title: Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X.
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.
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Eduard
authors.initials: E
authors.lastname: Schulz
authors.affiliation: 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.
authors.forename: Petra
authors.initials: P
authors.lastname: Klampfl
authors.affiliation: Institute of Human Genetics, Faculty of Medicine, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Stefanie
authors.initials: S
authors.lastname: Holzapfel
authors.affiliation: 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.
authors.forename: Andreas R
authors.initials: AR
authors.lastname: Janecke
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Peter
authors.initials: P
authors.lastname: Ulz
authors.affiliation: Clinical Institute of Medical and Chemical Laboratory Diagnostics, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Wilfried
authors.initials: W
authors.lastname: Renner
authors.affiliation: Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Karl
authors.initials: K
authors.lastname: Kashofer
authors.affiliation: 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.
authors.forename: Satoshi
authors.initials: S
authors.lastname: Nojima
authors.affiliation: Department of Ear, Nose and Throat, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Anita
authors.initials: A
authors.lastname: Leitner
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Armin
authors.initials: A
authors.lastname: Zebisch
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Albert
authors.initials: A
authors.lastname: Wölfler
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Sybille
authors.initials: S
authors.lastname: Hofer
authors.affiliation: Division of Oncology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Armin
authors.initials: A
authors.lastname: Gerger
authors.affiliation: Department of Pathology, General Hospital Graz West, 8020 Graz, Austria.
authors.forename: Sigurd
authors.initials: S
authors.lastname: Lax
authors.affiliation: Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Christine
authors.initials: C
authors.lastname: Beham-Schmid
authors.affiliation: Institute of Human Genetics, Faculty of Medicine, University of Bonn, D-53127 Bonn, Germany.
authors.forename: Verena
authors.initials: V
authors.lastname: Steinke
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Ellen
authors.initials: E
authors.lastname: Heitzer
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Jochen B
authors.initials: JB
authors.lastname: Geigl
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Christian
authors.initials: C
authors.lastname: Windpassinger
authors.affiliation: Institute of Pathology, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Gerald
authors.initials: G
authors.lastname: Hoefler
authors.affiliation: Institute of Human Genetics, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Michael R
authors.initials: MR
authors.lastname: Speicher
authors.affiliation: Division of Gastroenterology, Baylor University Medical Center, Dallas, Texas 75246-2017, USA.
authors.forename: C Richard
authors.initials: CR
authors.lastname: Boland
authors.affiliation: 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.
authors.forename: Atsushi
authors.initials: A
authors.lastname: Kumanogoh
authors.affiliation: Division of Hematology, Department of Internal Medicine, Medical University of Graz, A-8036 Graz, Austria.
authors.forename: Heinz
authors.initials: H
authors.lastname: Sill
mesh_terms: D000328:Adult; D000368:Aged; D000595:Amino Acid Sequence; D015179:Colorectal Neoplasms / Q000235:genetics* / Q000378:metabolism; D005260:Female; D020022:Genetic Predisposition to Disease; D014644:Genetic Variation; D005854:Germ Cells / Q000378:metabolism*; D006801:Humans; D008297:Male; D008875:Middle Aged; D008969:Molecular Sequence Data; D020125:Mutation, Missense; D010704:Phorbols; D039961:Semaphorins / Q000737:chemistry / Q000235:genetics* / Q000378:metabolism; D016415:Sequence Alignment
chemical_list: D010704:Phorbols; C574096:SEMA4A protein, human; D039961:Semaphorins; C470237:pedilstatin