BMPR2 as a Novel Predisposition Gene for Hereditary Colorectal Polyposis.
BACKGROUND & AIMS: Colorectal cancer (CRC) is one of the most prevalent tumors worldwide, with incidence quickly increasing (particularly in the context of early-onset cases), despite important prevention efforts, mainly in the form of population-wide screening programs. Although many cases pres...
| Autores: | , , , , , , , , , , , , , , , |
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| Tipo de documento: | artigo |
| Estado: | Versão publicada |
| Data de publicação: | 2023 |
| País: | España |
| Recursos: | Instituto de Investigación Biomédica y Sanitaria de Alicante (ISABIAL) |
| Repositório: | r-ISABIAL. Repositorio Institucional de Producción Científica del Instituto de Investigación Biomédica y Sanitaria de Alicante |
| OAI Identifier: | oai:isabial.fundanetsuite.com:p9606 |
| Acesso em linha: | https://isabial.portalinvestigacion.com/publicaciones9606 https://www.sciencedirect.com/science/article/pii/S0016508523002597?via%3Dihub |
| Access Level: | Acceso aberto |
| Palavra-chave: | BMP Pathway CRISPR-Cas9 Colorectal Cancer Germline Predisposition Whole-Exome Sequencing |
| Resumo: | BACKGROUND & AIMS: Colorectal cancer (CRC) is one of the most prevalent tumors worldwide, with incidence quickly increasing (particularly in the context of early-onset cases), despite important prevention efforts, mainly in the form of population-wide screening programs. Although many cases present a clear familial component, the current list of hereditary CRC genes leaves a considerable proportion of the cases unexplained. METHODS: In this work, we used 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: We found 8 individuals carrying 6 different variants in the BMPR2 gene (approximately 2% of our cohort of patients with unexplained colonic polyposis). CRISPR-Cas9 models of 3 of these variants showed that the p.(Asn442Thrfs*32) truncating variant completely abrogated BMP pathway function in a similar way to the BMPR2 knockout. Missense variants p.(Asn565Ser), p.(Ser967Pro) had varying effects on cell proliferation levels, with the former impairing cell control inhibition via noncanonical pathways. CONCLUSIONS: Collectively, these results support loss-of-function BMPR2 variants as candidates to be involved in CRC germline predisposition. |
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