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Suurmeijer, Albert J. H.; Dickson, Brendan C.; Swanson, David; Zhang, Lei; Sung, Yun‐Shao; Cotzia, Paolo; Fletcher, Christopher D. M.; Antonescu, Cristina R.
doi: 10.1002/gcc.22671pmid: 30276917
Tumors characterized by co‐expression of S100 and CD34, in the absence of SOX10, remain difficult to classify. Triggered by a few index cases with monomorphic cytomorphology and distinctive stromal and perivascular hyalinization, immunopositivity for S100 and CD34, and RAF1 and NTRK1 fusions, the authors undertook a systematic review of tumors with similar features. Most of the cases selected were previously diagnosed as low‐grade malignant peripheral nerve sheath tumors, while others were deemed unclassified. The tumors were studied with targeted RNA sequencing and/or FISH. A total of 25 cases (15 adults and 10 children) with kinase fusions were identified, including 8 cases involving RAF1, 2 BRAF, 14 NTRK1, and 1 NTRK2 gene rearrangements. Most tumors showed a monomorphic spindle cell proliferation with stromal and perivascular keloidal collagen, in a patternless architecture, with only occasional scattered pleomorphic or multinucleated cells. Most cases showed low cellularity, a low mitotic count, and absence of necrosis. Although a subset showed overlap with lipofibromatosis‐like neural tumors, the study group showed distinctive hyalinization and overt malignant features, such as highly cellular fascicular growth and primitive appearance. All tumors showed co‐expression of S100 and CD34, ranging from focal to diffuse. SOX10 was negative in all cases. NTRK1 immunohistochemistry showed high levels of expression in all tumors with NTRK1 gene rearrangements. H3K27me3 expression performed in a subset of cases was retained. These findings together with the recurrent gene fusions in RAF1, BRAF, and NTRK1/2 kinases suggest a distinct molecular tumor subtype with consistent S100 and CD34 immunoreactivity.
Fanoni, Daniele; Corti, Laura; Alberti‐Violetti, Silvia; Tensen, Cornelis P.; Venegoni, Luigia; Vermeer, Maarten; Willemze, Rein; Berti, Emilio
doi: 10.1002/gcc.22673pmid: 30307677
Primary cutaneous CD8+ aggressive epidermotropic cytotoxic T‐cell lymphoma (pcAECyTCL) is a rare provisionally categorized cutaneous lymphoma characterized by an aggressive course. Its pathogenesis and molecular mechanisms are still unknown, and only two individual cases have so far been molecularly characterized. The aim of this study was to define the pattern of numerical chromosomal alterations in tumor samples taken from 20 patients with pcAECyTCL at the time of diagnosis by means of array‐comparative genomic hybridization (a‐CGH). a‐CGH detected numerous genomic aberrations in all the patients and, putting these together as a whole, they affected all the chromosomes. However, no specific profile of recurrent copy number alterations (CNAs) was found. Most of the gains involved regions previously described in other aggressive cutaneous lymphomas such as 7q, 8q24.3, and 17q, whereas the most significant CNA was the loss of 9p21.3 (CDKN2A–CDKN2B), which has already been found in a variety of malignant tumors and is associated with aggressive cutaneous T‐cell lymphomas. In brief, CGH analysis revealed a large number of CNAs with only few recurring regions that probably do not represent driving events. The genomic instability found in this aggressive variant of cutaneous lymphoma may therefore be a secondary event but, at the time of the diagnosis of pcAECyTCL, the genomic integrity of tumor cells is already compromised.
Song, Nan; Kim, Kyeezu; Shin, Aesun; Park, Ji Won; Chang, Hee Jin; Shi, Jiajun; Cai, Qiuyin; Kim, Dae Yong; Zheng, Wei; Oh, Jae Hwan
doi: 10.1002/gcc.22674pmid: 30350386
Genome‐wide association studies (GWAS) have identified multiple single‐nucleotide polymorphisms (SNPs) associated with colorectal cancer risk. To evaluate the potential influence of colorectal cancer susceptibility SNPs on disease prognosis, we investigated whether GWAS‐identified colorectal cancer risk SNPs and polygenic risk scores (PRSs) might be associated with survival among colorectal cancer patients. A total of 1374 colorectal cancer patients were recruited from the Korean National Cancer Center. For genotyping, 30 colorectal cancer‐susceptibility SNPs previously identified by GWAS were selected. The Cox proportional hazard model was used to evaluate associations of these risk SNPs and PRSs with disease‐free survival (DFS) and overall survival (OS). The prognostic values were compared between genetic and nongenetic models using Harrell's c index. During the follow‐up period (median: 88, 91 months for DFS and OS), 570 DFS (41.5%) and 487 OS (35.4%) events were observed. We found that 5 SNPs were significantly associated with DFS or OS among colorectal cancer patients at P < .05: rs10936599 at 3q26.2 (MYNN), rs704017 at 10q22.3 (ZMIZ1‐AS1), rs11196172 at 10q25.2 (TCF7L2), rs3802842 at 11q23.1 (COLCA1‐2), and rs9929218 at 16q22.1 (CDH1). The PRSs constructed using these 5 SNPs were associated with worse survival (DFS: Ptrend = .02 unweighted PRS, Ptrend = .01 weighted PRS, OS: Ptrend = 3.7 × 10−3 unweighted, Ptrend = .02 weighted PRS). Our results suggest that several colorectal cancer susceptibility SNPs might also be related to survival by influencing disease progression.
Jeannot, Emmanuelle; Harlé, Alexandre; Holmes, Allyson; Sastre‐Garau, Xavier
doi: 10.1002/gcc.22675pmid: 30264502
Anal carcinomas (AC) are associated with human papillomavirus (HPV) DNA sequences, but little is known about the physical state of the viral genome in carcinoma cells. To define the integration status and gene(s) targeted by viral insertions in AC, tumor DNAs extracted from 35 tumor specimen samples in patients with HPV16‐associated invasive carcinoma were analyzed using the detection of integrated papillomavirus sequences‐PCR approach. The genomic status at integration sites was assessed using comparative genomic hybridization‐array assay and gene expression using reverse transcription quantitative PCR (RT‐qPCR). HPV16 DNA was found integrated in 25/35 (71%) cases and the integration locus could be determined at the molecular level in 19 cases (29 total integration loci). HPV DNA was inserted on different chromosomes, but 5 cases harbored viral sequences at 19p13.2, within the nuclear factor I X (NFIX) locus. Viral DNA mapped between the most distal and the two proximal alternatively expressed exons of this gene in three cases (CA21, CA04, and CA35) and upstream of this gene (663 kb and 2.3 Mb) in the others. CGH arrays showed genomic gains/amplifications at the NFIX region, associated with HPV within the gene and RT‐qPCR, revealed NFIX mRNA overexpression. Other genes targeted by integration were IL20RB, RPS6KA2, MSRA1, PIP5K1B, SLX4IP, CECR1, BCAR3, ATF6, CSNK1G1, APBA2, AGK, ILF3, PVT1, TRMT1, RAD51B, FASN, CCDC57, DSG3, and ZNF563. We identified recurrent targeting of NFIX by HPV16 insertion in anal carcinomas, supporting a role for this gene in oncogenesis, as reported for non‐HPV tumors.
Dong, Weilai; Nicolson, Norman G.; Choi, Jungmin; Barbieri, Andrea L.; Kunstman, John W.; Abou Azar, Sara; Knight, James; Bilguvar, Kaya; Mane, Shrikant M.; Lifton, Richard P.; Korah, Reju; Carling, Tobias
doi: 10.1002/gcc.22678pmid: 30136351
Foci of papillary or follicular thyroid carcinoma are frequently noted in thyroidectomy specimens of anaplastic thyroid carcinoma (ATC). However, whether ATCs evolve from these co‐existing well‐differentiated thyroid carcinomas (WDTCs) has not been well‐understood. To investigate the progression of ATC in patients with co‐existing WDTCs, five ATC tumors with co‐existing WDTCs and matching normal tissues were whole‐exome sequenced. After mapping the somatic alteration landscape, evolutionary lineages were constructed by sub‐clone analysis. Though each tumor harbored at least some unique private mutations, all five ATCs demonstrated numerous overlapping mutations with matched WDTCs. Clonal analysis further demonstrated that each ATC/WDTC pair shared a common ancestor, with some pairs diverging early in their evolution and others in which the ATC seems to arise directly from a sub‐clone of the WDTC. Though the precise lineal relationship remains ambiguous, based on the genetic relationship, our study clearly suggests a shared origin of ATC and WDTC.
Bastidas Torres, Armando N.; Cats, Davy; Mei, Hailiang; Szuhai, Karoly; Willemze, Rein; Vermeer, Maarten H.; Tensen, Cornelis P.
doi: 10.1002/gcc.22679pmid: 30144205
Mycosis fungoides (MF) is the most common cutaneous T‐cell lymphoma (CTCL). Causative genetic alterations in MF are unknown. The low recurrence of pathogenic small‐scale mutations (ie, nucleotide substitutions, indels) in the disease, calls for the study of additional aspects of MF genetics. Here, we investigated structural genomic alterations in tumor‐stage MF by integrating whole‐genome sequencing and RNA‐sequencing. Multiple genes with roles in cell physiology (n = 113) and metabolism (n = 92) were found to be impacted by genomic rearrangements, including 47 genes currently implicated in cancer. Fusion transcripts involving genes of interest such as DOT1L, KDM6A, LIFR, TP53, and TP63 were also observed. Additionally, we identified recurrent deletions of genes involved in cell cycle control, chromatin regulation, the JAK‐STAT pathway, and the PI‐3‐K pathway. Remarkably, many of these deletions result from genomic rearrangements. Deletion of tumor suppressors HNRNPK and SOCS1 were the most frequent genetic alterations in MF after deletion of CDKN2A. Notably, SOCS1 deletion could be detected in early‐stage MF. In agreement with the observed genomic alterations, transcriptome analysis revealed up‐regulation of the cell cycle, JAK‐STAT, PI‐3‐K and developmental pathways. Our results position inactivation of HNRNPK and SOCS1 as potential driver events in MF development.
Kudo, Ko; Ueno, Hiroo; Sato, Tomohiko; Kubo, Kaori; Kanezaki, Rika; Kobayashi, Akie; Kamio, Takuya; Sasaki, Shinya; Terui, Kiminori; Kurose, Akira; Yoshida, Kenichi; Shiozawa, Yusuke; Toki, Tsutomu; Ogawa, Seishi; Ito, Etsuro
doi: 10.1002/gcc.22676pmid: 30350464
The authors report two siblings with familial neuroblastoma with a germline R1275Q mutation of the tyrosine kinase domain of ALK. Whole exome sequencing and copy number variation assay were performed to investigate genetic alterations in the two cases. No common somatic mutations or gene polymorphisms related to the tumorigenesis of neuroblastoma were detected. A distinct pattern involving both segmental chromosomal alteration and MYCN amplification was detected. The diversity of biological behavior of familial neuroblastoma harboring a germline ALK mutation may depend on conventional prognostic factors, such as segmental chromosomal alterations and MYCN amplification, rather than additional acquired mutations.
Diness, Birgitte R.; Risom, Lotte; Frandsen, Thomas L.; Hansen, Bente; Andersen, Mette K.; Schmiegelow, Kjeld; Wadt, Karin A. W.
doi: 10.1002/gcc.22680pmid: 30144193
DDX41 has recently been identified as a new autosomal dominantly inherited cancer predisposition syndrome causing increased risk of adult onset acute myeloid leukemia (AML) or myelodysplastic syndrome (MDS). We report for the first time compound heterozygote germline missense DDX41 mutations located in the DEAD‐box domain, identified in two siblings by exome sequencing. Both siblings have slight dysmorphic findings, psychomotor delays and intellectual disability, and one developed blastic plasmacytoid dendritic cell neoplasm (BPDCN) at age five. RNA‐sequencing of bone marrow showed DDX41 expression including both mutations. However, the allele fraction of p.Pro321Leu accounted for 96% in the RNA‐sequencing indicating this mutation to be the more significant variant. Exome sequencing of the leukemic blasts identified no additional known driver mutations. There is no pattern indicating autosomal dominantly inherited cancer predisposition in the family, but the father has sarcoidosis, which has been associated with heterozygous DDX41 mutation. We propose that bi‐allelic mutations in DDX41 could potentially be a new cancer predisposition syndrome associated with delayed psychomotor development.
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