0%  0.49  N = 311  N = 71  N = 240  N = 158  N = 45  N = 113  N = 153  N = 26  N = 127   P value  0.41  0.083  0.027    0.63  0.39  <0.0001    0.44  0.84  0.55    18qLOH+  68.3%  53.3%  72.2%  0.052  74.5%  55.6%  81.6%  0.012  62.9%  52.6%  65.0%  0.43  N = 223  N = 47  N = 176  N = 105  N = 28  N = 77  N = 118  N = 19  N = 99  18qLOH−  73.8%  60.9%  73.2%  0.86  80.0%  84.2%  77.4%  0.66  64.4%  55.6%  67.8%  0.59  N = 87  N = 30  N = 57  N = 53  N = 21  N = 32  N = 34  N = 9  N = 25   P value  0.26  0.61  0.70    0.42  0.047  0.73    0.68  0.80  0.67    CIMP+  51.9%  51.4%  50.0%  0.55  60.0%  66.7%  NA  0.070  43.6%  33.3%  60.0%  0.74  N = 21  N = 15  N = 6  N = 10  N = 9  N = 1  N = 11  N = 6  N = 5  CIMP−  69.8%  69.8%  72.0%  0.203  77.1%  65.3%  80.9%  0.068  62.5%  54.5%  63.9%  0.59  N = 296  N = 60  N = 233  N = 150  N = 38  N = 112  N = 146  N = 22  N = 124   P value  0.083  0.19  0.091    0.19  0.95  <0.0001    0.25  0.45  0.69    DFS  Stage II/III (5-year DFS rate)  Stage II (5-year DFS rate)  Stage III (5-year DFS rate)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  69.0%  60.9%  71.5%  0.18  76.5%  80.3%  66.9%  0.084  61.5%  51.7%  63.8%  0.40  N = 322  N = 79  N = 243  N = 164  N = 50  N = 114  N = 158  N = 29  N = 129  MSI  90.5%  63.7%  66.6%  0.56  100%  100%  100%  0.29  66.7%  50.0%  75.0%  0.70    N = 23  N = 11  N = 12    N = 17  N = 9  N = 8    N = 6  N = 2  N = 4    MSS  67.4%  59.7%  73.1%  0.078  74.0%  60.2%  79.0%  0.027  61.3%  51.9%  63.4%  0.44  N = 299  N = 68  N = 231  N = 147  N = 41  N = 106  N = 152  N = 27  N = 125   P value  0.031  0.72  0.19    0.029  0.035  0.19    0.77  0.91  0.71    KRAS MT  65.6%  62.5%  66.6%  0.90  75.9%  74.1%  76.5%  0.80  55.0%  53.8%  55.6%  0.68  N = 86  N = 28  N = 58  N = 45  N = 15  N = 30  N = 41  N = 13  N = 28  KRAS WT  70.2%  60.9%  73.1%  0.16  76.7%  64.6%  81.7%  0.10  63.7%  50.0%  66.0%  0.33  N = 236  N = 51  N = 185  N = 119  N = 35  N = 84  N = 117  N = 16  N = 101   P value  0.31  0.64  0.19    0.95  0.43  0.60    0.13  0.94  0.096    BRAF MT  54.5%  53.8%  33.3%  0.17  66.7%  65.4%  NA  0.025  40.0%  33.3%  50.0%  0.98  N = 11  N = 8  N = 3  N = 6  N = 5  N = 1  N = 5  N = 3  N = 2  BRAF WT  69.5%  75.0%  72.0%  0.18  76.9%  80.0%  81.1%  0.065  62.2%  53.8%  64.0%  0.49  N = 311  N = 71  N = 240  N = 158  N = 45  N = 113  N = 153  N = 26  N = 127   P value  0.41  0.083  0.027    0.63  0.39  <0.0001    0.44  0.84  0.55    18qLOH+  68.3%  53.3%  72.2%  0.052  74.5%  55.6%  81.6%  0.012  62.9%  52.6%  65.0%  0.43  N = 223  N = 47  N = 176  N = 105  N = 28  N = 77  N = 118  N = 19  N = 99  18qLOH−  73.8%  60.9%  73.2%  0.86  80.0%  84.2%  77.4%  0.66  64.4%  55.6%  67.8%  0.59  N = 87  N = 30  N = 57  N = 53  N = 21  N = 32  N = 34  N = 9  N = 25   P value  0.26  0.61  0.70    0.42  0.047  0.73    0.68  0.80  0.67    CIMP+  51.9%  51.4%  50.0%  0.55  60.0%  66.7%  NA  0.070  43.6%  33.3%  60.0%  0.74  N = 21  N = 15  N = 6  N = 10  N = 9  N = 1  N = 11  N = 6  N = 5  CIMP−  69.8%  69.8%  72.0%  0.203  77.1%  65.3%  80.9%  0.068  62.5%  54.5%  63.9%  0.59  N = 296  N = 60  N = 233  N = 150  N = 38  N = 112  N = 146  N = 22  N = 124   P value  0.083  0.19  0.091    0.19  0.95  <0.0001    0.25  0.45  0.69    aAnalyzed with Fisher’s exact test; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients. In multivariate analysis for disease-free survival (Table 5), MSI status and CIMP status were independent prognostic factors in colorectal cancer. No was independent prognostic factor in RCC, while lymphatic invasion was independent prognostic factor in LCRC. In Stage II, BRAF status and CIMP status were independent prognostic factors in LCRC (Supplemental Table 4). In Stage III, no was independent prognostic factor in colorectal cancer (Supplemental Table 5). Table 5. Univariate and multivariate analyses of factors associated with disease-free survivals in colorectal cancer patientsa Variables  All  Right-sided colon cancer  Left-sided colorectal cancer    Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate    5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           ≥65  66.1  0.18      60.3  0.97      68.5  0.22       <65  73.9        62.5        75.7        Gender                           Male  67.4  0.45      63.2  0.86      68.4  0.22       Female  71.2        58.9        76.5        Location                           Right  60.9  0.18                       Left  71.5                        Stage                           II  76.5  0.002  0.80 (0.51–1.27)  0.35  59.0  0.25      72.0  0.65       III  61.5    1.0    83.3        63.5        Histology                           Differentiated type  68.9  0.82      66.3  0.48      82.2  0.00078  0.81 (0.33–2.03)  0.66   Non-differentiated type  69.6        56.9        62.8    1.0    Lymphatic invasion                           −  77.7  0.001  1.0    75.6  0.11      87.5  0.063  1.0     +  61.1    1.57 (0.98–2.49)  0.058  66.4        69.1    2.22 (1.33–3.71)  0.0023  Venous invasion                           −  83.2  0.024  1.0    90.0  0.051  1.0    90.9  0.16       +  66.4    1.80 (0.98–2.49)  0.058  56.6    2.29 (0.79–6.60)  0.13  70.6        MSI status                           MSI  90.5  0.031  1.0    63.7  0.72      66.6  0.19       MSS  67.4    6.03 (1.41–25.8)  0.015  59.7        73.1        KRAS status                           Mutant type  65.6  0.31      62.5  0.64      66.6  0.19       Wild type  70.2        60.9        73.1        BRAF status                           Mutant type  54.5  0.41      53.8  0.083  1.20 (0.36–3.97)  0.77  33.3  0.027  1.0     Wild type  69.5        75.0    1.0    72.0    0.34 (0.08–1.43)  0.14  18qLOH status                           18qLOH+  68.3  0.26      53.3  0.61      72.2  0.70       18qLOH−  73.8        60.9        73.2        CIMP status                           (+)  51.9  0.083  2.66 (1.35–5.24)  0.0048  51.4  0.19      50.0  0.092  2.26 (0.70–7.28)  0.17   (−)  69.8    1.0    63.2        72.0        Variables  All  Right-sided colon cancer  Left-sided colorectal cancer    Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate    5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           ≥65  66.1  0.18      60.3  0.97      68.5  0.22       <65  73.9        62.5        75.7        Gender                           Male  67.4  0.45      63.2  0.86      68.4  0.22       Female  71.2        58.9        76.5        Location                           Right  60.9  0.18                       Left  71.5                        Stage                           II  76.5  0.002  0.80 (0.51–1.27)  0.35  59.0  0.25      72.0  0.65       III  61.5    1.0    83.3        63.5        Histology                           Differentiated type  68.9  0.82      66.3  0.48      82.2  0.00078  0.81 (0.33–2.03)  0.66   Non-differentiated type  69.6        56.9        62.8    1.0    Lymphatic invasion                           −  77.7  0.001  1.0    75.6  0.11      87.5  0.063  1.0     +  61.1    1.57 (0.98–2.49)  0.058  66.4        69.1    2.22 (1.33–3.71)  0.0023  Venous invasion                           −  83.2  0.024  1.0    90.0  0.051  1.0    90.9  0.16       +  66.4    1.80 (0.98–2.49)  0.058  56.6    2.29 (0.79–6.60)  0.13  70.6        MSI status                           MSI  90.5  0.031  1.0    63.7  0.72      66.6  0.19       MSS  67.4    6.03 (1.41–25.8)  0.015  59.7        73.1        KRAS status                           Mutant type  65.6  0.31      62.5  0.64      66.6  0.19       Wild type  70.2        60.9        73.1        BRAF status                           Mutant type  54.5  0.41      53.8  0.083  1.20 (0.36–3.97)  0.77  33.3  0.027  1.0     Wild type  69.5        75.0    1.0    72.0    0.34 (0.08–1.43)  0.14  18qLOH status                           18qLOH+  68.3  0.26      53.3  0.61      72.2  0.70       18qLOH−  73.8        60.9        73.2        CIMP status                           (+)  51.9  0.083  2.66 (1.35–5.24)  0.0048  51.4  0.19      50.0  0.092  2.26 (0.70–7.28)  0.17   (−)  69.8    1.0    63.2        72.0        aAnalyzed with the Cox proportional hazards model; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; HR, hazard ratio; CI, confidence interval; MT, mutant type; WT, wild type; CIMP, CpG island methylator phenotype. Table 5. Univariate and multivariate analyses of factors associated with disease-free survivals in colorectal cancer patientsa Variables  All  Right-sided colon cancer  Left-sided colorectal cancer    Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate    5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           ≥65  66.1  0.18      60.3  0.97      68.5  0.22       <65  73.9        62.5        75.7        Gender                           Male  67.4  0.45      63.2  0.86      68.4  0.22       Female  71.2        58.9        76.5        Location                           Right  60.9  0.18                       Left  71.5                        Stage                           II  76.5  0.002  0.80 (0.51–1.27)  0.35  59.0  0.25      72.0  0.65       III  61.5    1.0    83.3        63.5        Histology                           Differentiated type  68.9  0.82      66.3  0.48      82.2  0.00078  0.81 (0.33–2.03)  0.66   Non-differentiated type  69.6        56.9        62.8    1.0    Lymphatic invasion                           −  77.7  0.001  1.0    75.6  0.11      87.5  0.063  1.0     +  61.1    1.57 (0.98–2.49)  0.058  66.4        69.1    2.22 (1.33–3.71)  0.0023  Venous invasion                           −  83.2  0.024  1.0    90.0  0.051  1.0    90.9  0.16       +  66.4    1.80 (0.98–2.49)  0.058  56.6    2.29 (0.79–6.60)  0.13  70.6        MSI status                           MSI  90.5  0.031  1.0    63.7  0.72      66.6  0.19       MSS  67.4    6.03 (1.41–25.8)  0.015  59.7        73.1        KRAS status                           Mutant type  65.6  0.31      62.5  0.64      66.6  0.19       Wild type  70.2        60.9        73.1        BRAF status                           Mutant type  54.5  0.41      53.8  0.083  1.20 (0.36–3.97)  0.77  33.3  0.027  1.0     Wild type  69.5        75.0    1.0    72.0    0.34 (0.08–1.43)  0.14  18qLOH status                           18qLOH+  68.3  0.26      53.3  0.61      72.2  0.70       18qLOH−  73.8        60.9        73.2        CIMP status                           (+)  51.9  0.083  2.66 (1.35–5.24)  0.0048  51.4  0.19      50.0  0.092  2.26 (0.70–7.28)  0.17   (−)  69.8    1.0    63.2        72.0        Variables  All  Right-sided colon cancer  Left-sided colorectal cancer    Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate    5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           ≥65  66.1  0.18      60.3  0.97      68.5  0.22       <65  73.9        62.5        75.7        Gender                           Male  67.4  0.45      63.2  0.86      68.4  0.22       Female  71.2        58.9        76.5        Location                           Right  60.9  0.18                       Left  71.5                        Stage                           II  76.5  0.002  0.80 (0.51–1.27)  0.35  59.0  0.25      72.0  0.65       III  61.5    1.0    83.3        63.5        Histology                           Differentiated type  68.9  0.82      66.3  0.48      82.2  0.00078  0.81 (0.33–2.03)  0.66   Non-differentiated type  69.6        56.9        62.8    1.0    Lymphatic invasion                           −  77.7  0.001  1.0    75.6  0.11      87.5  0.063  1.0     +  61.1    1.57 (0.98–2.49)  0.058  66.4        69.1    2.22 (1.33–3.71)  0.0023  Venous invasion                           −  83.2  0.024  1.0    90.0  0.051  1.0    90.9  0.16       +  66.4    1.80 (0.98–2.49)  0.058  56.6    2.29 (0.79–6.60)  0.13  70.6        MSI status                           MSI  90.5  0.031  1.0    63.7  0.72      66.6  0.19       MSS  67.4    6.03 (1.41–25.8)  0.015  59.7        73.1        KRAS status                           Mutant type  65.6  0.31      62.5  0.64      66.6  0.19       Wild type  70.2        60.9        73.1        BRAF status                           Mutant type  54.5  0.41      53.8  0.083  1.20 (0.36–3.97)  0.77  33.3  0.027  1.0     Wild type  69.5        75.0    1.0    72.0    0.34 (0.08–1.43)  0.14  18qLOH status                           18qLOH+  68.3  0.26      53.3  0.61      72.2  0.70       18qLOH−  73.8        60.9        73.2        CIMP status                           (+)  51.9  0.083  2.66 (1.35–5.24)  0.0048  51.4  0.19      50.0  0.092  2.26 (0.70–7.28)  0.17   (−)  69.8    1.0    63.2        72.0        aAnalyzed with the Cox proportional hazards model; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; HR, hazard ratio; CI, confidence interval; MT, mutant type; WT, wild type; CIMP, CpG island methylator phenotype. Discussion Recently, the various subtypes according to molecular markers have been proposed in CRC (16–19). Currently, clarification of the clinicopathological features of each CRC subtype is of great interest. The frequencies of RCC were similar in this study (26.3%) and a previous report from Japan (29.3%) (20), while the frequency of RCC was reported to be 42% in the United States (21). Thus, the frequency of RCC in Japan may be different from that in the United States. With respect to the clinicopathological features in RCC and LCRC, Japan is similar to Western countries; RCC was found more frequently in elderly patients (22,23), in the female sex (22), and in poorly differentiated tumors (24). Moreover, it has been reported that MSI (9,25,26), BRAF mutation (26–29), KRAS mutation (29,30), and CIMP+ (26) are predominantly found in RCC, whereas 18qLOH is more frequently found in LCRC (31,32). The proportions of biomarkers of CRC were also similar in Japan and Western countries. However, with respect to the frequencies of molecular biomarkers, differences between Japan and Western countries exist. It has been reported that the frequencies of MSI, KRAS mutant type, BRAF mutant type, 18qLOH+, and CIMP+ are 19.1–39.0% (9,33,34), 38.5–39.7% (29,30), 17.0–19.4% (29,34,35), 27% (36) and 8.4% (37), respectively, in RCC in Western countries. However, in the present study, the frequencies of MSI, KRAS mutant type, BRAF mutant type, 18qLOH+ and CIMP+ were 12.6%, 35.0%, 11.3%, 59.3% and 7.4%, respectively, in RCC of Japan. The frequencies of MSI and BRAF mutant type of RCC in Japan were lower than those in Western counties. Actually, the frequencies of BRAF mutation and MSI in Asian RCC are reported to be 4–10% (38–40), and 16.3–24% (41–44), respectively. Thus, the proportions of molecular biomarkers of CRC were different between Western populations and Asian populations. The lower incidences of BRAF mutation and MSI in Asian CRC patients could be due to an ethnic difference with varied underlying genetic predisposition. We need further investigation to elucidate the impact of other environmental and genetic factors. In this study, we showed independent prognostic factors, including molecular biomarkers, in colorectal cancer. It was interesting that the independent prognostic factors in RCC were different from those in LCRC in each stage. To our knowledge, no one has reported the differences of prognostic factors between RCC and LCRC in each stage. However, the consistency between OS and DFS was not observed in this study, excluding lymphatic invasion in LCRC, because of small sample sizes in each stage. Therefore, we cannot lead any generalized conclusions. The clinical outcomes of CRC, e.g., disease-free survival after adjuvant chemotherapy in Stage III colon cancer (45,46) as well as overall survival after intensive chemotherapy in unresectable CRC (47,48), were reported to be better in Japan than in Western countries. However, the prognostic difference in the tumor location between Japan and Western countries may be a factor of the frequency difference in the tumor location between Japan and Western countries. In fact, RCC has a poor prognosis compared with LCRC not only in Japan but also in Western countries (24). In addition, MSI, which was one of the chemo-resistant factors, and BRAF mutation, which was one of the poor prognosis factors, were less frequent in Japanese CRC patients. Consequently, it is difficult to compare the data from Japan with the data from Western countries. The following limitations of this study were included: (1) selection bias caused by the retrospective nature of the study; (2) the lack of treatment data; (3) a single-center study; (4) the lack of data on RAS mutations except for KRAS exon 2; however, we consider the influence of this on the overall results to be small because of low frequencies of minor RAS mutations; (5) the low statistical power because of the small sample size. Therefore, we might not have been able to show significant difference between RCC and LCRC in histology. Additionally, the number of patients was small (<10) in several subgroups (e.g., MSI in Stage III/IV, BRAF MT in Stage II/III/IV, BRAF MT in Stage II/III/IV), which was not enough for statistical analysis. Nonetheless, considering that there are only a few publications on molecular biomarkers from Asia, we believe that our findings will help researchers and physicians clarify the nature of CRC. In conclusion, comparing RCC with LCRC, RCC is different from LCRC in clinicopathological features, molecular biomarkers and prognostic factors in Japanese colorectal cancer patients. Since the proportions of molecular biomarkers of CRC in this study are different from Western CRCs, further studies are required to clarify the clinicopathological differences between Japanese CRCs and Western CRCs. Supplementary data Supplementary data are available at Japanese Journal of Clinical Oncology online. Acknowledgements The authors would like to acknowledge all the patients and their families. Our deepest appreciation goes to Kaori Toneyama who supports our study. Funding This work was supported by the Office of Metropolitan Hospital Management, Tokyo Metropolitan Government. Conflict of interest statement The authors have declared no conflicts of interest. References 1 Ogino S, Goel A. Molecular classification and correlates in colorectal cancer. J Mol Diagn  2008; 10: 13– 27. 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For permissions, please e-mail: journals.permissions@oup.com. This article is published and distributed under the terms of the Oxford University Press, Standard Journals Publication Model (https://academic.oup.com/journals/pages/about_us/legal/notices) http://www.deepdyve.com/assets/images/DeepDyve-Logo-lg.png Japanese Journal of Clinical Oncology Oxford University Press

Clinicopathological and molecular differences between right-sided and left-sided colorectal cancer in Japanese patients

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Oxford University Press
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© The Author(s) 2018. Published by Oxford University Press. All rights reserved. For permissions, please e-mail: journals.permissions@oup.com.
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0368-2811
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1465-3621
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10.1093/jjco/hyy069
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Abstract

Abstract Background The aim of this study was to clarify clinicopathological features, frequencies of molecular biomarkers, and prognoses in Japanese colorectal cancer patients and compare them with right-sided colon cancer (RCC) and left-sided colorectal cancer (LCRC). Methods We consecutively selected 575 colorectal cancer patients who underwent surgical resection from 2008 to 2011. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum. Frequencies of KRAS gene mutation, BRAF gene mutation, microsatellite instability (MSI), l18qLOH and CpG island methylator phenotype (CIMP) were statistically analyzed between groups. Results Tumors were located in the RCC in 26.3% of patients and in the LCRC in 73.7%. Elderly patients, females and advanced diseases were significantly more frequent in the RCC group than in the LCRC group. However, venous invasion was significantly more frequent in LCRC than in RCC. Between groups, BRAF mutant type, KRAS mutant type, MSI and CIMP+ were significantly more frequent in RCC, whereas 18qLOH was significantly more frequent in LCRC. In overall survival, RCC demonstrated poor prognosis compared with LCRC; however, age, gender, stage, lymphatic invasion, KRAS status and BRAF status rather than tumor location were independent prognostic factors. In addition, the independent prognostic factors in RCC were different from those in LCRC in each stage. However, the consistency between OS and DFS was not observed in this study, excluding lymphatic invasion in LCRC. Conclusion Comparing RCC with LCRC, RCC is different from LCRC in clinicopathological features, molecular biomarkers and prognostic factors in Japanese colorectal cancer patients. Since the proportions of molecular biomarkers of CRC in this study are different from Western CRCs, further studies are required to clarify the clinicopathological differences between Japanese CRCs and Western CRCs. BRAF, CpG island methylator phenotype, colorectal cancer, loss of heterozygosity, microsatellite instability Introduction Over the past two decades, molecular biomarkers of colorectal cancer (CRC) have been studied in detail. Among them, the following three biomarkers have been proposed as global genomic/epigenomic status: microsatellite instability (MSI), 18q loss of heterozygosity (18qLOH) and CpG island methylator phenotype (CIMP) (1). An MSI tumor develops by the accumulation of frameshift mutations of target genes due to a mismatch repair system failure (2), whereas the typical development of microsatellite stable (MSS) tumor proceeds stepwise by the accumulation of inactivated tumor suppressor genes and activated oncogenes (3,4). 18qLOH commonly presents in CRC with chromosomal instability (CIN) and is associated with global hypomethylation in tumor cells. CIN and MSI tend to be exclusive of each other in CRC (5). CIMP with aberrant hypermethylation of promoter regions of various genes is a different epigenetic phenotype in CRC (6), which is associated with MSI (7). In addition to these three biomarkers, KRAS and BRAF genes also play important roles as biomarkers in CRC. Both genes frequently mutate in CRC, and their mutations influence chemo-sensitivity and prognosis. The large bowel is divided into two anatomical categories, i.e., the colon and rectum. However, from the oncological point of view, two anatomical categories of CRC have been proposed according to the tumor location with respect to the right side or left side of the splenic flexure, and clinicopathological differences between right-sided colon cancer (RCC) and left-sided CRC (LCRC) have been observed (8,9). To date, reports on the differences between RCC and LCRC with respect to the status of molecular biomarkers are mostly from Western countries, and few reports have been published from Japan. Thus, it is important to clarify these molecular characteristics in RCC and LCRC from Japanese patients. The aim of this study was to clarify the clinicopathological features and frequencies of molecular biomarkers in Japanese patients with CRC, comparing RCC and LCRC. Materials and methods Patients We consecutively selected 953 CRC patients who underwent surgical resection at the Tokyo Metropolitan Cancer and Infectious diseases Center Komagome Hospital from January 2008 to March 2011 after obtaining informed consent. Patients with inflammatory bowel disease or a known history of familial adenomatous polyposis were excluded. Finally, 575 CRC patients were available for analysis in this study (Fig. 1). If a patient had two or more colorectal tumors resected, the more advanced tumor was selected for analysis. Clinical information was collected either from medical records or directly from patients. RCC was located from the cecum to the transverse colon, and LCRC was located from the splenic flexure to the rectum. The study was approved by the institutional review board of our hospital (approval number: 612, 1202, 1433 and 2001). Figure 1. View largeDownload slide CONSORT diagram. Figure 1. View largeDownload slide CONSORT diagram. MSI and 18qLOH analysis Colorectal cancers and corresponding normal tissues, obtained after informed consent, were stored –80°C immediately after resection. Genomic DNA samples from them were extracted using the QIAamp DNA mini kit (QIAGEN, Valencia, CA). Microsatellite status was determined using two microsatellite markers (BAT25 and BAT26). Polymerase chain reaction (PCR) was performed to amplify cancer and corresponding normal DNAs. The reaction mixture (25 μl) contained 50 ng of genomic DNA, 0.4 μM of each primer, 0.2 μM concentrations of each four deoxynucleotide triphosphate, 1 × PCR buffer, and Taq polymerase. PCR was performed as follows: 5 min at 95°C once; 1 min at 94°C, 1 min at 50°C, and 1 min at 72°C for 35 cycles; and 10 min at 72°C once. Amplified PCR products were diluted with formamide, and run on an Applied Biosystems 3100xl automated capillary electrophoresis DNA sequencer. Allelic sizes for each of the markers were estimated using GeneMapper Software ver.4.0 (Applied Biosystems, Foster City, CA). Microsatellite instability status was defined as MSI (≥ one marker unstable of the informative markers), and MSS (no unstable markers) as described by the National Cancer Institute guidelines for MSI testing (10). For 18qLOH analysis, we excluded MSI tumors, because 18qLOH is rare in MSI tumors, and interpretation of 18qLOH is difficult in MSI tumors (11). LOH analysis was performed for three 18q markers (D18S56 at 18q12.1, D18S474 at 18q21.2, and D18S55 at 18q22.1) to exclude allele dropouts of one of two alleles using GeneMapper Software ver.4.0. LOH at each locus was defined as <0.67 or >1.35 of one of two allele peak heights in tumor DNA relative to corresponding normal tissue DNA. LOH positivity (18qLOH+) was defined as the presence of LOH in any of the 18q markers. LOH negativity (18qLOH–) was strictly defined as the presence of at least two informative markers and the absence of LOH (12). BRAF and KRAS genes mutation analysis In the mutation analysis, all samples were analyzed BRAF (V600E) and KRAS (codons 12 and 13) through direct sequencing. The PCR reaction mixture (10 μl) contained 200 ng of genomic DNA, 0.4 μM of each primer, 5 μl of the AmpliTaq Gold Fast PCR Master Mix (Applied Biosystems). Cycling steps were: initial Taq activation (97°C) for 5 min, 35 cycles as follows: denature for 95°C 1 s, annealing for 1 min at 60°C for BRAF and 60°C for KRAS, extend for 72°C 1 min and final extension 72°C 10 min. Primers are shown in the Supplementary Table 1. The PCR products were purified using the ExoSAP-IT (General Electric Company, Fairfield, CT). Amplified fragments went through a PCR sequencing amplification. Briefly, the PCR product was amplified using the BigDye Terminator v1.1 Cycle Sequencing Kit, (Applied Biosystems). The resulting PCR product was purified with the BigDye XTerminator Purification kit (Applied Biosystems). The cleaned product was loaded into a 3130xl Genetic Analyzer (Applied Biosystems). Sequence histograms were analyzed searching for heterozygous and homozygous substitutions using Sequencing Analysis Software ver.3.7 (Applied Biosystems). CIMP The bisulfite conversion and recovery of bisulfite-converted DNA steps were perfumed using the Zymo EZ DNA methylation kit (Zymo Research, CA, USA) according to the manufacturer’s instructions. Polymerase chain reaction (PCR) primers and probes for the CpG island loci (MLH1, CDKN2A, CRABP1, NEUROG1, CACNA1G) were used as described previously. DNA methylation analysis was performed by MethyLight as described previously. Briefly, the 20 μl MethyLight reaction mixture contained 10 μl 2 × EpiTect MethyLight Master Mix (Qiagen, Valencia, CA, USA), 0.4 μmol/l of each primer, 0.2 μmol/l probe, and 50 ng template. A LightCycler 480 system II (Roche Diagnostics, Indianapolis, IN, USA) was used to conduct the PCR reactions using the following thermal conditions: 5 min at 95°C once, followed by 45 cycles of 15 s at 95°C and 1 min at 60°C. The differences in the amounts of input genomic DNA were normalized by the COL2A1 gene. Duplicate tubes were used for each sample. The percentage methylated of reference (PMR) was calculated by dividing the GENE:COL2A1 ratio of a sample by the GENE:COL2A1 ratio of CpGenome Human Methylated DNA Standard (Millipore, Billerica, MA, USA) and multiplying by 100. The methylation status of each sample was determined to be positive when PMR > 4, a cut-off value based on validated data (13). We used the five-marker CIMP panel, including CACNA1G, CDKN2A, CRABP1, MLH1 and NEUROG1. The CIMP status was defined as CIMP+ (more than four markers positive of the five markers used) and CIMP– (less than three markers positive of the five markers used) (14). Statistical analysis Fisher’s exact test was used to evaluate the relationship between two discrete and dichotomous variables. In the survival analysis, the survival period was calculated from the time of initial resection of the primary colorectal tumor. Disease-free survival was defined as the time from the date of initial operation to the date of the first evidence of tumor recurrence. Overall survival was defined as the time from the date of initial operation to the date of death or last follow-up. Statistical comparisons of potentially predictive factors were first performed using the log-lank analysis for univariate analysis. The Cox proportional hazards model multivariate analysis was performed by only variables with a P value less than 0.10 at in univariate analysis. Statistical significance was defined as P < 0.05. All statistical analyses were performed with EZR, which is a graphical user interface for R (15). This interface is a modified version of R commander and includes statistical functions that are frequently used in biostatistics. Results Clinicopathological characteristics and molecular alterations in RCC and LCRC Among the 575 patients with CRC, the ascertainment rates were 100% in MSI status, 100% in KRAS status, 100% in BRAF status, 95.8% in 18qLOH status, and 97.0% in CIMP status. The summary of baseline characteristics according to the tumor location is shown in Table 1. With respect to the tumor location, 26.3% (95% CI: 22.7–30.1%) were RCC and 73.7% (95% CI: 69.9–77.3%) were LCRC. In RCC, elderly patients (P < 0.001), females (P = 0.007) and advanced diseases (P = 0.036) were significantly more frequent than in LCRC. However, venous invasion was significantly more frequent in LCRC than in RCC (P = 0.013). Table 1. Clinicopathological characteristics     Total  RCC  LCRC  P value      N = 575  N = 151 (26.3%)  N = 424 (73.7%)  (RCC vs. LCRC)  Age  Median (range)  66.1 (32–93)  70.1 (34–93)  64.7 (32–92)  <0.0001*  Gender  Male: female  332:243  73:78  259:165  0.007**  Stage (UICC)  I: II: III: IV  65:209:198:103  13:63:41:34  52:146:157:69  0.036**  T  T1: T2: T3: T4  14:69:375:116  4:11:93:42  10:58:282:74  0.009**  N  N0: N1: N2  294:164:117  80:40:31  212:124:86  0.81**  M  M0: M1  472:103  117:34  355:69  0.11**  Histology  Differentiated type: non-differentiated type  532:41  135:15  397:26  0.14**  Lymphatic invasion  (+): (−)  299:274  80:71  220:203  0.85**  Venous invasion  (+): (−)  472:102  114:37  358:65  0.013**  Curability  A: B: C  466:35:74  115:9:27  351:26:47  0.10**  MSI status  MSI: MSS  34:541  19:132  15:409  <0.0001**  KRAS status  Mutant type: wild type  150:425  53:98  97:327  0.005**  BRAF status  Mutant type: wild type  24:551  17:134  7:417  <0.0001**  18qLOH status  18qLOH+: 18qLOH-  394:157  86:59  308:98  <0.0001**  CIMP status  (+): (−)  42:527  31:115  11:412  <0.0001**  In Stage II/III            Site of recurrence  Recurrence (+): (−)  100:306  18:86  82:220  0.048**    Liver (+): (−)  33:373  9:95  24:278  0.84**    Lung (+): (−)  34:372  4:100  30:272  0.064**    Peritoneum (+): (−)  12:394  7:97  5:297  0.015**    Lymph node (+): (−)  14:392  0:104  14:288  0.025**    Bone (+): (−)  5:401  0:104  5:297  0.34**    Brain (+): (−)  4:402  1:103  3:299  1.0**    Ova (+): (−)  2:404  2:102  0:302  0.065**    Other (+): (−)  5:401  2:102  3:299  0.61**    Local recurrence (+): (−)  25:381  1:103  24:278  0.008**  In Stage IV            Site of metastasis  Liver (+): (−)  72:31  18:16  54:15  0.012**    Lung (+): (−)  14:89  2:32  12:57  0.14**    Peritoneum (+): (−)  29:74  15:19  14:55  0.019**    Lymph node (+): (−)  16:87  6:28  10:59  0.77**    Bone (+): (−)  1:102  0:34  1:68  1.0**    Ovary (+): (−)  1:102  0:34  1:68  1.0**    Other (+): (−)  3:100  0:34  3:66  0.55**      Total  RCC  LCRC  P value      N = 575  N = 151 (26.3%)  N = 424 (73.7%)  (RCC vs. LCRC)  Age  Median (range)  66.1 (32–93)  70.1 (34–93)  64.7 (32–92)  <0.0001*  Gender  Male: female  332:243  73:78  259:165  0.007**  Stage (UICC)  I: II: III: IV  65:209:198:103  13:63:41:34  52:146:157:69  0.036**  T  T1: T2: T3: T4  14:69:375:116  4:11:93:42  10:58:282:74  0.009**  N  N0: N1: N2  294:164:117  80:40:31  212:124:86  0.81**  M  M0: M1  472:103  117:34  355:69  0.11**  Histology  Differentiated type: non-differentiated type  532:41  135:15  397:26  0.14**  Lymphatic invasion  (+): (−)  299:274  80:71  220:203  0.85**  Venous invasion  (+): (−)  472:102  114:37  358:65  0.013**  Curability  A: B: C  466:35:74  115:9:27  351:26:47  0.10**  MSI status  MSI: MSS  34:541  19:132  15:409  <0.0001**  KRAS status  Mutant type: wild type  150:425  53:98  97:327  0.005**  BRAF status  Mutant type: wild type  24:551  17:134  7:417  <0.0001**  18qLOH status  18qLOH+: 18qLOH-  394:157  86:59  308:98  <0.0001**  CIMP status  (+): (−)  42:527  31:115  11:412  <0.0001**  In Stage II/III            Site of recurrence  Recurrence (+): (−)  100:306  18:86  82:220  0.048**    Liver (+): (−)  33:373  9:95  24:278  0.84**    Lung (+): (−)  34:372  4:100  30:272  0.064**    Peritoneum (+): (−)  12:394  7:97  5:297  0.015**    Lymph node (+): (−)  14:392  0:104  14:288  0.025**    Bone (+): (−)  5:401  0:104  5:297  0.34**    Brain (+): (−)  4:402  1:103  3:299  1.0**    Ova (+): (−)  2:404  2:102  0:302  0.065**    Other (+): (−)  5:401  2:102  3:299  0.61**    Local recurrence (+): (−)  25:381  1:103  24:278  0.008**  In Stage IV            Site of metastasis  Liver (+): (−)  72:31  18:16  54:15  0.012**    Lung (+): (−)  14:89  2:32  12:57  0.14**    Peritoneum (+): (−)  29:74  15:19  14:55  0.019**    Lymph node (+): (−)  16:87  6:28  10:59  0.77**    Bone (+): (−)  1:102  0:34  1:68  1.0**    Ovary (+): (−)  1:102  0:34  1:68  1.0**    Other (+): (−)  3:100  0:34  3:66  0.55**  Differentiated type, well differentiated adenocarcinoma and moderately differentiated adenocarcinoma; non-differentiated, poorly differentiated adenocarcinoma and mucinous carcinoma; MSI, microsatellite instability; MSS, microsatellite stable; LOH, loss of heterozygosity; *, Mann–Whitney’s U test; **, Fisher’s exact test. Table 1. Clinicopathological characteristics     Total  RCC  LCRC  P value      N = 575  N = 151 (26.3%)  N = 424 (73.7%)  (RCC vs. LCRC)  Age  Median (range)  66.1 (32–93)  70.1 (34–93)  64.7 (32–92)  <0.0001*  Gender  Male: female  332:243  73:78  259:165  0.007**  Stage (UICC)  I: II: III: IV  65:209:198:103  13:63:41:34  52:146:157:69  0.036**  T  T1: T2: T3: T4  14:69:375:116  4:11:93:42  10:58:282:74  0.009**  N  N0: N1: N2  294:164:117  80:40:31  212:124:86  0.81**  M  M0: M1  472:103  117:34  355:69  0.11**  Histology  Differentiated type: non-differentiated type  532:41  135:15  397:26  0.14**  Lymphatic invasion  (+): (−)  299:274  80:71  220:203  0.85**  Venous invasion  (+): (−)  472:102  114:37  358:65  0.013**  Curability  A: B: C  466:35:74  115:9:27  351:26:47  0.10**  MSI status  MSI: MSS  34:541  19:132  15:409  <0.0001**  KRAS status  Mutant type: wild type  150:425  53:98  97:327  0.005**  BRAF status  Mutant type: wild type  24:551  17:134  7:417  <0.0001**  18qLOH status  18qLOH+: 18qLOH-  394:157  86:59  308:98  <0.0001**  CIMP status  (+): (−)  42:527  31:115  11:412  <0.0001**  In Stage II/III            Site of recurrence  Recurrence (+): (−)  100:306  18:86  82:220  0.048**    Liver (+): (−)  33:373  9:95  24:278  0.84**    Lung (+): (−)  34:372  4:100  30:272  0.064**    Peritoneum (+): (−)  12:394  7:97  5:297  0.015**    Lymph node (+): (−)  14:392  0:104  14:288  0.025**    Bone (+): (−)  5:401  0:104  5:297  0.34**    Brain (+): (−)  4:402  1:103  3:299  1.0**    Ova (+): (−)  2:404  2:102  0:302  0.065**    Other (+): (−)  5:401  2:102  3:299  0.61**    Local recurrence (+): (−)  25:381  1:103  24:278  0.008**  In Stage IV            Site of metastasis  Liver (+): (−)  72:31  18:16  54:15  0.012**    Lung (+): (−)  14:89  2:32  12:57  0.14**    Peritoneum (+): (−)  29:74  15:19  14:55  0.019**    Lymph node (+): (−)  16:87  6:28  10:59  0.77**    Bone (+): (−)  1:102  0:34  1:68  1.0**    Ovary (+): (−)  1:102  0:34  1:68  1.0**    Other (+): (−)  3:100  0:34  3:66  0.55**      Total  RCC  LCRC  P value      N = 575  N = 151 (26.3%)  N = 424 (73.7%)  (RCC vs. LCRC)  Age  Median (range)  66.1 (32–93)  70.1 (34–93)  64.7 (32–92)  <0.0001*  Gender  Male: female  332:243  73:78  259:165  0.007**  Stage (UICC)  I: II: III: IV  65:209:198:103  13:63:41:34  52:146:157:69  0.036**  T  T1: T2: T3: T4  14:69:375:116  4:11:93:42  10:58:282:74  0.009**  N  N0: N1: N2  294:164:117  80:40:31  212:124:86  0.81**  M  M0: M1  472:103  117:34  355:69  0.11**  Histology  Differentiated type: non-differentiated type  532:41  135:15  397:26  0.14**  Lymphatic invasion  (+): (−)  299:274  80:71  220:203  0.85**  Venous invasion  (+): (−)  472:102  114:37  358:65  0.013**  Curability  A: B: C  466:35:74  115:9:27  351:26:47  0.10**  MSI status  MSI: MSS  34:541  19:132  15:409  <0.0001**  KRAS status  Mutant type: wild type  150:425  53:98  97:327  0.005**  BRAF status  Mutant type: wild type  24:551  17:134  7:417  <0.0001**  18qLOH status  18qLOH+: 18qLOH-  394:157  86:59  308:98  <0.0001**  CIMP status  (+): (−)  42:527  31:115  11:412  <0.0001**  In Stage II/III            Site of recurrence  Recurrence (+): (−)  100:306  18:86  82:220  0.048**    Liver (+): (−)  33:373  9:95  24:278  0.84**    Lung (+): (−)  34:372  4:100  30:272  0.064**    Peritoneum (+): (−)  12:394  7:97  5:297  0.015**    Lymph node (+): (−)  14:392  0:104  14:288  0.025**    Bone (+): (−)  5:401  0:104  5:297  0.34**    Brain (+): (−)  4:402  1:103  3:299  1.0**    Ova (+): (−)  2:404  2:102  0:302  0.065**    Other (+): (−)  5:401  2:102  3:299  0.61**    Local recurrence (+): (−)  25:381  1:103  24:278  0.008**  In Stage IV            Site of metastasis  Liver (+): (−)  72:31  18:16  54:15  0.012**    Lung (+): (−)  14:89  2:32  12:57  0.14**    Peritoneum (+): (−)  29:74  15:19  14:55  0.019**    Lymph node (+): (−)  16:87  6:28  10:59  0.77**    Bone (+): (−)  1:102  0:34  1:68  1.0**    Ovary (+): (−)  1:102  0:34  1:68  1.0**    Other (+): (−)  3:100  0:34  3:66  0.55**  Differentiated type, well differentiated adenocarcinoma and moderately differentiated adenocarcinoma; non-differentiated, poorly differentiated adenocarcinoma and mucinous carcinoma; MSI, microsatellite instability; MSS, microsatellite stable; LOH, loss of heterozygosity; *, Mann–Whitney’s U test; **, Fisher’s exact test. In Stage IV cases, liver metastasis was significantly more frequent in LCRC than in RCC (P = 0.012), while peritoneal dissemination was significantly more frequent in RCC than in LCRC (P = 0.019). In Stage II/III cases, lymph node recurrence (P = 0.025) and local recurrence (P = 0.008) were significantly more frequent in LCRC than in RCC, while peritoneal dissemination was significantly more frequent in RCC than in LCRC (P = 0.015). The frequencies of molecular biomarkers were 5.9% (95% CI: 4.1–8.2%) for MSI, 26.1% (95% CI: 22.5–29.9%) for KRAS mutant type, 4.2% (95% CI: 2.7–6.1%) for BRAF mutant type, 71.5% (95% CI: 67.7–75.4%) for 18qLOH+, and 7.4% (95% CI: 5.4–9.8%) for CIMP+. When RCC and LCRC were compared, MSI (P = 0.002), KRAS mutant type (P = 0.005), and BRAF mutant type (P < 0.001) were significantly more frequent in RCC, whereas 18qLOH was significantly more frequent in LCRC (P < 0.001). Overall survival In overall survival analyses (Table 2), patients with RCC had significantly poorer prognosis than patients with LCRC (P < 0.0001). MSS predicted significantly poorer prognosis than MSI in LCRC (P = 0.038); however, there was no prognostic difference of MSI status in RCC (P = 0.64). KRAS mutant type was associated with significantly poorer prognosis than KRAS wild type (P = 0.041), and KRAS mutant type was poorer prognosis in LCRC (P = 0.035). BRAF mutant type was associated with significantly poorer prognosis than BRAF wild type (P < 0.0001), and the prognostic differences were observed in both RCC (P = 0.021) and LCRC (P = 0.0097). The presence of CIMP+ predicted significantly poorer prognosis than CIMP– (P = 0.0034). Between RCC and LCRC, RCC was associated with significantly poorer prognosis than LCRC with MSI (P = 0.019), MSS (P = 0.0010), KRAS wild type (P = 0.0020), BRAF wild type (P = 0.0040), 18qLOH– (P = 0.0010), and CIMP– (P = 0.0050). Table 2. Univariate analyses of tumor location associated with overall survivals by molecular biomarker in colorectal cancer patientsa   All (5-year survival rate)  Stage II (5-year survival rate)  Stage III (5-year survival rate)  Stage IV (MST, months)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  71.9%  61.1%  75.5%  <0.0001  86.2%  77.7%  89.9%  0.0077  74.7%  65.6%  77.0%  0.24  28.6  21.0  35.2  0.13  N = 575  N = 151  N = 424  N = 207  N = 63  N = 144  N = 198  N = 41  N = 157  N = 102  N = 34  N = 68  MSI  81.2%  66.7%  100%  0.019  89.9%  80.0%  100%  0.19  71.4%  80.0%  100%  0.070  22.8  22.8  NA  NA  N = 34  N = 19  N = 15  N = 20  N = 11  N = 9  N = 7  N = 3  N = 4  N = 2  N = 2  N = 0  MSS  71.2%  70.4%  74.7%  0.0010  86.1%  77.3%  89.3%  0.0082  74.7%  77.3%  76.4%  0.45  26.7  21.0  37.4  0.14  N = 541  N = 132  N = 409  N = 187  N = 52  N = 135  N = 191  N = 38  N = 153  N = 100  N = 32  N = 32   P value  0.21  0.64  0.038    0.62  0.71  0.32    0.82  0.71  0.31    0.36  0.53  NA    KRAS MT  65.5%  60.4%  68.1%  0.30  84.3%  81.4%  85.4%  0.28  84.3%  68.8%  69.5%  0.73  22.8  21.2  30.6  0.26  N = 150  N = 53  N = 97  N = 55  N = 20  N = 35  N = 49  N = 16  N = 33  N = 29  N = 12  N = 17  KRAS WT  73.9%  61.4%  77.9%  0.0020  87.1%  76.2%  91.3%  0.017  87.1%  64.0%  78.7%  0.15  26.9  20.8  35.2  0.25  N = 425  N = 98  N = 327  N = 152  N = 43  N = 109  N = 149  N = 25  N = 124  N = 73  N = 22  N = 51  P value  0.041  0.93  0.035    0.58  0.94  0.46    0.58  0.74  0.065    0.64  0.87  0.80    BRAF MT  41.2%  40.3%  42.9%  0.88  71.4%  83.3%  NA  0.17  50.0%  20.0%  100%  0.053  13.2  17.4  10.8  0.25    N = 24  N = 17  N = 7  N = 7  N = 6  N = 1  N = 8  N = 5  N = 3  N = 8  N = 5  N = 3  BRAF WT  73.1%  63.7%  76.1%  0.0040  86.9%  77.0%  90.6%  0.0027  75.6%  71.9%  76.5%  0.79  32.8888  21.3  37.4  0.21  N = 551  N = 134  N = 417  N = 200  N = 57  N = 143  N = 190  N = 36  N = 154  N = 94  N = 29  N = 65  P value  <0.0001  0.021  0.0097    0.25  0.63  <0.0001    0.10  0.0034  0.33    <0.0001  0.019  <0.0001    18qLOH+  71.3%  62.7%  73.7%  0.069  86.3%  76.9%  89.6%  0.056  76.7%  67.2%  78.9%  0.31  26.1  21.1  32.8  0.68  N = 394  N = 86  N = 308  N = 136  N = 36  N = 100  N = 147  N = 28  N = 119  N = 74  N = 19  N = 55  18qLOH−  72.9%  58.9%  81.2%  0.0010  87.1%  79.2%  92.1%  0.029  71.4%  63.6%  74.2%  0.50  28.5  20.9  44.7  0.024  N = 157  N = 59  N = 98  N = 65  N = 26  N = 39  N = 42  N = 11  N = 31  N = 25  N = 13  N = 12  P value  0.69  0.53  0.10    0.93  0.93  0.55    0.48  0.71  0.62    0.52  0.21  0.49    CIMP+  54.4%  51.4%  63.6%  0.69  72.7%  70.0%  NA  0.56  61.9%  54.5%  80.0%  0.44  18.4  19.4  13.7  0.62  N = 42  N = 31  N = 11  N = 11  N = 10  N = 1  N = 16  N = 11  N = 5  N = 10  N = 7  N = 3  CIMP−  73.1%  63.2%  75.8%  0.0050  87.0%  78.5%  89.8%  0.0085  75.5%  68.4%  76.9%  0.54  34.3  21.0  37.4  0.31  N = 527  N = 115  N = 412  N = 192  N = 50  N = 142  N = 181  N = 29  N = 151  N = 91  N = 26  N = 65  P value  0.0034  0.19  0.20    0.22  0.73  0.76    0.19  0.30  0.97    0.0034  0.14  0.031      All (5-year survival rate)  Stage II (5-year survival rate)  Stage III (5-year survival rate)  Stage IV (MST, months)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  71.9%  61.1%  75.5%  <0.0001  86.2%  77.7%  89.9%  0.0077  74.7%  65.6%  77.0%  0.24  28.6  21.0  35.2  0.13  N = 575  N = 151  N = 424  N = 207  N = 63  N = 144  N = 198  N = 41  N = 157  N = 102  N = 34  N = 68  MSI  81.2%  66.7%  100%  0.019  89.9%  80.0%  100%  0.19  71.4%  80.0%  100%  0.070  22.8  22.8  NA  NA  N = 34  N = 19  N = 15  N = 20  N = 11  N = 9  N = 7  N = 3  N = 4  N = 2  N = 2  N = 0  MSS  71.2%  70.4%  74.7%  0.0010  86.1%  77.3%  89.3%  0.0082  74.7%  77.3%  76.4%  0.45  26.7  21.0  37.4  0.14  N = 541  N = 132  N = 409  N = 187  N = 52  N = 135  N = 191  N = 38  N = 153  N = 100  N = 32  N = 32   P value  0.21  0.64  0.038    0.62  0.71  0.32    0.82  0.71  0.31    0.36  0.53  NA    KRAS MT  65.5%  60.4%  68.1%  0.30  84.3%  81.4%  85.4%  0.28  84.3%  68.8%  69.5%  0.73  22.8  21.2  30.6  0.26  N = 150  N = 53  N = 97  N = 55  N = 20  N = 35  N = 49  N = 16  N = 33  N = 29  N = 12  N = 17  KRAS WT  73.9%  61.4%  77.9%  0.0020  87.1%  76.2%  91.3%  0.017  87.1%  64.0%  78.7%  0.15  26.9  20.8  35.2  0.25  N = 425  N = 98  N = 327  N = 152  N = 43  N = 109  N = 149  N = 25  N = 124  N = 73  N = 22  N = 51  P value  0.041  0.93  0.035    0.58  0.94  0.46    0.58  0.74  0.065    0.64  0.87  0.80    BRAF MT  41.2%  40.3%  42.9%  0.88  71.4%  83.3%  NA  0.17  50.0%  20.0%  100%  0.053  13.2  17.4  10.8  0.25    N = 24  N = 17  N = 7  N = 7  N = 6  N = 1  N = 8  N = 5  N = 3  N = 8  N = 5  N = 3  BRAF WT  73.1%  63.7%  76.1%  0.0040  86.9%  77.0%  90.6%  0.0027  75.6%  71.9%  76.5%  0.79  32.8888  21.3  37.4  0.21  N = 551  N = 134  N = 417  N = 200  N = 57  N = 143  N = 190  N = 36  N = 154  N = 94  N = 29  N = 65  P value  <0.0001  0.021  0.0097    0.25  0.63  <0.0001    0.10  0.0034  0.33    <0.0001  0.019  <0.0001    18qLOH+  71.3%  62.7%  73.7%  0.069  86.3%  76.9%  89.6%  0.056  76.7%  67.2%  78.9%  0.31  26.1  21.1  32.8  0.68  N = 394  N = 86  N = 308  N = 136  N = 36  N = 100  N = 147  N = 28  N = 119  N = 74  N = 19  N = 55  18qLOH−  72.9%  58.9%  81.2%  0.0010  87.1%  79.2%  92.1%  0.029  71.4%  63.6%  74.2%  0.50  28.5  20.9  44.7  0.024  N = 157  N = 59  N = 98  N = 65  N = 26  N = 39  N = 42  N = 11  N = 31  N = 25  N = 13  N = 12  P value  0.69  0.53  0.10    0.93  0.93  0.55    0.48  0.71  0.62    0.52  0.21  0.49    CIMP+  54.4%  51.4%  63.6%  0.69  72.7%  70.0%  NA  0.56  61.9%  54.5%  80.0%  0.44  18.4  19.4  13.7  0.62  N = 42  N = 31  N = 11  N = 11  N = 10  N = 1  N = 16  N = 11  N = 5  N = 10  N = 7  N = 3  CIMP−  73.1%  63.2%  75.8%  0.0050  87.0%  78.5%  89.8%  0.0085  75.5%  68.4%  76.9%  0.54  34.3  21.0  37.4  0.31  N = 527  N = 115  N = 412  N = 192  N = 50  N = 142  N = 181  N = 29  N = 151  N = 91  N = 26  N = 65  P value  0.0034  0.19  0.20    0.22  0.73  0.76    0.19  0.30  0.97    0.0034  0.14  0.031    aAnalyzed with Fisher’s exact test; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients; NA, not available. Table 2. Univariate analyses of tumor location associated with overall survivals by molecular biomarker in colorectal cancer patientsa   All (5-year survival rate)  Stage II (5-year survival rate)  Stage III (5-year survival rate)  Stage IV (MST, months)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  71.9%  61.1%  75.5%  <0.0001  86.2%  77.7%  89.9%  0.0077  74.7%  65.6%  77.0%  0.24  28.6  21.0  35.2  0.13  N = 575  N = 151  N = 424  N = 207  N = 63  N = 144  N = 198  N = 41  N = 157  N = 102  N = 34  N = 68  MSI  81.2%  66.7%  100%  0.019  89.9%  80.0%  100%  0.19  71.4%  80.0%  100%  0.070  22.8  22.8  NA  NA  N = 34  N = 19  N = 15  N = 20  N = 11  N = 9  N = 7  N = 3  N = 4  N = 2  N = 2  N = 0  MSS  71.2%  70.4%  74.7%  0.0010  86.1%  77.3%  89.3%  0.0082  74.7%  77.3%  76.4%  0.45  26.7  21.0  37.4  0.14  N = 541  N = 132  N = 409  N = 187  N = 52  N = 135  N = 191  N = 38  N = 153  N = 100  N = 32  N = 32   P value  0.21  0.64  0.038    0.62  0.71  0.32    0.82  0.71  0.31    0.36  0.53  NA    KRAS MT  65.5%  60.4%  68.1%  0.30  84.3%  81.4%  85.4%  0.28  84.3%  68.8%  69.5%  0.73  22.8  21.2  30.6  0.26  N = 150  N = 53  N = 97  N = 55  N = 20  N = 35  N = 49  N = 16  N = 33  N = 29  N = 12  N = 17  KRAS WT  73.9%  61.4%  77.9%  0.0020  87.1%  76.2%  91.3%  0.017  87.1%  64.0%  78.7%  0.15  26.9  20.8  35.2  0.25  N = 425  N = 98  N = 327  N = 152  N = 43  N = 109  N = 149  N = 25  N = 124  N = 73  N = 22  N = 51  P value  0.041  0.93  0.035    0.58  0.94  0.46    0.58  0.74  0.065    0.64  0.87  0.80    BRAF MT  41.2%  40.3%  42.9%  0.88  71.4%  83.3%  NA  0.17  50.0%  20.0%  100%  0.053  13.2  17.4  10.8  0.25    N = 24  N = 17  N = 7  N = 7  N = 6  N = 1  N = 8  N = 5  N = 3  N = 8  N = 5  N = 3  BRAF WT  73.1%  63.7%  76.1%  0.0040  86.9%  77.0%  90.6%  0.0027  75.6%  71.9%  76.5%  0.79  32.8888  21.3  37.4  0.21  N = 551  N = 134  N = 417  N = 200  N = 57  N = 143  N = 190  N = 36  N = 154  N = 94  N = 29  N = 65  P value  <0.0001  0.021  0.0097    0.25  0.63  <0.0001    0.10  0.0034  0.33    <0.0001  0.019  <0.0001    18qLOH+  71.3%  62.7%  73.7%  0.069  86.3%  76.9%  89.6%  0.056  76.7%  67.2%  78.9%  0.31  26.1  21.1  32.8  0.68  N = 394  N = 86  N = 308  N = 136  N = 36  N = 100  N = 147  N = 28  N = 119  N = 74  N = 19  N = 55  18qLOH−  72.9%  58.9%  81.2%  0.0010  87.1%  79.2%  92.1%  0.029  71.4%  63.6%  74.2%  0.50  28.5  20.9  44.7  0.024  N = 157  N = 59  N = 98  N = 65  N = 26  N = 39  N = 42  N = 11  N = 31  N = 25  N = 13  N = 12  P value  0.69  0.53  0.10    0.93  0.93  0.55    0.48  0.71  0.62    0.52  0.21  0.49    CIMP+  54.4%  51.4%  63.6%  0.69  72.7%  70.0%  NA  0.56  61.9%  54.5%  80.0%  0.44  18.4  19.4  13.7  0.62  N = 42  N = 31  N = 11  N = 11  N = 10  N = 1  N = 16  N = 11  N = 5  N = 10  N = 7  N = 3  CIMP−  73.1%  63.2%  75.8%  0.0050  87.0%  78.5%  89.8%  0.0085  75.5%  68.4%  76.9%  0.54  34.3  21.0  37.4  0.31  N = 527  N = 115  N = 412  N = 192  N = 50  N = 142  N = 181  N = 29  N = 151  N = 91  N = 26  N = 65  P value  0.0034  0.19  0.20    0.22  0.73  0.76    0.19  0.30  0.97    0.0034  0.14  0.031      All (5-year survival rate)  Stage II (5-year survival rate)  Stage III (5-year survival rate)  Stage IV (MST, months)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  71.9%  61.1%  75.5%  <0.0001  86.2%  77.7%  89.9%  0.0077  74.7%  65.6%  77.0%  0.24  28.6  21.0  35.2  0.13  N = 575  N = 151  N = 424  N = 207  N = 63  N = 144  N = 198  N = 41  N = 157  N = 102  N = 34  N = 68  MSI  81.2%  66.7%  100%  0.019  89.9%  80.0%  100%  0.19  71.4%  80.0%  100%  0.070  22.8  22.8  NA  NA  N = 34  N = 19  N = 15  N = 20  N = 11  N = 9  N = 7  N = 3  N = 4  N = 2  N = 2  N = 0  MSS  71.2%  70.4%  74.7%  0.0010  86.1%  77.3%  89.3%  0.0082  74.7%  77.3%  76.4%  0.45  26.7  21.0  37.4  0.14  N = 541  N = 132  N = 409  N = 187  N = 52  N = 135  N = 191  N = 38  N = 153  N = 100  N = 32  N = 32   P value  0.21  0.64  0.038    0.62  0.71  0.32    0.82  0.71  0.31    0.36  0.53  NA    KRAS MT  65.5%  60.4%  68.1%  0.30  84.3%  81.4%  85.4%  0.28  84.3%  68.8%  69.5%  0.73  22.8  21.2  30.6  0.26  N = 150  N = 53  N = 97  N = 55  N = 20  N = 35  N = 49  N = 16  N = 33  N = 29  N = 12  N = 17  KRAS WT  73.9%  61.4%  77.9%  0.0020  87.1%  76.2%  91.3%  0.017  87.1%  64.0%  78.7%  0.15  26.9  20.8  35.2  0.25  N = 425  N = 98  N = 327  N = 152  N = 43  N = 109  N = 149  N = 25  N = 124  N = 73  N = 22  N = 51  P value  0.041  0.93  0.035    0.58  0.94  0.46    0.58  0.74  0.065    0.64  0.87  0.80    BRAF MT  41.2%  40.3%  42.9%  0.88  71.4%  83.3%  NA  0.17  50.0%  20.0%  100%  0.053  13.2  17.4  10.8  0.25    N = 24  N = 17  N = 7  N = 7  N = 6  N = 1  N = 8  N = 5  N = 3  N = 8  N = 5  N = 3  BRAF WT  73.1%  63.7%  76.1%  0.0040  86.9%  77.0%  90.6%  0.0027  75.6%  71.9%  76.5%  0.79  32.8888  21.3  37.4  0.21  N = 551  N = 134  N = 417  N = 200  N = 57  N = 143  N = 190  N = 36  N = 154  N = 94  N = 29  N = 65  P value  <0.0001  0.021  0.0097    0.25  0.63  <0.0001    0.10  0.0034  0.33    <0.0001  0.019  <0.0001    18qLOH+  71.3%  62.7%  73.7%  0.069  86.3%  76.9%  89.6%  0.056  76.7%  67.2%  78.9%  0.31  26.1  21.1  32.8  0.68  N = 394  N = 86  N = 308  N = 136  N = 36  N = 100  N = 147  N = 28  N = 119  N = 74  N = 19  N = 55  18qLOH−  72.9%  58.9%  81.2%  0.0010  87.1%  79.2%  92.1%  0.029  71.4%  63.6%  74.2%  0.50  28.5  20.9  44.7  0.024  N = 157  N = 59  N = 98  N = 65  N = 26  N = 39  N = 42  N = 11  N = 31  N = 25  N = 13  N = 12  P value  0.69  0.53  0.10    0.93  0.93  0.55    0.48  0.71  0.62    0.52  0.21  0.49    CIMP+  54.4%  51.4%  63.6%  0.69  72.7%  70.0%  NA  0.56  61.9%  54.5%  80.0%  0.44  18.4  19.4  13.7  0.62  N = 42  N = 31  N = 11  N = 11  N = 10  N = 1  N = 16  N = 11  N = 5  N = 10  N = 7  N = 3  CIMP−  73.1%  63.2%  75.8%  0.0050  87.0%  78.5%  89.8%  0.0085  75.5%  68.4%  76.9%  0.54  34.3  21.0  37.4  0.31  N = 527  N = 115  N = 412  N = 192  N = 50  N = 142  N = 181  N = 29  N = 151  N = 91  N = 26  N = 65  P value  0.0034  0.19  0.20    0.22  0.73  0.76    0.19  0.30  0.97    0.0034  0.14  0.031    aAnalyzed with Fisher’s exact test; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients; NA, not available. In Stage II, survival was significantly worse in RCC compared with that in LCRC (P = 0.0077). However, no significant difference of prognosis was observed according to the molecular biomarker status. Compared with RCC and LCRC, RCC was associated with a significantly poorer prognosis than LCRC with MSS (P = 0.0082), and KRAS wild type (P = 0.017), BRAF wild type (P = 0.0027), 18qLOH– (P = 0.029), CIMP– (P = 0.0085). In Stage III, no significant difference of prognosis was observed according to the location. BRAF mutant type was associated with significantly poorer prognosis than BRAF wild type in RCC (P = 0.0034). Compared with RCC and LCRC, RCC tend to have poorer prognosis than LCRC with MSI (P = 0.070) and BRAF mutant type (P = 0.053); however, no significant difference of prognosis was observed according to the molecular biomarker status. In Stage IV, BRAF mutant type was associated with significantly poorer prognosis than BRAF wild type (P < 0.0001). CIMP+ was associated with a significantly poorer prognosis than CIMP– (P = 0.0034). Between RCC and LCRC, RCC had a significantly poorer prognosis than LCRC in 18qLOH– (P = 0.024). In multivariate analysis for overall survival (Table 3), age, gender, stage, lymphatic invasion, KRAS status and BRAF status were independent prognostic factors in colorectal cancer. Gender, stage and BRAF status were independent prognostic factors in RCC, and age, gender, stage, lymphatic invasion, KRAS status and BRAF status were independent prognostic factors in LCRC. Age, gender and lymphatic invasion in Stage II, histology in Stage III, and BRAF status in Stage IV were independent prognostic factors in colorectal cancer (Supplemental Tables 1–3). In RCC, gender in Stage II, and BRAF status in Stage III and Stage IV were independent prognostic factors. In LCRC, age and lymphatic invasion in Stage II, histology and KRAS status in Stage III, and age, venous invasion and BRAF status in Stage IV were independent prognostic factors. Table 3. Univariate and multivariate analyses of factors associated with overall survivals in colorectal cancer patientsa Variables  All  Right-sided colon cancer  Left-sided colorectal cancer  Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           >=65  68.3  0.0074  1.88 (1.32–2.66)  0.0004  61.4  0.63      71.6  0.023  2.18 (1.45–3.30)  0.0002   <65  77.2    1.0    60.8        80.5    1.0    Gender                           Male  68.1  0.017  1.92 (1.37–2.68)  0.0001  54.7  0.042  1.94 (1.12–3.37)  0.018  71.9  0.050  1.70 (1.11–2.59)  0.014   Female  76.8    1.0    67.1    1.0    81.1    1.0    Location                           Right  61.1  0.0005  1.21 (0.84–1.74)  0.30                   Left  75.5    1.0                    Stage                           I or II or III  81.4  <0.0001  1.0    73.6  <0.0001  1.0    83.9  <0.0001  1.0     IV  26.9    6.27 (4.47–8.79)  <0.0001  19.6    5.98 (3.29–10.9)  <0.0001  30.8    6.46 (4.27–9.78)  <0.0001  Histology                           Differentiated type  73.5  <0.0001  0.81 (0.48–1.36)  0.43  63.3  0.052  0.92 (0.40–2.10)  0.83  76.9  0.013  0.58 (0.30–1.09)  0.089   Non-differentiated type  53.3    1.0    46.7    1.0    57.2    1.0    Lymphatic invasion                           −  82.7  <0.0001  1.0    70.7  0.034  0.91 (0.48–1.72)  0.76  86.7  <0.0001  1.0     +  62.1    1.83 (1.28–2.60)  0.0008  52.7    1.0    65.6    2.32 (1.51–3.58)  0.0001  Venous invasion                           −  85.0  0.0027  1.0    75.4  0.024  1.0    90.1  0.010  1.0     +  69.0    1.21 (0.71–2.07)  0.48  56.2    1.74 (0.80–3.79)  0.76  73.1    1.25 (0.59–2.65)  0.56  MSI status                           MSI  81.2  0.21      66.7  0.64      100.0  0.038  1.0     MSS  71.2        70.4        74.7    1.44e+7 (0.00-Inf)  0.99  KRAS status                           Mutant type  65.5  0.041  1.0    60.4  0.93      68.1  0.035  1.0     Wild type  73.9    0.60 (0.42–0.84)  0.0037  61.4        77.9    0.58 (0.37–0886)  0.012  BRAF status                           Mutant type  41.2  <0.0001  1.0    40.3  0.021  1.0    42.9  0.0097  1.0     Wild type  73.1    0.44 (0.20–0.96)  0.040  63.7    0.32 (0.14–0.72)  0.0058  76.1    0.22 (0.078–0.61)  0.011  18qLOH status                           18qLOH+  71.3  0.69      62.7  0.53      73.7  0.10       18qLOH−  72.9        58.9        81.2        CIMP status                           (+)  54.4  0.0034  1.0    51.4  0.19      63.6  0.20       (−)  73.1    1.30 (0.66–2.57)  0.45  63.2        75.8        Variables  All  Right-sided colon cancer  Left-sided colorectal cancer  Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           >=65  68.3  0.0074  1.88 (1.32–2.66)  0.0004  61.4  0.63      71.6  0.023  2.18 (1.45–3.30)  0.0002   <65  77.2    1.0    60.8        80.5    1.0    Gender                           Male  68.1  0.017  1.92 (1.37–2.68)  0.0001  54.7  0.042  1.94 (1.12–3.37)  0.018  71.9  0.050  1.70 (1.11–2.59)  0.014   Female  76.8    1.0    67.1    1.0    81.1    1.0    Location                           Right  61.1  0.0005  1.21 (0.84–1.74)  0.30                   Left  75.5    1.0                    Stage                           I or II or III  81.4  <0.0001  1.0    73.6  <0.0001  1.0    83.9  <0.0001  1.0     IV  26.9    6.27 (4.47–8.79)  <0.0001  19.6    5.98 (3.29–10.9)  <0.0001  30.8    6.46 (4.27–9.78)  <0.0001  Histology                           Differentiated type  73.5  <0.0001  0.81 (0.48–1.36)  0.43  63.3  0.052  0.92 (0.40–2.10)  0.83  76.9  0.013  0.58 (0.30–1.09)  0.089   Non-differentiated type  53.3    1.0    46.7    1.0    57.2    1.0    Lymphatic invasion                           −  82.7  <0.0001  1.0    70.7  0.034  0.91 (0.48–1.72)  0.76  86.7  <0.0001  1.0     +  62.1    1.83 (1.28–2.60)  0.0008  52.7    1.0    65.6    2.32 (1.51–3.58)  0.0001  Venous invasion                           −  85.0  0.0027  1.0    75.4  0.024  1.0    90.1  0.010  1.0     +  69.0    1.21 (0.71–2.07)  0.48  56.2    1.74 (0.80–3.79)  0.76  73.1    1.25 (0.59–2.65)  0.56  MSI status                           MSI  81.2  0.21      66.7  0.64      100.0  0.038  1.0     MSS  71.2        70.4        74.7    1.44e+7 (0.00-Inf)  0.99  KRAS status                           Mutant type  65.5  0.041  1.0    60.4  0.93      68.1  0.035  1.0     Wild type  73.9    0.60 (0.42–0.84)  0.0037  61.4        77.9    0.58 (0.37–0886)  0.012  BRAF status                           Mutant type  41.2  <0.0001  1.0    40.3  0.021  1.0    42.9  0.0097  1.0     Wild type  73.1    0.44 (0.20–0.96)  0.040  63.7    0.32 (0.14–0.72)  0.0058  76.1    0.22 (0.078–0.61)  0.011  18qLOH status                           18qLOH+  71.3  0.69      62.7  0.53      73.7  0.10       18qLOH−  72.9        58.9        81.2        CIMP status                           (+)  54.4  0.0034  1.0    51.4  0.19      63.6  0.20       (−)  73.1    1.30 (0.66–2.57)  0.45  63.2        75.8        aAnalyzed with the Cox proportional hazards model; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients; NA, not available. Table 3. Univariate and multivariate analyses of factors associated with overall survivals in colorectal cancer patientsa Variables  All  Right-sided colon cancer  Left-sided colorectal cancer  Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           >=65  68.3  0.0074  1.88 (1.32–2.66)  0.0004  61.4  0.63      71.6  0.023  2.18 (1.45–3.30)  0.0002   <65  77.2    1.0    60.8        80.5    1.0    Gender                           Male  68.1  0.017  1.92 (1.37–2.68)  0.0001  54.7  0.042  1.94 (1.12–3.37)  0.018  71.9  0.050  1.70 (1.11–2.59)  0.014   Female  76.8    1.0    67.1    1.0    81.1    1.0    Location                           Right  61.1  0.0005  1.21 (0.84–1.74)  0.30                   Left  75.5    1.0                    Stage                           I or II or III  81.4  <0.0001  1.0    73.6  <0.0001  1.0    83.9  <0.0001  1.0     IV  26.9    6.27 (4.47–8.79)  <0.0001  19.6    5.98 (3.29–10.9)  <0.0001  30.8    6.46 (4.27–9.78)  <0.0001  Histology                           Differentiated type  73.5  <0.0001  0.81 (0.48–1.36)  0.43  63.3  0.052  0.92 (0.40–2.10)  0.83  76.9  0.013  0.58 (0.30–1.09)  0.089   Non-differentiated type  53.3    1.0    46.7    1.0    57.2    1.0    Lymphatic invasion                           −  82.7  <0.0001  1.0    70.7  0.034  0.91 (0.48–1.72)  0.76  86.7  <0.0001  1.0     +  62.1    1.83 (1.28–2.60)  0.0008  52.7    1.0    65.6    2.32 (1.51–3.58)  0.0001  Venous invasion                           −  85.0  0.0027  1.0    75.4  0.024  1.0    90.1  0.010  1.0     +  69.0    1.21 (0.71–2.07)  0.48  56.2    1.74 (0.80–3.79)  0.76  73.1    1.25 (0.59–2.65)  0.56  MSI status                           MSI  81.2  0.21      66.7  0.64      100.0  0.038  1.0     MSS  71.2        70.4        74.7    1.44e+7 (0.00-Inf)  0.99  KRAS status                           Mutant type  65.5  0.041  1.0    60.4  0.93      68.1  0.035  1.0     Wild type  73.9    0.60 (0.42–0.84)  0.0037  61.4        77.9    0.58 (0.37–0886)  0.012  BRAF status                           Mutant type  41.2  <0.0001  1.0    40.3  0.021  1.0    42.9  0.0097  1.0     Wild type  73.1    0.44 (0.20–0.96)  0.040  63.7    0.32 (0.14–0.72)  0.0058  76.1    0.22 (0.078–0.61)  0.011  18qLOH status                           18qLOH+  71.3  0.69      62.7  0.53      73.7  0.10       18qLOH−  72.9        58.9        81.2        CIMP status                           (+)  54.4  0.0034  1.0    51.4  0.19      63.6  0.20       (−)  73.1    1.30 (0.66–2.57)  0.45  63.2        75.8        Variables  All  Right-sided colon cancer  Left-sided colorectal cancer  Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           >=65  68.3  0.0074  1.88 (1.32–2.66)  0.0004  61.4  0.63      71.6  0.023  2.18 (1.45–3.30)  0.0002   <65  77.2    1.0    60.8        80.5    1.0    Gender                           Male  68.1  0.017  1.92 (1.37–2.68)  0.0001  54.7  0.042  1.94 (1.12–3.37)  0.018  71.9  0.050  1.70 (1.11–2.59)  0.014   Female  76.8    1.0    67.1    1.0    81.1    1.0    Location                           Right  61.1  0.0005  1.21 (0.84–1.74)  0.30                   Left  75.5    1.0                    Stage                           I or II or III  81.4  <0.0001  1.0    73.6  <0.0001  1.0    83.9  <0.0001  1.0     IV  26.9    6.27 (4.47–8.79)  <0.0001  19.6    5.98 (3.29–10.9)  <0.0001  30.8    6.46 (4.27–9.78)  <0.0001  Histology                           Differentiated type  73.5  <0.0001  0.81 (0.48–1.36)  0.43  63.3  0.052  0.92 (0.40–2.10)  0.83  76.9  0.013  0.58 (0.30–1.09)  0.089   Non-differentiated type  53.3    1.0    46.7    1.0    57.2    1.0    Lymphatic invasion                           −  82.7  <0.0001  1.0    70.7  0.034  0.91 (0.48–1.72)  0.76  86.7  <0.0001  1.0     +  62.1    1.83 (1.28–2.60)  0.0008  52.7    1.0    65.6    2.32 (1.51–3.58)  0.0001  Venous invasion                           −  85.0  0.0027  1.0    75.4  0.024  1.0    90.1  0.010  1.0     +  69.0    1.21 (0.71–2.07)  0.48  56.2    1.74 (0.80–3.79)  0.76  73.1    1.25 (0.59–2.65)  0.56  MSI status                           MSI  81.2  0.21      66.7  0.64      100.0  0.038  1.0     MSS  71.2        70.4        74.7    1.44e+7 (0.00-Inf)  0.99  KRAS status                           Mutant type  65.5  0.041  1.0    60.4  0.93      68.1  0.035  1.0     Wild type  73.9    0.60 (0.42–0.84)  0.0037  61.4        77.9    0.58 (0.37–0886)  0.012  BRAF status                           Mutant type  41.2  <0.0001  1.0    40.3  0.021  1.0    42.9  0.0097  1.0     Wild type  73.1    0.44 (0.20–0.96)  0.040  63.7    0.32 (0.14–0.72)  0.0058  76.1    0.22 (0.078–0.61)  0.011  18qLOH status                           18qLOH+  71.3  0.69      62.7  0.53      73.7  0.10       18qLOH−  72.9        58.9        81.2        CIMP status                           (+)  54.4  0.0034  1.0    51.4  0.19      63.6  0.20       (−)  73.1    1.30 (0.66–2.57)  0.45  63.2        75.8        aAnalyzed with the Cox proportional hazards model; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients; NA, not available. Disease-free survival In disease-free survival analysis (Table 4), MSS was associated with a significantly poorer prognosis than MSI in Stage II of RCC (P = 0.035). BRAF mutant type was associated with a significantly poorer prognosis than BRAF wild type in Stage II/III of LCRC (P = 0.027) and in Stage II of LRCR (P < 0.0001). CIMP+ was associated with a significantly poorer prognosis than CIMP– in Stage II of LCRC (P < 0.0001). Between RCC and LCRC, RCC had a significantly poorer prognosis than LCRC in Stage II of MSS (P = 0.027) and in Stage II of 18qLOH+ (P = 0.012). However, LCRC had a significantly poorer prognosis than RCC in Stage II with BRAF mutant type (P = 0.025). Table 4. Five-year disease free survival rate according to tumor locationa DFS  Stage II/III (5-year DFS rate)  Stage II (5-year DFS rate)  Stage III (5-year DFS rate)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  69.0%  60.9%  71.5%  0.18  76.5%  80.3%  66.9%  0.084  61.5%  51.7%  63.8%  0.40  N = 322  N = 79  N = 243  N = 164  N = 50  N = 114  N = 158  N = 29  N = 129  MSI  90.5%  63.7%  66.6%  0.56  100%  100%  100%  0.29  66.7%  50.0%  75.0%  0.70    N = 23  N = 11  N = 12    N = 17  N = 9  N = 8    N = 6  N = 2  N = 4    MSS  67.4%  59.7%  73.1%  0.078  74.0%  60.2%  79.0%  0.027  61.3%  51.9%  63.4%  0.44  N = 299  N = 68  N = 231  N = 147  N = 41  N = 106  N = 152  N = 27  N = 125   P value  0.031  0.72  0.19    0.029  0.035  0.19    0.77  0.91  0.71    KRAS MT  65.6%  62.5%  66.6%  0.90  75.9%  74.1%  76.5%  0.80  55.0%  53.8%  55.6%  0.68  N = 86  N = 28  N = 58  N = 45  N = 15  N = 30  N = 41  N = 13  N = 28  KRAS WT  70.2%  60.9%  73.1%  0.16  76.7%  64.6%  81.7%  0.10  63.7%  50.0%  66.0%  0.33  N = 236  N = 51  N = 185  N = 119  N = 35  N = 84  N = 117  N = 16  N = 101   P value  0.31  0.64  0.19    0.95  0.43  0.60    0.13  0.94  0.096    BRAF MT  54.5%  53.8%  33.3%  0.17  66.7%  65.4%  NA  0.025  40.0%  33.3%  50.0%  0.98  N = 11  N = 8  N = 3  N = 6  N = 5  N = 1  N = 5  N = 3  N = 2  BRAF WT  69.5%  75.0%  72.0%  0.18  76.9%  80.0%  81.1%  0.065  62.2%  53.8%  64.0%  0.49  N = 311  N = 71  N = 240  N = 158  N = 45  N = 113  N = 153  N = 26  N = 127   P value  0.41  0.083  0.027    0.63  0.39  <0.0001    0.44  0.84  0.55    18qLOH+  68.3%  53.3%  72.2%  0.052  74.5%  55.6%  81.6%  0.012  62.9%  52.6%  65.0%  0.43  N = 223  N = 47  N = 176  N = 105  N = 28  N = 77  N = 118  N = 19  N = 99  18qLOH−  73.8%  60.9%  73.2%  0.86  80.0%  84.2%  77.4%  0.66  64.4%  55.6%  67.8%  0.59  N = 87  N = 30  N = 57  N = 53  N = 21  N = 32  N = 34  N = 9  N = 25   P value  0.26  0.61  0.70    0.42  0.047  0.73    0.68  0.80  0.67    CIMP+  51.9%  51.4%  50.0%  0.55  60.0%  66.7%  NA  0.070  43.6%  33.3%  60.0%  0.74  N = 21  N = 15  N = 6  N = 10  N = 9  N = 1  N = 11  N = 6  N = 5  CIMP−  69.8%  69.8%  72.0%  0.203  77.1%  65.3%  80.9%  0.068  62.5%  54.5%  63.9%  0.59  N = 296  N = 60  N = 233  N = 150  N = 38  N = 112  N = 146  N = 22  N = 124   P value  0.083  0.19  0.091    0.19  0.95  <0.0001    0.25  0.45  0.69    DFS  Stage II/III (5-year DFS rate)  Stage II (5-year DFS rate)  Stage III (5-year DFS rate)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  69.0%  60.9%  71.5%  0.18  76.5%  80.3%  66.9%  0.084  61.5%  51.7%  63.8%  0.40  N = 322  N = 79  N = 243  N = 164  N = 50  N = 114  N = 158  N = 29  N = 129  MSI  90.5%  63.7%  66.6%  0.56  100%  100%  100%  0.29  66.7%  50.0%  75.0%  0.70    N = 23  N = 11  N = 12    N = 17  N = 9  N = 8    N = 6  N = 2  N = 4    MSS  67.4%  59.7%  73.1%  0.078  74.0%  60.2%  79.0%  0.027  61.3%  51.9%  63.4%  0.44  N = 299  N = 68  N = 231  N = 147  N = 41  N = 106  N = 152  N = 27  N = 125   P value  0.031  0.72  0.19    0.029  0.035  0.19    0.77  0.91  0.71    KRAS MT  65.6%  62.5%  66.6%  0.90  75.9%  74.1%  76.5%  0.80  55.0%  53.8%  55.6%  0.68  N = 86  N = 28  N = 58  N = 45  N = 15  N = 30  N = 41  N = 13  N = 28  KRAS WT  70.2%  60.9%  73.1%  0.16  76.7%  64.6%  81.7%  0.10  63.7%  50.0%  66.0%  0.33  N = 236  N = 51  N = 185  N = 119  N = 35  N = 84  N = 117  N = 16  N = 101   P value  0.31  0.64  0.19    0.95  0.43  0.60    0.13  0.94  0.096    BRAF MT  54.5%  53.8%  33.3%  0.17  66.7%  65.4%  NA  0.025  40.0%  33.3%  50.0%  0.98  N = 11  N = 8  N = 3  N = 6  N = 5  N = 1  N = 5  N = 3  N = 2  BRAF WT  69.5%  75.0%  72.0%  0.18  76.9%  80.0%  81.1%  0.065  62.2%  53.8%  64.0%  0.49  N = 311  N = 71  N = 240  N = 158  N = 45  N = 113  N = 153  N = 26  N = 127   P value  0.41  0.083  0.027    0.63  0.39  <0.0001    0.44  0.84  0.55    18qLOH+  68.3%  53.3%  72.2%  0.052  74.5%  55.6%  81.6%  0.012  62.9%  52.6%  65.0%  0.43  N = 223  N = 47  N = 176  N = 105  N = 28  N = 77  N = 118  N = 19  N = 99  18qLOH−  73.8%  60.9%  73.2%  0.86  80.0%  84.2%  77.4%  0.66  64.4%  55.6%  67.8%  0.59  N = 87  N = 30  N = 57  N = 53  N = 21  N = 32  N = 34  N = 9  N = 25   P value  0.26  0.61  0.70    0.42  0.047  0.73    0.68  0.80  0.67    CIMP+  51.9%  51.4%  50.0%  0.55  60.0%  66.7%  NA  0.070  43.6%  33.3%  60.0%  0.74  N = 21  N = 15  N = 6  N = 10  N = 9  N = 1  N = 11  N = 6  N = 5  CIMP−  69.8%  69.8%  72.0%  0.203  77.1%  65.3%  80.9%  0.068  62.5%  54.5%  63.9%  0.59  N = 296  N = 60  N = 233  N = 150  N = 38  N = 112  N = 146  N = 22  N = 124   P value  0.083  0.19  0.091    0.19  0.95  <0.0001    0.25  0.45  0.69    aAnalyzed with Fisher’s exact test; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients. Table 4. Five-year disease free survival rate according to tumor locationa DFS  Stage II/III (5-year DFS rate)  Stage II (5-year DFS rate)  Stage III (5-year DFS rate)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  69.0%  60.9%  71.5%  0.18  76.5%  80.3%  66.9%  0.084  61.5%  51.7%  63.8%  0.40  N = 322  N = 79  N = 243  N = 164  N = 50  N = 114  N = 158  N = 29  N = 129  MSI  90.5%  63.7%  66.6%  0.56  100%  100%  100%  0.29  66.7%  50.0%  75.0%  0.70    N = 23  N = 11  N = 12    N = 17  N = 9  N = 8    N = 6  N = 2  N = 4    MSS  67.4%  59.7%  73.1%  0.078  74.0%  60.2%  79.0%  0.027  61.3%  51.9%  63.4%  0.44  N = 299  N = 68  N = 231  N = 147  N = 41  N = 106  N = 152  N = 27  N = 125   P value  0.031  0.72  0.19    0.029  0.035  0.19    0.77  0.91  0.71    KRAS MT  65.6%  62.5%  66.6%  0.90  75.9%  74.1%  76.5%  0.80  55.0%  53.8%  55.6%  0.68  N = 86  N = 28  N = 58  N = 45  N = 15  N = 30  N = 41  N = 13  N = 28  KRAS WT  70.2%  60.9%  73.1%  0.16  76.7%  64.6%  81.7%  0.10  63.7%  50.0%  66.0%  0.33  N = 236  N = 51  N = 185  N = 119  N = 35  N = 84  N = 117  N = 16  N = 101   P value  0.31  0.64  0.19    0.95  0.43  0.60    0.13  0.94  0.096    BRAF MT  54.5%  53.8%  33.3%  0.17  66.7%  65.4%  NA  0.025  40.0%  33.3%  50.0%  0.98  N = 11  N = 8  N = 3  N = 6  N = 5  N = 1  N = 5  N = 3  N = 2  BRAF WT  69.5%  75.0%  72.0%  0.18  76.9%  80.0%  81.1%  0.065  62.2%  53.8%  64.0%  0.49  N = 311  N = 71  N = 240  N = 158  N = 45  N = 113  N = 153  N = 26  N = 127   P value  0.41  0.083  0.027    0.63  0.39  <0.0001    0.44  0.84  0.55    18qLOH+  68.3%  53.3%  72.2%  0.052  74.5%  55.6%  81.6%  0.012  62.9%  52.6%  65.0%  0.43  N = 223  N = 47  N = 176  N = 105  N = 28  N = 77  N = 118  N = 19  N = 99  18qLOH−  73.8%  60.9%  73.2%  0.86  80.0%  84.2%  77.4%  0.66  64.4%  55.6%  67.8%  0.59  N = 87  N = 30  N = 57  N = 53  N = 21  N = 32  N = 34  N = 9  N = 25   P value  0.26  0.61  0.70    0.42  0.047  0.73    0.68  0.80  0.67    CIMP+  51.9%  51.4%  50.0%  0.55  60.0%  66.7%  NA  0.070  43.6%  33.3%  60.0%  0.74  N = 21  N = 15  N = 6  N = 10  N = 9  N = 1  N = 11  N = 6  N = 5  CIMP−  69.8%  69.8%  72.0%  0.203  77.1%  65.3%  80.9%  0.068  62.5%  54.5%  63.9%  0.59  N = 296  N = 60  N = 233  N = 150  N = 38  N = 112  N = 146  N = 22  N = 124   P value  0.083  0.19  0.091    0.19  0.95  <0.0001    0.25  0.45  0.69    DFS  Stage II/III (5-year DFS rate)  Stage II (5-year DFS rate)  Stage III (5-year DFS rate)    All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  RCC  LCRC  P value  All  69.0%  60.9%  71.5%  0.18  76.5%  80.3%  66.9%  0.084  61.5%  51.7%  63.8%  0.40  N = 322  N = 79  N = 243  N = 164  N = 50  N = 114  N = 158  N = 29  N = 129  MSI  90.5%  63.7%  66.6%  0.56  100%  100%  100%  0.29  66.7%  50.0%  75.0%  0.70    N = 23  N = 11  N = 12    N = 17  N = 9  N = 8    N = 6  N = 2  N = 4    MSS  67.4%  59.7%  73.1%  0.078  74.0%  60.2%  79.0%  0.027  61.3%  51.9%  63.4%  0.44  N = 299  N = 68  N = 231  N = 147  N = 41  N = 106  N = 152  N = 27  N = 125   P value  0.031  0.72  0.19    0.029  0.035  0.19    0.77  0.91  0.71    KRAS MT  65.6%  62.5%  66.6%  0.90  75.9%  74.1%  76.5%  0.80  55.0%  53.8%  55.6%  0.68  N = 86  N = 28  N = 58  N = 45  N = 15  N = 30  N = 41  N = 13  N = 28  KRAS WT  70.2%  60.9%  73.1%  0.16  76.7%  64.6%  81.7%  0.10  63.7%  50.0%  66.0%  0.33  N = 236  N = 51  N = 185  N = 119  N = 35  N = 84  N = 117  N = 16  N = 101   P value  0.31  0.64  0.19    0.95  0.43  0.60    0.13  0.94  0.096    BRAF MT  54.5%  53.8%  33.3%  0.17  66.7%  65.4%  NA  0.025  40.0%  33.3%  50.0%  0.98  N = 11  N = 8  N = 3  N = 6  N = 5  N = 1  N = 5  N = 3  N = 2  BRAF WT  69.5%  75.0%  72.0%  0.18  76.9%  80.0%  81.1%  0.065  62.2%  53.8%  64.0%  0.49  N = 311  N = 71  N = 240  N = 158  N = 45  N = 113  N = 153  N = 26  N = 127   P value  0.41  0.083  0.027    0.63  0.39  <0.0001    0.44  0.84  0.55    18qLOH+  68.3%  53.3%  72.2%  0.052  74.5%  55.6%  81.6%  0.012  62.9%  52.6%  65.0%  0.43  N = 223  N = 47  N = 176  N = 105  N = 28  N = 77  N = 118  N = 19  N = 99  18qLOH−  73.8%  60.9%  73.2%  0.86  80.0%  84.2%  77.4%  0.66  64.4%  55.6%  67.8%  0.59  N = 87  N = 30  N = 57  N = 53  N = 21  N = 32  N = 34  N = 9  N = 25   P value  0.26  0.61  0.70    0.42  0.047  0.73    0.68  0.80  0.67    CIMP+  51.9%  51.4%  50.0%  0.55  60.0%  66.7%  NA  0.070  43.6%  33.3%  60.0%  0.74  N = 21  N = 15  N = 6  N = 10  N = 9  N = 1  N = 11  N = 6  N = 5  CIMP−  69.8%  69.8%  72.0%  0.203  77.1%  65.3%  80.9%  0.068  62.5%  54.5%  63.9%  0.59  N = 296  N = 60  N = 233  N = 150  N = 38  N = 112  N = 146  N = 22  N = 124   P value  0.083  0.19  0.091    0.19  0.95  <0.0001    0.25  0.45  0.69    aAnalyzed with Fisher’s exact test; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; MSI, microsatellite instability; MSS, microsatellite stable; MT, mutant type; WT, wild type; LOH, loss of heterozygosity; CIMP, CpG island methylator phenotype; N, number of patients. In multivariate analysis for disease-free survival (Table 5), MSI status and CIMP status were independent prognostic factors in colorectal cancer. No was independent prognostic factor in RCC, while lymphatic invasion was independent prognostic factor in LCRC. In Stage II, BRAF status and CIMP status were independent prognostic factors in LCRC (Supplemental Table 4). In Stage III, no was independent prognostic factor in colorectal cancer (Supplemental Table 5). Table 5. Univariate and multivariate analyses of factors associated with disease-free survivals in colorectal cancer patientsa Variables  All  Right-sided colon cancer  Left-sided colorectal cancer    Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate    5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           ≥65  66.1  0.18      60.3  0.97      68.5  0.22       <65  73.9        62.5        75.7        Gender                           Male  67.4  0.45      63.2  0.86      68.4  0.22       Female  71.2        58.9        76.5        Location                           Right  60.9  0.18                       Left  71.5                        Stage                           II  76.5  0.002  0.80 (0.51–1.27)  0.35  59.0  0.25      72.0  0.65       III  61.5    1.0    83.3        63.5        Histology                           Differentiated type  68.9  0.82      66.3  0.48      82.2  0.00078  0.81 (0.33–2.03)  0.66   Non-differentiated type  69.6        56.9        62.8    1.0    Lymphatic invasion                           −  77.7  0.001  1.0    75.6  0.11      87.5  0.063  1.0     +  61.1    1.57 (0.98–2.49)  0.058  66.4        69.1    2.22 (1.33–3.71)  0.0023  Venous invasion                           −  83.2  0.024  1.0    90.0  0.051  1.0    90.9  0.16       +  66.4    1.80 (0.98–2.49)  0.058  56.6    2.29 (0.79–6.60)  0.13  70.6        MSI status                           MSI  90.5  0.031  1.0    63.7  0.72      66.6  0.19       MSS  67.4    6.03 (1.41–25.8)  0.015  59.7        73.1        KRAS status                           Mutant type  65.6  0.31      62.5  0.64      66.6  0.19       Wild type  70.2        60.9        73.1        BRAF status                           Mutant type  54.5  0.41      53.8  0.083  1.20 (0.36–3.97)  0.77  33.3  0.027  1.0     Wild type  69.5        75.0    1.0    72.0    0.34 (0.08–1.43)  0.14  18qLOH status                           18qLOH+  68.3  0.26      53.3  0.61      72.2  0.70       18qLOH−  73.8        60.9        73.2        CIMP status                           (+)  51.9  0.083  2.66 (1.35–5.24)  0.0048  51.4  0.19      50.0  0.092  2.26 (0.70–7.28)  0.17   (−)  69.8    1.0    63.2        72.0        Variables  All  Right-sided colon cancer  Left-sided colorectal cancer    Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate    5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           ≥65  66.1  0.18      60.3  0.97      68.5  0.22       <65  73.9        62.5        75.7        Gender                           Male  67.4  0.45      63.2  0.86      68.4  0.22       Female  71.2        58.9        76.5        Location                           Right  60.9  0.18                       Left  71.5                        Stage                           II  76.5  0.002  0.80 (0.51–1.27)  0.35  59.0  0.25      72.0  0.65       III  61.5    1.0    83.3        63.5        Histology                           Differentiated type  68.9  0.82      66.3  0.48      82.2  0.00078  0.81 (0.33–2.03)  0.66   Non-differentiated type  69.6        56.9        62.8    1.0    Lymphatic invasion                           −  77.7  0.001  1.0    75.6  0.11      87.5  0.063  1.0     +  61.1    1.57 (0.98–2.49)  0.058  66.4        69.1    2.22 (1.33–3.71)  0.0023  Venous invasion                           −  83.2  0.024  1.0    90.0  0.051  1.0    90.9  0.16       +  66.4    1.80 (0.98–2.49)  0.058  56.6    2.29 (0.79–6.60)  0.13  70.6        MSI status                           MSI  90.5  0.031  1.0    63.7  0.72      66.6  0.19       MSS  67.4    6.03 (1.41–25.8)  0.015  59.7        73.1        KRAS status                           Mutant type  65.6  0.31      62.5  0.64      66.6  0.19       Wild type  70.2        60.9        73.1        BRAF status                           Mutant type  54.5  0.41      53.8  0.083  1.20 (0.36–3.97)  0.77  33.3  0.027  1.0     Wild type  69.5        75.0    1.0    72.0    0.34 (0.08–1.43)  0.14  18qLOH status                           18qLOH+  68.3  0.26      53.3  0.61      72.2  0.70       18qLOH−  73.8        60.9        73.2        CIMP status                           (+)  51.9  0.083  2.66 (1.35–5.24)  0.0048  51.4  0.19      50.0  0.092  2.26 (0.70–7.28)  0.17   (−)  69.8    1.0    63.2        72.0        aAnalyzed with the Cox proportional hazards model; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; HR, hazard ratio; CI, confidence interval; MT, mutant type; WT, wild type; CIMP, CpG island methylator phenotype. Table 5. Univariate and multivariate analyses of factors associated with disease-free survivals in colorectal cancer patientsa Variables  All  Right-sided colon cancer  Left-sided colorectal cancer    Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate    5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           ≥65  66.1  0.18      60.3  0.97      68.5  0.22       <65  73.9        62.5        75.7        Gender                           Male  67.4  0.45      63.2  0.86      68.4  0.22       Female  71.2        58.9        76.5        Location                           Right  60.9  0.18                       Left  71.5                        Stage                           II  76.5  0.002  0.80 (0.51–1.27)  0.35  59.0  0.25      72.0  0.65       III  61.5    1.0    83.3        63.5        Histology                           Differentiated type  68.9  0.82      66.3  0.48      82.2  0.00078  0.81 (0.33–2.03)  0.66   Non-differentiated type  69.6        56.9        62.8    1.0    Lymphatic invasion                           −  77.7  0.001  1.0    75.6  0.11      87.5  0.063  1.0     +  61.1    1.57 (0.98–2.49)  0.058  66.4        69.1    2.22 (1.33–3.71)  0.0023  Venous invasion                           −  83.2  0.024  1.0    90.0  0.051  1.0    90.9  0.16       +  66.4    1.80 (0.98–2.49)  0.058  56.6    2.29 (0.79–6.60)  0.13  70.6        MSI status                           MSI  90.5  0.031  1.0    63.7  0.72      66.6  0.19       MSS  67.4    6.03 (1.41–25.8)  0.015  59.7        73.1        KRAS status                           Mutant type  65.6  0.31      62.5  0.64      66.6  0.19       Wild type  70.2        60.9        73.1        BRAF status                           Mutant type  54.5  0.41      53.8  0.083  1.20 (0.36–3.97)  0.77  33.3  0.027  1.0     Wild type  69.5        75.0    1.0    72.0    0.34 (0.08–1.43)  0.14  18qLOH status                           18qLOH+  68.3  0.26      53.3  0.61      72.2  0.70       18qLOH−  73.8        60.9        73.2        CIMP status                           (+)  51.9  0.083  2.66 (1.35–5.24)  0.0048  51.4  0.19      50.0  0.092  2.26 (0.70–7.28)  0.17   (−)  69.8    1.0    63.2        72.0        Variables  All  Right-sided colon cancer  Left-sided colorectal cancer    Univariate  Multivariate  Univariate  Multivariate  Univariate  Multivariate    5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  5-year survival rate  P value  HR (95% CI)  P value  Age                           ≥65  66.1  0.18      60.3  0.97      68.5  0.22       <65  73.9        62.5        75.7        Gender                           Male  67.4  0.45      63.2  0.86      68.4  0.22       Female  71.2        58.9        76.5        Location                           Right  60.9  0.18                       Left  71.5                        Stage                           II  76.5  0.002  0.80 (0.51–1.27)  0.35  59.0  0.25      72.0  0.65       III  61.5    1.0    83.3        63.5        Histology                           Differentiated type  68.9  0.82      66.3  0.48      82.2  0.00078  0.81 (0.33–2.03)  0.66   Non-differentiated type  69.6        56.9        62.8    1.0    Lymphatic invasion                           −  77.7  0.001  1.0    75.6  0.11      87.5  0.063  1.0     +  61.1    1.57 (0.98–2.49)  0.058  66.4        69.1    2.22 (1.33–3.71)  0.0023  Venous invasion                           −  83.2  0.024  1.0    90.0  0.051  1.0    90.9  0.16       +  66.4    1.80 (0.98–2.49)  0.058  56.6    2.29 (0.79–6.60)  0.13  70.6        MSI status                           MSI  90.5  0.031  1.0    63.7  0.72      66.6  0.19       MSS  67.4    6.03 (1.41–25.8)  0.015  59.7        73.1        KRAS status                           Mutant type  65.6  0.31      62.5  0.64      66.6  0.19       Wild type  70.2        60.9        73.1        BRAF status                           Mutant type  54.5  0.41      53.8  0.083  1.20 (0.36–3.97)  0.77  33.3  0.027  1.0     Wild type  69.5        75.0    1.0    72.0    0.34 (0.08–1.43)  0.14  18qLOH status                           18qLOH+  68.3  0.26      53.3  0.61      72.2  0.70       18qLOH−  73.8        60.9        73.2        CIMP status                           (+)  51.9  0.083  2.66 (1.35–5.24)  0.0048  51.4  0.19      50.0  0.092  2.26 (0.70–7.28)  0.17   (−)  69.8    1.0    63.2        72.0        aAnalyzed with the Cox proportional hazards model; RCC, right-sided colon cancer; LCRC, left-sided colorectal cancer; HR, hazard ratio; CI, confidence interval; MT, mutant type; WT, wild type; CIMP, CpG island methylator phenotype. Discussion Recently, the various subtypes according to molecular markers have been proposed in CRC (16–19). Currently, clarification of the clinicopathological features of each CRC subtype is of great interest. The frequencies of RCC were similar in this study (26.3%) and a previous report from Japan (29.3%) (20), while the frequency of RCC was reported to be 42% in the United States (21). Thus, the frequency of RCC in Japan may be different from that in the United States. With respect to the clinicopathological features in RCC and LCRC, Japan is similar to Western countries; RCC was found more frequently in elderly patients (22,23), in the female sex (22), and in poorly differentiated tumors (24). Moreover, it has been reported that MSI (9,25,26), BRAF mutation (26–29), KRAS mutation (29,30), and CIMP+ (26) are predominantly found in RCC, whereas 18qLOH is more frequently found in LCRC (31,32). The proportions of biomarkers of CRC were also similar in Japan and Western countries. However, with respect to the frequencies of molecular biomarkers, differences between Japan and Western countries exist. It has been reported that the frequencies of MSI, KRAS mutant type, BRAF mutant type, 18qLOH+, and CIMP+ are 19.1–39.0% (9,33,34), 38.5–39.7% (29,30), 17.0–19.4% (29,34,35), 27% (36) and 8.4% (37), respectively, in RCC in Western countries. However, in the present study, the frequencies of MSI, KRAS mutant type, BRAF mutant type, 18qLOH+ and CIMP+ were 12.6%, 35.0%, 11.3%, 59.3% and 7.4%, respectively, in RCC of Japan. The frequencies of MSI and BRAF mutant type of RCC in Japan were lower than those in Western counties. Actually, the frequencies of BRAF mutation and MSI in Asian RCC are reported to be 4–10% (38–40), and 16.3–24% (41–44), respectively. Thus, the proportions of molecular biomarkers of CRC were different between Western populations and Asian populations. The lower incidences of BRAF mutation and MSI in Asian CRC patients could be due to an ethnic difference with varied underlying genetic predisposition. We need further investigation to elucidate the impact of other environmental and genetic factors. In this study, we showed independent prognostic factors, including molecular biomarkers, in colorectal cancer. It was interesting that the independent prognostic factors in RCC were different from those in LCRC in each stage. To our knowledge, no one has reported the differences of prognostic factors between RCC and LCRC in each stage. However, the consistency between OS and DFS was not observed in this study, excluding lymphatic invasion in LCRC, because of small sample sizes in each stage. Therefore, we cannot lead any generalized conclusions. The clinical outcomes of CRC, e.g., disease-free survival after adjuvant chemotherapy in Stage III colon cancer (45,46) as well as overall survival after intensive chemotherapy in unresectable CRC (47,48), were reported to be better in Japan than in Western countries. However, the prognostic difference in the tumor location between Japan and Western countries may be a factor of the frequency difference in the tumor location between Japan and Western countries. In fact, RCC has a poor prognosis compared with LCRC not only in Japan but also in Western countries (24). In addition, MSI, which was one of the chemo-resistant factors, and BRAF mutation, which was one of the poor prognosis factors, were less frequent in Japanese CRC patients. Consequently, it is difficult to compare the data from Japan with the data from Western countries. The following limitations of this study were included: (1) selection bias caused by the retrospective nature of the study; (2) the lack of treatment data; (3) a single-center study; (4) the lack of data on RAS mutations except for KRAS exon 2; however, we consider the influence of this on the overall results to be small because of low frequencies of minor RAS mutations; (5) the low statistical power because of the small sample size. Therefore, we might not have been able to show significant difference between RCC and LCRC in histology. Additionally, the number of patients was small (<10) in several subgroups (e.g., MSI in Stage III/IV, BRAF MT in Stage II/III/IV, BRAF MT in Stage II/III/IV), which was not enough for statistical analysis. Nonetheless, considering that there are only a few publications on molecular biomarkers from Asia, we believe that our findings will help researchers and physicians clarify the nature of CRC. 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Japanese Journal of Clinical OncologyOxford University Press

Published: May 15, 2018

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