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; Heinz Sill

doi:10.1038/ncomms6191

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

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

Authors

Eduard Schulz¹, Petra Klampfl², Stefanie Holzapfel³, Andreas R Janecke⁴, Peter Ulz⁵, Wilfried Renner⁶, Karl Kashofer⁷, Satoshi Nojima⁸, Anita Leitner⁹, Armin Zebisch¹, Albert Wölfler¹, Sybille Hofer¹, Armin Gerger¹⁰, Sigurd Lax¹¹, Christine Beham-Schmid⁷, Verena Steinke³, Ellen Heitzer⁵, Jochen B Geigl⁵, Christian Windpassinger⁵, Gerald Hoefler⁷, Michael R Speicher⁵, C Richard Boland¹², Atsushi Kumanogoh¹³, Heinz Sill¹

Affiliations

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Adult
Aged
Amino Acid Sequence
Colorectal Neoplasms / genetics*
Colorectal Neoplasms / metabolism
Female
Genetic Predisposition to Disease*
Genetic Variation
Germ Cells / metabolism*
Humans
Male
Middle Aged
Molecular Sequence Data
Mutation, Missense
Phorbols
Semaphorins / chemistry
Semaphorins / genetics*
Semaphorins / metabolism
Sequence Alignment

Substances

Phorbols
SEMA4A protein, human
Semaphorins
pedilstatin