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

Author

Listed:
  • Eduard Schulz

    (Medical University of Graz)

  • Petra Klampfl

    (Medical University of Graz
    General Hospital Graz West)

  • Stefanie Holzapfel

    (Institute of Human Genetics, Faculty of Medicine, University of Bonn)

  • Andreas R. Janecke

    (Molecular and Clinical Pharmacology, Medical University of Innsbruck
    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
    Osaka University Graduate School of Medicine, 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
    Allergy and Rheumatic Disease, Graduate School of Medicine, Osaka University
    JST, CREST)

  • Heinz Sill

    (Medical University of Graz)

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.

Suggested Citation

  • 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 , 2014. "Germline variants in the SEMA4A gene predispose to familial colorectal cancer type X," Nature Communications, Nature, vol. 5(1), pages 1-11, December.
    • Handle: RePEc:nat:natcom:v:5:y:2014:i:1:d:10.1038_ncomms6191
    DOI: 10.1038/ncomms6191
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