BMPR2 as a Novel Predisposition Gene for Hereditary Colorectal Polyposis

Area of Science:

• Genetics
• Oncology
• Molecular Biology

Background:

• Colorectal cancer (CRC) is a leading global malignancy with increasing incidence, particularly in early-onset cases.
• Despite screening, a significant portion of hereditary CRC cases remain genetically unexplained.
• Existing hereditary CRC gene panels do not account for all familial predispositions.

Purpose of the Study:

• To identify novel candidate genes predisposing to colorectal cancer in patients with unexplained colonic polyposis.
• To investigate the role of the BMPR2 gene in colorectal cancer germline predisposition.
• To validate candidate genes using functional studies and larger patient cohorts.

Main Methods:

• Whole-exome sequencing was performed on 19 unrelated patients with unexplained colonic polyposis.
• Candidate genes were validated in an additional cohort of 365 patients.
• CRISPR-Cas9 gene editing models were utilized to assess the functional impact of BMPR2 variants.

Main Results:

• Six distinct variants in the BMPR2 gene were identified in 8 individuals (approximately 2% of the cohort).
• A truncating BMPR2 variant (p.(Asn442Thrfs*32)) completely abolished BMP pathway function.
• Missense BMPR2 variants (p.(Asn565Ser), p.(Ser967Pro)) demonstrated varying impacts on cell proliferation and control.

Conclusions:

• Loss-of-function BMPR2 variants are strong candidates for involvement in hereditary colorectal cancer predisposition.
• BMPR2 mutations may contribute to a subset of unexplained familial colorectal cancer cases.
• Further research into BMPR2's role in CRC pathogenesis is warranted.