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

E Schulz ,Sybille Hofer,Anita Leitner,Christian Windpassinger,Michael R Speicher,Peter Ulz,Karl Kashofer,Petra Klampfl,Atsushi Kumanogoh,Stefanie Holzapfel,Albert Wölfler,Andreas R Janecke,Sigurd Lax,Satoshi Nojima,Heinz Sill,Jochen B Geigl,Wilfried Renner,Armin Gerger,Ellen Heitzer,Armin Zebisch,Verena Steinke,C Richard Boland,Gerald Höefler ,Christine Beham‐Schmid

doi:10.1038/ncomms6191

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.

Highlights

Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background
In contrast to Lynch syndrome (LS)—the hereditary non-polyposis colorectal cancer (HNPCC) entity characterized by germline DNA mismatch repair (MMR) gene mutations and somatically acquired microsatellite instability— individuals with FCCTX exhibit decreased risk for extracolonic neoplasms, that is, endometrial, stomach, small bowel and urinary tract carcinomas and tumour formation including Colorectal cancer (CRC) development tends to occur at a later age[5,8,9]
semaphorine 4A (SEMA4A) V78M segregated with all CRC cases and was detected in individuals K9 with testicular and K14 with breast cancer, respectively (Fig. 1a)

Summary

Introduction

Familial colorectal cancer type X (FCCTX) is characterized by clinical features of hereditary non-polyposis colorectal cancer with a yet undefined genetic background. 40 to 50% of patients with HNPCC fulfilling AC-I lack detectable germline mutations in cancer predisposition genes and are classified as familial colorectal cancer type X (FCCTX)[5,6,7].

Results

Conclusion