Background: The rs2147578 C > G polymorphism in the long non-coding RNA gene Lnc-LAMC2–1:1 is associated with increased susceptibility to a few types of cancers. However, its role in neuroblastoma has not been evaluated yet. Methods: We investigated the association between the lnc-LAMC2–1:1 rs2147578 C > G polymorphism and neuroblastoma susceptibility in Chinese Han populations. A total of 393 neuroblastoma cases and 812 healthy individuals from the Henan and Guangdong provinces were enrolled and subjected to genotyping. Odds ratio (OR) and 95% confidence interval (CI) were used to determine the strength of the association of interest. Results: Combined analysis revealed that the lnc-LAMC2–1:1 rs2147578 C > G polymorphism was associated with increased neuroblastoma susceptibility (CG vs. CC: adjusted OR = 1.33, 95% CI = 1.01–1.75, P = 0.045; CG/GG vs. CC: adjusted OR = 1.34, 95% CI = 1.03–1.74, P = 0.028). In stratification analysis, children under 18 months with rs2147578 CG/GG genotypes had an increased neuroblastoma risk (adjusted OR = 1.70, 95% CI = 1.08–2.67, P = 0.022). Females with rs2147578 CG/GG genotypes also had increased neuroblastoma susceptibility (adjusted OR = 2.08, 95% CI = 1.37– 3.18, P = 0.0007). In addition, children with lnc-LAMC2–1:1 rs2147578 CG/GG genotypes were prone to develop earlier stages of neuroblastoma (adjusted OR = 1.46, 95% CI = 1.01–2.12, P =0.046). Conclusions: The Lnc-LAMC2–1:1 rs2147578 C > G polymorphism may contribute to increased neuroblastoma susceptibility in children of Henan province. Keywords: rs2147578, Neuroblastoma, Long non-coding RNA, Polymorphism Background stage, N-myc status, DNA ploidy, and structural chromo- Neuroblastoma is the most common malignant extracranial somal aberrations [3–5]. solid tumor in children, accounting for 7–10% of all tumors Genetic factors are critically important in neuroblast- [1, 2]. Neuroblastoma originates from neural crest precur- oma tumorigenesis. Approximately 1% of the patients sor cells of the sympathetic nervous system and is mainly have a family history of neuroblastoma, and are carriers of located in the adrenal medulla, paraspinal ganglia, and certain genetic mutations. For instance, anaplastic lymph- sympathetic trunk [3–5]. The outcome of neuroblastoma is oma kinase (ALK)and PHOX2B gene variants are among affected by several factors such as age of onset, pathological the predisposing factors to familial neuroblastoma [6–8]. subtype, International Neuroblastoma Staging System (INSS) Evidence of genome-wide association studies (GWASs) of sporadic cases also suggests that genetic factors may be in- * Correspondence: email@example.com; firstname.lastname@example.org; volved in the pathogenesis of neuroblastoma [9, 10]. These email@example.com; firstname.lastname@example.org 1 studies indicate an important role of genetic characteris- Department of Pediatric Surgery, Guangzhou Women and Children’s Medical Center, Guangzhou Medical University, 9 Jinsui Road, Guangzhou tics in the tumorigenesis of this disease. 510623, Guangdong, China Full list of author information is available at the end of the article © The Author(s). 2018 Open Access This article is distributed under the terms of the Creative Commons Attribution 4.0 International License (http://creativecommons.org/licenses/by/4.0/), which permits unrestricted use, distribution, and reproduction in any medium, provided you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons license, and indicate if changes were made. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated. Yang et al. BMC Cancer (2018) 18:948 Page 2 of 6 Long non-coding RNAs (lncRNAs) are mRNA-like their legal guardians for the use of their children’smedical molecules whose genes belong to the non-protein coding data and biological samples. genome. LncRNAs are involved in many biological pro- cesses such as gene imprinting, epigenetic regulation, SNP selection and genotyping translational regulation, splicing, and aging [11–15]. The Lnc-LAMC2–1:1 rs2147578 C > G polymorphism LncRNAs are also involved in apoptosis and cell differ- was genotyped using the TaqMan real-time PCR system entiation, which are critical in tumorigenesis [16, 17]. on a 7900 Sequence Detection System (Applied Biosys- LncRNAs such as HULC, PCAT-1, HOTAIR, ANRIL, tems, Foster City, CA), as described previously [29–31]. and H19 are found to play important roles in cancer de- Briefly, high-quality DNA samples were genotyped using velopment . Single nucleotide polymorphism (SNP) Taqman real-time PCR method on a 7900 HT sequence at HULC is associated with decreased hepatocellular car- detector system. The call rate for the SNPs was 99%, cinoma risk . GWAS show that neuroblastoma pa- which met the pre-set criterion. For quality control, tients with the G allele of SNP rs6939340, which is eight duplicate positive and eight negative controls with- located in the lncRNA LOC729177 gene, have a high out DNA were used in each 384-well plate [32, 33]. Add- risk of metastasis and poor outcome [19, 20]. These itionally, 10% samples were randomly selected and studies indicate that evaluation of lncRNA gene poly- repeated, and the reproducibility was 100% concordant. morphism would be of great value in the risk assessment of neuroblastoma. Statistical analysis The rs2147578 C > G polymorphism in the lncRNA All statistical tests were two-sided, with a significance gene Lnc-LAMC2–1:1 is associated with susceptibility to level of P < 0.05. All statistical analyses were performed several types of cancer, and functional polymorphism in using SAS software (Version 9.4; SAS Institute, Cary, lnc-LAMC2–1:1 may confer a high risk of colorectal NC, USA). Two-sided χ tests were used to analyze cancer through affecting miRNA binding . Moreover, demographic data and genotype frequencies. The the lnc-LAMC2–1:1 rs2147578 polymorphism is also Hardy-Weinberg equilibrium was assessed using the considered a possible risk factor for acute lymphoblastic goodness-of-χ test. Odds ratios (OR) and 95% confi- leukemia (ALL) in children . However, few studies dence intervals (CIs) were calculated using the Woolf have focused on this polymorphism in neuroblastoma. approximation method to evaluate association between Here we hypothesized that the lnc-LAMC2–1:1 rs214757 the lnc-LAMC2–1:1 rs2147578 C > G polymorphism and 8 C > G polymorphism may contribute to neuroblastoma neuroblastoma susceptibility. Crude and age- and susceptibility, and we tested our hypothesis via a gender-adjusted OR were evaluated using the uncondi- case-control study. tional logistic regression method. Results Materials and methods Demographic characteristics of the study population Study subjects A total of 275 cases of neuroblastoma and 531 health The subjects enrolled were described in previous studies controls in Guangdong province and 118 neuroblastoma [23, 24]. Briefly, 393 neuroblastoma patients and 812 cases and 281 health controls in Henan province were cancer-free controls were enrolled from two different prov- evaluated (Additional File 1 Table S1). Age and gender inces of China: 275 neuroblastoma patients and 531 controls distributions were similar between cases and controls in from the Guangzhou Women and Children’s Medical Cen- both Guangdong and Henan province subgroups (P > ter in Southern China, and 118 neuroblastoma patients and 0.05). Distribution of clinical stages and sites of tumor 281 controls from the Henan province in Northern China origin are also listed in Additional file 1 Table S1. [25, 26]. Diagnosis and clinical stages of neuroblastoma were assigned according to the Shimada system and the inter- Lnc-LAMC2–1:1 rs2147578 C > G polymorphism and national criteria for neuroblastoma staging system [27, 28]. susceptibility to neuroblastoma Healthy controls had no history of malignancies and were Genotype and allele frequencies of the lnc-LAMC2–1:1 matched to the neuroblastoma cases in terms of age rs2147578 C > G polymorphism and associations with (±5 years), gender, ethnicity, and geographical region. Both neuroblastoma risk are summarized in Table 1. In both cases and controls were unrelated Chinese Han individuals combined and subgroup analyses, the genotype distribu- living in the Guangdong and Henan provinces of China. tion of the lnc-LAMC2–1:1 rs2147578 C > G polymorph- This study was approved by the Institutional Review ism in the controls and cases were consistent with Board of Guangzhou Women and Children’sMedical Hardy-Weinberg equilibrium (P = 0.164 for combined Center (Guangzhou, China), and written informed con- subjects, P = 0.279 for Guangdong province, and sent was obtained from the parents of the participants or P = 0.386 for Henan province). Yang et al. BMC Cancer (2018) 18:948 Page 3 of 6 Table 1 Genotype distribution of the lnc-LAMC2–1:1 rs2147578 C > G polymorphism and neuroblastoma susceptibility a b Genotype Case Control P Crude OR P Adjusted OR P (95% CI) (95% CI) Guangdong province (HWE = 0.279) CC 88 (32.00) 195 (36.79) 1.00 1.00 CG 130 (47.27) 243 (45.85) 1.19 (0.85–1.65) 0.312 1.18 (0.85–1.64) 0.332 GG 57 (20.73) 92 (17.36) 1.37 (0.91–2.08) 0.135 1.38 (0.91–2.10) 0.127 Additive 0.305 1.17 (0.96–1.44) 0.124 1.18 (0.96–1.44) 0.120 Dominant 187 (68.00) 335 (63.21) 0.177 1.24 (0.91–1.68) 0.177 1.23 (0.91–1.68) 0.183 Recessive 218 (79.27) 438 (82.64) 0.243 1.25 (0.86–1.80) 0.244 1.26 (0.87–1.82) 0.223 Henan province (HWE = 0.386) CC 29 (24.58) 99 (35.36) 1.00 1.00 CG 67 (56.78) 129 (46.07) 1.77 (1.07–2.95) 0.027 1.73 (1.03–2.89) 0.037 GG 22 (18.64) 52 (18.57) 1.44 (0.76–2.76) 0.266 1.42 (0.74–2.74) 0.291 Additive 0.085 1.25 (0.92–1.70) 0.158 1.23 (0.90–1.69) 0.186 Dominant 89 (75.42) 181 (64.64) 0.036 1.68 (1.03–2.73) 0.037 1.64 (1.004–2.68) 0.048 Recessive 96 (81.36) 228 (81.43) 0.986 1.01 (0.58–1.75) 0.986 1.00 (0.57–1.74) 1.000 Combined (HWE = 0.164) CC 117 (29.77) 294 (36.30) 1.00 1.00 CG 197 (50.13) 372 (45.93) 1.33 (1.01–1.75) 0.042 1.33 (1.01–1.75) 0.045 GG 79 (20.10) 144 (17.78) 1.38 (0.97–1.95) 0.071 1.38 (0.97–1.95) 0.074 Additive 0.080 1.19 (1.01–1.41) 0.043 1.19 (1.004–1.41) 0.045 Dominant 276 (70.23) 516 (63.70) 0.025 1.34 (1.04–1.74) 0.025 1.34 (1.03–1.74) 0.028 Recessive 314 (79.90) 666 (82.22) 0.331 1.16 (0.86–1.58) 0.331 1.16 (0.86–1.58) 0.333 a 2 χ test for genotype distribution in neuroblastoma cases and cancer-free controls Adjusted for age and gender OR odds ratio, CI confidence interval The values were in bold if the 95% CI excluded 1, or P<0.05 No significant difference in CC, CG, and GG genotype CG/GG genotypes in children younger than 18 months distributions was found in the Guangdong subgroup, in- were associated with increased neuroblastoma risk (ad- dicating that the Lnc-LAMC2–1:1 rs2147578 C > G poly- justed OR = 1.70, 95% CI = 1.08–2.67, P = 0.022). Fe- morphism is not associated with neuroblastoma risk in males with the CG/GG genotypes were associated with the Guangdong study population. However, the increased neuroblastoma risk (adjusted OR = 2.08, 95% lnc-LAMC2–1:1 rs2147578 C > G polymorphism was as- CI = 1.37–3.18, P = 0.0007). In addition, Individuals with sociated with increased neuroblastoma risk in the Henan the CG/GG genotypes tended to be in an earlier clinical population (CG vs. CC: adjusted OR = 1.73, 95% CI = stage of neuroblastoma (adjusted OR = 1.46, 95% CI = 1.01– 1.03–2.89, P = 0.048; CG/GG vs. CC: adjusted OR = 1.64, 2.12, P = 0.046). Finally, no significant association between 95% CI = 1.004–2.68, P = 0.048). the lnc-LAMC2–1:1 rs2147578 C > G polymorphism and The combined analysis showed that the distribution of the site of tumor origin was found (Table 2). the CG genotype was significantly higher in the neuro- blastoma group (adjusted OR = 1.33, 95% CI = 1.01–1.75, Discussion P = 0.045), indicating that the lnc-LAMC2–1:1 rs2147578 In this study, we investigated the association between CG/GG genotype carriers had an increased risk of neuro- the lnc-LAMC2–1:1 rs2147578 C > G polymorphism and blastoma (CG/GG vs. CC: adjusted OR = 1.34, 95% CI = neuroblastoma susceptibility in Chinese Han popula- 1.03–1.74, P =0.028). tions. We found that the lnc-LAMC2–1:1 rs2147578 C > G polymorphism is associated with increased neuro- Stratification analysis of the lnc-LAMC2–1:1 rs2147578 C > blastoma susceptibility. Specifically, females and children G polymorphism and neuroblastoma risk younger than 18 months with specific genotypes in the Stratification analyses according to age, gender, site of lnc-LAMC2–1:1 rs2147578 C > G polymorphism are at origin, and clinical stage were further conducted. The an increased risk of neuroblastoma. Fortunately, Yang et al. BMC Cancer (2018) 18:948 Page 4 of 6 Table 2 Stratification analysis of the association between the lnc-LAMC2–1:1 rs2147578 C > G polymorphism and neuroblastoma susceptibility for combined subjects a a Variable rs2147578 (case/control) Crude OR P Adjusted OR P CC CG/GG (95% CI) (95% CI) Age, month ≤ 18 35/120 91/184 1.70 (1.08–2.67) 0.022 1.70 (1.08–2.67) 0.022 > 18 82/174 185/332 1.18 (0.86–1.63) 0.302 1.18 (0.86–1.62) 0.312 Gender Female 39/130 129/211 2.04 (1.34–3.10) 0.0009 2.08 (1.37–3.18) 0.0007 Male 78/164 147/305 1.01 (0.73–1.42) 0.938 1.00 (0.72–1.40) 0.981 Site of origin Adrenal gland 43/294 110/516 1.46 (1.00–2.13) 0.052 1.41 (0.96–2.07) 0.077 Retroperitoneal region 31/294 56/516 1.03 (0.65–1.63) 0.903 1.04 (0.66–1.66) 0.863 Mediastinum 32/294 77/516 1.37 (0.89–2.12) 0.157 1.39 (0.90–2.16) 0.138 Others 9/294 27/516 1.71 (0.79–3.68) 0.171 1.75 (0.81–3.78) 0.155 Clinical stage I + II + 4 s 46/294 116/516 1.44 (0.99–2.08) 0.055 1.46 (1.01–2.12) 0.046 III + IV 68/294 143/516 1.20 (0.87–1.65) 0.272 1.16 (0.84–1.61) 0.362 Adjusted for age and gender OR odds ratio; CI confidence interval The values were in bold if the 95% CI excluded 1, or P<0.05 individuals with the CG/GG variation tended to have the LAMC2 can interact with the epidermal growth factor re- earlier stages of neuroblastoma. ceptor (EGFR), and influence its downstream pathway . Neuroblastoma accounts for approximately 15% of all Previous studies revealed that the EGF receptor is overex- childhood cancer mortality, and understanding the under- pressed in neuroblastoma tissues and cells, and anti-EGFR lying mechanisms of this disease would be of great value for agents are potential targeted therapies for neuroblastoma diagnosis and treatment [1, 2]. Genetic variants are critical [39–41]. The possible interaction between the lnc-LAMC2– in neuroblastoma tumorigenesis and disease progression. 1:1 rs2147578 polymorphism and the EGFR pathway may Missense mutations in PHOX2B, located on chromosome account for the increased risk of neuroblastoma of the G 4p, were the first germline mutations identified to be associ- allele. ated with neuroblastoma predisposition. Other genetic mu- Our results from Guangdong (Southern China) and tations, such as SNPs in the ALK and BARD1 genes and Henan (Northern China) provinces were inconsistent. In the copy number polymorphism of NBPF23, may also have a Henanprovincesubgroup, theCGgenotypedistribution role in neuroblastoma development [6–8]. was significantly higher in the neuroblastoma group, and LncRNAs are involved in many biological processes, with subjects with the GG and CG genotypes had a significantly LncRNA-MALAT1 and GAS5 being reported to mediate cell increased risk of neuroblastoma. In contrast, no association invasion, migration, and apoptosis in human neuroblastoma between the G allele and neuroblastoma was found in the [34, 35]. The lnc-LAMC2–1:1 polymorphism is located in Guangdong province subgroup. A possible explanation for the LAMC1 gene and close to the LAMC2 gene. Rs2147578 this inconsistency may be the relatively complex genetic is in the first exon of lnc-LAMC2–1:1, and the 26th intron background of the Guangdong Chinese Han population. of the LAMC1 gene near the LAMC2 gene . Carriers Studies on Y-chromosome phylogeny suggest that people in with the G allele have a slightly increased expression of Southern China, including Guangdong province, are much lnc-LAMC2–1:1 through binding between rs2147578G and more polymorphic than populations in Northern China, in- miR-128-3p . Previous evidence also suggests that the cluding Henan province [42–44]. However, the relatively lnc-LAMC2–1:1 rs2147578 C > G polymorphism may con- smallsamplesizeofour studymay introducebias. tribute to childhood ALL development . Our results show that the lnc-LAMC2–1:1 rs2147578 C > G polymorph- Conclusion ism may also be involved in neuroblastoma tumorigenesis. The Lnc-LAMC2–1:1 rs2147578 C > G polymorphism is as- Abnormal expression of LAMC2 was found in several sociated with increased neuroblastoma susceptibility in Han types of cancer, and elevated expression of LAMC2 is associ- populations of Northern China. 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