Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X
نویسندگان
چکیده
Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background. Here we identify the SEMA4A p.Val78Met germline mutation in an Austrian kindred with FCCTX, using an integrative genomics strategy. Compared with wild-type protein, SEMA4A(V78M) demonstrates significantly increased MAPK/Erk and PI3K/Akt signalling as well as cell cycle progression of SEMA4A-deficient HCT-116 colorectal cancer cells. In a cohort of 53 patients with FCCTX, we depict two further SEMA4A mutations, p.Gly484Ala and p.Ser326Phe and the single-nucleotide polymorphism (SNP) p.Pro682Ser. This SNP is highly associated with the FCCTX phenotype exhibiting increased risk for colorectal cancer (OR 6.79, 95% CI 2.63 to 17.52). Our study shows previously unidentified germline variants in SEMA4A predisposing to FCCTX, which has implications for surveillance strategies of patients and their families.
منابع مشابه
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متن کاملCorrespondence: Reply to 'SEMA4A variation and risk of colorectal cancer'.
Kinnersley et al. comment on our recently published study1 and report a failure to support semaphorin A (SEMA4A) variations as risk alleles for colorectal cancer (CRC)2. The authors investigated the contribution of the recurrent SEMA4A variants p.Gly484Ala (rs148744804) and p.Pro682Ser (rs76381440) in cohorts of CRC cases from different European populations. No significant association could be ...
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Abstract Background: Hereditary non-polyposis colorectal cancer is the most common cause of early onset of hereditary colorectal cancer. In the majority of Hereditary non-polyposis colorectal cancer families, microsatellite instability and germline mutation in one of the DNA mismatch repair genes in clouding MSH2, MLH1, MSH6 and PMS2 are found. The Objective of this study was to determine th...
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OBJECTIVE The characteristics of familial colorectal cancer type X are poorly defined. Here we aimed to clarify the differences in clinical features between suspected familial colorectal cancer type X and Lynch syndrome in Japanese patients. METHODS We performed germline mutation analyses of mismatch repair genes in 125 patients. Patients who met the Amsterdam Criteria I but lacked mismatch r...
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عنوان ژورنال:
دوره 5 شماره
صفحات -
تاریخ انتشار 2014