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

Eduard Schulz, Petra Klampfl, Stefanie Holzapfel, Andreas R. Janecke, Peter Ulz, Wilfried Renner, Karl Kashofer, Satoshi Nojima, Anita Leitner, Armin Zebisch, Albert Wölfler, Sybille Hofer, Armin Gerger, Sigurd Lax, Christine Beham-Schmid, Verena Steinke, Ellen Heitzer, Jochen B. Geigl, Christian Windpassinger, Gerald Hoefler, Michael R. Speicher, C. Richard Boland, Atsushi Kumanogoh and Heinz Sill ()
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Eduard Schulz: Medical University of Graz
Petra Klampfl: Medical University of Graz
Stefanie Holzapfel: Institute of Human Genetics, Faculty of Medicine, University of Bonn
Andreas R. Janecke: Molecular and Clinical Pharmacology, Medical University of Innsbruck
Peter Ulz: Institute of Human Genetics, Medical University of Graz
Wilfried Renner: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz
Karl Kashofer: Institute of Pathology, Medical University of Graz
Satoshi Nojima: WPI Immunology Frontier Research Center, Osaka University
Anita Leitner: Nose and Throat, Medical University of Graz
Armin Zebisch: Medical University of Graz
Albert Wölfler: Medical University of Graz
Sybille Hofer: Medical University of Graz
Armin Gerger: Medical University of Graz
Sigurd Lax: General Hospital Graz West
Christine Beham-Schmid: Institute of Pathology, Medical University of Graz
Verena Steinke: Institute of Human Genetics, Faculty of Medicine, University of Bonn
Ellen Heitzer: Institute of Human Genetics, Medical University of Graz
Jochen B. Geigl: Institute of Human Genetics, Medical University of Graz
Christian Windpassinger: Institute of Human Genetics, Medical University of Graz
Gerald Hoefler: Institute of Pathology, Medical University of Graz
Michael R. Speicher: Institute of Human Genetics, Medical University of Graz
C. Richard Boland: Baylor University Medical Center
Atsushi Kumanogoh: WPI Immunology Frontier Research Center, Osaka University
Heinz Sill: Medical University of Graz

Nature Communications, 2014, vol. 5, issue 1, 1-11

Abstract: 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, SEMA4AV78M 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.

Date: 2014
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DOI: 10.1038/ncomms6191

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