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Nat Commun. 2014 Oct 13;5:5191. doi: 10.1038/ncomms6191.

Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X.

Author information

1
Division of Hematology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.
2
1] Division of Hematology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria [2] Department of Internal Medicine, General Hospital Graz West, A-8020 Graz, Austria.
3
Institute of Human Genetics, Faculty of Medicine, University of Bonn, D-53127 Bonn, Germany.
4
1] Division of Human Genetics, Department of Medical Genetics, Molecular and Clinical Pharmacology, Medical University of Innsbruck, A-6020 Innsbruck, Austria [2] Department of Pediatrics I, Medical University of Innsbruck, A-6020 Innsbruck, Austria.
5
Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
6
Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, A-8036 Graz, Austria.
7
Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria.
8
1] Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan [2] Department of Pathology, Osaka University Graduate School of Medicine, Osaka University, Suita City, Osaka 565-0871, Japan.
9
Department of Ear, Nose and Throat, Medical University of Graz, A-8036 Graz, Austria.
10
Division of Oncology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.
11
Department of Pathology, General Hospital Graz West, 8020 Graz, Austria.
12
Division of Gastroenterology, Baylor University Medical Center, Dallas, Texas 75246-2017, USA.
13
1] Department of Immunopathology, WPI Immunology Frontier Research Center, Osaka University, Suita City, Osaka 565-0871, Japan [2] Department of Respiratory Medicine, Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University, Suita City, Osaka 565-0871, Japan [3] JST, CREST, Suita City, Osaka 565-0871, Japan.

Abstract

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.

PMID:
25307848
PMCID:
PMC4214414
DOI:
10.1038/ncomms6191
[Indexed for MEDLINE]
Free PMC Article

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