A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene
dc.contributor.author | Fierheller, CT | |
dc.contributor.author | Guitton-Sert, L | |
dc.contributor.author | Alenezi, WM | |
dc.contributor.author | Revil, T | |
dc.contributor.author | Oros, KK | |
dc.contributor.author | Gao, Y | |
dc.contributor.author | Bedard, K | |
dc.contributor.author | Arcand, SL | |
dc.contributor.author | Serruya, C | |
dc.contributor.author | Behl, S | |
dc.contributor.author | Meunier, L | |
dc.contributor.author | Fleury, H | |
dc.contributor.author | Fewings, E | |
dc.contributor.author | Subramanian, DN | |
dc.contributor.author | Nadaf, J | |
dc.contributor.author | Bruce, JP | |
dc.contributor.author | Bell, R | |
dc.contributor.author | Provencher, D | |
dc.contributor.author | Foulkes, WD | |
dc.contributor.author | El Haffaf, Z | |
dc.contributor.author | Mes-Masson, A-M | |
dc.contributor.author | Majewski, J | |
dc.contributor.author | Pugh, TJ | |
dc.contributor.author | Tischkowitz, M | |
dc.contributor.author | James, PA | |
dc.contributor.author | Campbell, IG | |
dc.contributor.author | Greenwood, CMT | |
dc.contributor.author | Ragoussis, J | |
dc.contributor.author | Masson, J-Y | |
dc.contributor.author | Tonin, PN | |
dc.date.accessioned | 2024-01-11T13:31:54Z | |
dc.date.available | 2021-10-27 | |
dc.date.available | 2024-01-11T13:31:54Z | |
dc.date.issued | 2021-12-03 | |
dc.identifier.uri | https://qmro.qmul.ac.uk/xmlui/handle/123456789/93789 | |
dc.description.abstract | BACKGROUND: Familial ovarian cancer (OC) cases not harbouring pathogenic variants in either of the BRCA1 and BRCA2 OC-predisposing genes, which function in homologous recombination (HR) of DNA, could involve pathogenic variants in other DNA repair pathway genes. METHODS: Whole exome sequencing was used to identify rare variants in HR genes in a BRCA1 and BRCA2 pathogenic variant negative OC family of French Canadian (FC) ancestry, a population exhibiting genetic drift. OC cases and cancer-free individuals from FC and non-FC populations were investigated for carrier frequency of FANCI c.1813C>T; p.L605F, the top-ranking candidate. Gene and protein expression were investigated in cancer cell lines and tissue microarrays, respectively. RESULTS: In FC subjects, c.1813C>T was more common in familial (7.1%, 3/42) than sporadic (1.6%, 7/439) OC cases (P = 0.048). Carriers were detected in 2.5% (74/2950) of cancer-free females though female/male carriers were more likely to have a first-degree relative with OC (121/5249, 2.3%; Spearman correlation = 0.037; P = 0.011), suggesting a role in risk. Many of the cancer-free females had host factors known to reduce risk to OC which could influence cancer risk in this population. There was an increased carrier frequency of FANCI c.1813C>T in BRCA1 and BRCA2 pathogenic variant negative OC families, when including the discovery family, compared to cancer-free females (3/23, 13%; OR = 5.8; 95%CI = 1.7-19; P = 0.005). In non-FC subjects, 10 candidate FANCI variants were identified in 4.1% (21/516) of Australian OC cases negative for pathogenic variants in BRCA1 and BRCA2, including 10 carriers of FANCI c.1813C>T. Candidate variants were significantly more common in familial OC than in sporadic OC (P = 0.04). Localization of FANCD2, part of the FANCI-FANCD2 (ID2) binding complex in the Fanconi anaemia (FA) pathway, to sites of induced DNA damage was severely impeded in cells expressing the p.L605F isoform. This isoform was expressed at a reduced level, destabilized by DNA damaging agent treatment in both HeLa and OC cell lines, and exhibited sensitivity to cisplatin but not to a poly (ADP-ribose) polymerase inhibitor. By tissue microarray analyses, FANCI protein was consistently expressed in fallopian tube epithelial cells and only expressed at low-to-moderate levels in 88% (83/94) of OC samples. CONCLUSIONS: This is the first study to describe candidate OC variants in FANCI, a member of the ID2 complex of the FA DNA repair pathway. Our data suggest that pathogenic FANCI variants may modify OC risk in cancer families. | en_US |
dc.format.extent | 186 - ? | |
dc.language | eng | |
dc.publisher | BMC | en_US |
dc.relation.ispartof | Genome Med | |
dc.rights | Attribution 3.0 United States | * |
dc.rights.uri | http://creativecommons.org/licenses/by/3.0/us/ | * |
dc.subject | Cancer-predisposing gene | en_US |
dc.subject | DNA repair | en_US |
dc.subject | FANCI | en_US |
dc.subject | Familial aggregation of cancer | en_US |
dc.subject | Fanconi anaemia pathway | en_US |
dc.subject | Hereditary cancer | en_US |
dc.subject | Ovarian cancer | en_US |
dc.subject | Protein expression | en_US |
dc.subject | Tissue microarray | en_US |
dc.subject | Whole exome sequencing | en_US |
dc.subject | BRCA1 Protein | en_US |
dc.subject | BRCA2 Protein | en_US |
dc.subject | Breast Neoplasms | en_US |
dc.subject | Canada | en_US |
dc.subject | Fanconi Anemia Complementation Group Proteins | en_US |
dc.subject | Female | en_US |
dc.subject | Genetic Predisposition to Disease | en_US |
dc.subject | Humans | en_US |
dc.subject | Male | en_US |
dc.subject | Ovarian Neoplasms | en_US |
dc.title | A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene | en_US |
dc.type | Article | en_US |
dc.identifier.doi | 10.1186/s13073-021-00998-5 | |
pubs.author-url | https://www.ncbi.nlm.nih.gov/pubmed/34861889 | en_US |
pubs.issue | 1 | en_US |
pubs.notes | Not known | en_US |
pubs.publication-status | Published online | en_US |
pubs.volume | 13 | en_US |
dcterms.dateAccepted | 2021-10-27 | |
rioxxterms.funder | Default funder | en_US |
rioxxterms.identifier.project | Default project | en_US |
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