A functionally impaired missense variant identified in French Canadian families implicates FANCI as a candidate ovarian cancer-predisposing gene.

Autor:	Fierheller CT; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.; Cancer Research Program, Centre for Translational Biology, The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3 J1, Canada., Guitton-Sert L; Genome Stability Laboratory, CHU de Québec-Université Laval Research Center, Oncology Division, Quebec City, Quebec, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Quebec City, Quebec, Canada., Alenezi WM; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.; Cancer Research Program, Centre for Translational Biology, The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3 J1, Canada.; Department of Medical Laboratory Technology, Taibah University, Medina, Saudi Arabia., Revil T; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.; McGill Genome Centre, McGill University, Montreal, Quebec, Canada., Oros KK; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada., Gao Y; Genome Stability Laboratory, CHU de Québec-Université Laval Research Center, Oncology Division, Quebec City, Quebec, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Quebec City, Quebec, Canada., Bedard K; Laboratoire de Diagnostic Moléculaire, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, Quebec, Canada.; Département de pathologie et biologie cellulaire, Université de Montréal, Montreal, Quebec, Canada., Arcand SL; Cancer Research Program, Centre for Translational Biology, The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3 J1, Canada., Serruya C; Cancer Research Program, Centre for Translational Biology, The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3 J1, Canada., Behl S; Department of Human Genetics, McGill University, Montreal, Quebec, Canada., Meunier L; Centre de recherche du Centre hospitalier de l'Université de Montréal and Institut du cancer de Montréal, Montreal, Quebec, Canada., Fleury H; Centre de recherche du Centre hospitalier de l'Université de Montréal and Institut du cancer de Montréal, Montreal, Quebec, Canada., Fewings E; Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK., Subramanian DN; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia., Nadaf J; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.; McGill Genome Centre, McGill University, Montreal, Quebec, Canada., Bruce JP; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Bell R; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada., Provencher D; Centre de recherche du Centre hospitalier de l'Université de Montréal and Institut du cancer de Montréal, Montreal, Quebec, Canada.; Division of Gynecologic Oncology, Université de Montréal, Montreal, Quebec, Canada., Foulkes WD; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.; Cancer Research Program, Centre for Translational Biology, The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3 J1, Canada.; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.; Department of Medicine, McGill University, Montreal, Quebec, Canada., El Haffaf Z; Centre de recherche du Centre Hospitalier de l'Université de Montréal, Montreal, Quebec, Canada., Mes-Masson AM; Centre de recherche du Centre hospitalier de l'Université de Montréal and Institut du cancer de Montréal, Montreal, Quebec, Canada.; Department of Medicine, Université de Montréal, Montreal, Quebec, Canada., Majewski J; Department of Human Genetics, McGill University, Montreal, Quebec, Canada., Pugh TJ; Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.; Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.; Ontario Institute for Cancer Research, Toronto, Ontario, Canada., Tischkowitz M; Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge, UK., James PA; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia.; The Parkville Familial Cancer Centre, Peter MacCallum Cancer Centre and The Royal Melbourne Hospital, Melbourne, Victoria, Australia., Campbell IG; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, Victoria, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, Victoria, Australia., Greenwood CMT; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, Quebec, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montreal, Quebec, Canada.; Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, Quebec, Canada., Ragoussis J; Department of Human Genetics, McGill University, Montreal, Quebec, Canada.; McGill Genome Centre, McGill University, Montreal, Quebec, Canada., Masson JY; Genome Stability Laboratory, CHU de Québec-Université Laval Research Center, Oncology Division, Quebec City, Quebec, Canada.; Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University Cancer Research Center, Quebec City, Quebec, Canada., Tonin PN; Department of Human Genetics, McGill University, Montreal, Quebec, Canada. patricia.tonin@mcgill.ca.; Cancer Research Program, Centre for Translational Biology, The Research Institute of the McGill University Health Centre, 1001 Decarie Boulevard, Montreal, Quebec, H4A 3 J1, Canada. patricia.tonin@mcgill.ca.; Department of Medicine, McGill University, Montreal, Quebec, Canada. patricia.tonin@mcgill.ca.
Jazyk:	angličtina
Zdroj:	Genome medicine [Genome Med] 2021 Dec 03; Vol. 13 (1), pp. 186. Date of Electronic Publication: 2021 Dec 03.
DOI:	10.1186/s13073-021-00998-5
Abstrakt:	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. (© 2021. The Author(s).)
Databáze:	MEDLINE
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