Evaluation of germline BMP4 mutation as a cause of colorectal cancer.

Steven Lubbe (1) , Cornelis Matijssen (2) , Alan M Pittman (3) , Philip Twiss (3) , Bianca Olver (3) , Amy Llyod (3) , Mobshra Qureshi (3) , Nathan Brown (2) , Emma Nye (4) , Gordon Stamp (4, 5, 6) , Julian Blagg (2) , Richard S. Houlston (3)

1 Section of Cancer Genetics
2 Medicinal Chemistry, Cancer Research UK Centre for Cancer Therapeutics
3 Section of Cancer Genetics
4 Experimental Pathology Laboratory
5 Royal Marsden Hospital
6 Imperial College Faculty of Medicine

Transforming growth factor-β (TGF-β) signalling plays a key role in colorectal cancer (CRC). Bone morphogenetic protein-4 (BMP4) is a member of the TGF-β family of signal transduction molecules. To examine if germline mutation in BMP4 causes CRC we analysed 504 genetically enriched CRC cases (by virtue of early-onset disease, family history of CRC) for mutations in the coding sequence of BMP4. We identified three pathogenic mutations, p.R286X (g.8330C>T), p.W325C (g.8449G>T) and p.C373S (g.8592G>C), amongst the CRC cases which were not observed in 524 healthy controls. p.R286X localises to the N-terminal of the TGF-β1 prodomain truncating the protein prior to the active domain. p.W325C and p.C373S mutations are predicted from protein homology modelling with BMP2 to impact deleteriously on BMP4 function. Segregation of p.C373S with adenoma and hyperplastic polyp in first-degree relatives of the case suggests germline mutations may confer a juvenile polyposis-type phenotype. These findings suggest mutation of BMP4 is a cause of CRC and the value of protein-based modelling in the elucidation of rare disease-causing variants.

Mots clés: Life Sciences

Steven Lubbe, Cornelis Matijssen, Alan M Pittman, Philip Twiss, Bianca Olver, et al.. Evaluation of germline BMP4 mutation as a cause of colorectal cancer.. Human Mutation, 2010, 32 (1), ⟨10.1002/humu.21376⟩. ⟨hal-00613754⟩