BMPR2 as a novel predisposition gene for hereditary colorectal polyposis.

BACKGROUND AND AIMS: Colorectal cancer (CRC) is one of the most prevalent tumours worldwide, with incidences (particularly in the context of early-onset cases) quickly increasing despite important prevention efforts, mainly in the form of population-wide screening programmes. Although many cases present a clear familial component, the current list of hereditary CRC genes still leaves a considerable proportion of the cases unexplained.

METHODS: In this work, we utilised whole-exome sequencing approaches on 19 unrelated patients with unexplained colonic polyposis to identify candidate CRC predisposition genes. The candidate genes were then validated in an additional series of 365 patients. CRISPR-Cas9 models were used to validate BMPR2 as a potential candidate for CRC risk.

RESULTS: Altogether, we found 8 individuals carrying 6 different variants in the BMPR2 gene (〜2% of our cohort of patients with unexplained colonic polyposis). CRISPR-Cas9 models of three of these variants showed that the p.(Asn442Thrfs*32) truncating variant completely abrogated BMP pathway function in a way similar to the BMPR2 knock-out. Missense variants p.(Asn565Ser), p.(Ser967Pro) had varying effects on cell proliferation levels, with the former impairing cell control inhibition via non-canonical pathways.

CONCLUSIONS: Collectively, these results support loss-of-function BMPR2 variants as candidates to be involved in CRC germline predisposition.