BMPR2 as a Novel Predisposition Gene for Hereditary Colorectal Polyposis.
BMP Pathway
CRISPR-Cas9
Colorectal Cancer
Germline Predisposition
Whole-Exome Sequencing
Journal
Gastroenterology
ISSN: 1528-0012
Titre abrégé: Gastroenterology
Pays: United States
ID NLM: 0374630
Informations de publication
Date de publication:
Jul 2023
Jul 2023
Historique:
received:
08
11
2022
revised:
27
02
2023
accepted:
05
03
2023
medline:
26
6
2023
pubmed:
13
3
2023
entrez:
12
3
2023
Statut:
ppublish
Résumé
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. 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. 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. Collectively, these results support loss-of-function BMPR2 variants as candidates to be involved in CRC germline predisposition.
Sections du résumé
BACKGROUND & AIMS
OBJECTIVE
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
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
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
CONCLUSIONS
Collectively, these results support loss-of-function BMPR2 variants as candidates to be involved in CRC germline predisposition.
Identifiants
pubmed: 36907526
pii: S0016-5085(23)00259-7
doi: 10.1053/j.gastro.2023.03.006
pii:
doi:
Substances chimiques
BMPR2 protein, human
EC 2.7.11.30
Bone Morphogenetic Protein Receptors, Type II
EC 2.7.11.30
Types de publication
Journal Article
Langues
eng
Sous-ensembles de citation
IM
Pagination
162-172.e5Commentaires et corrections
Type : ErratumIn
Informations de copyright
Copyright © 2023 The Authors. Published by Elsevier Inc. All rights reserved.