Molecular Genetic Characteristics of FANCI , a Proposed New Ovarian Cancer Predisposing Gene.

Autor: Fierheller CT; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Alenezi WM; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.; Department of Medical Laboratory Technology, Taibah University, Medina 42353, Saudi Arabia., Serruya C; Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada., Revil T; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; McGill Genome Centre, McGill University, Montreal, QC H3A 0G1, Canada., Amuzu S; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; McGill Genome Centre, McGill University, Montreal, QC H3A 0G1, Canada., Bedard K; Laboratoire de Diagnostic Moléculaire, Centre Hospitalier de l'Université de Montréal (CHUM), Montreal, QC H2X 3E4, Canada.; Département de Pathologie et Biologie Cellulaire, Université de Montréal, Montreal, QC H3T 1J4, Canada., Subramanian DN; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia., Fewings E; Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 1TN, UK., Bruce JP; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Prokopec S; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Bouchard L; Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada.; Department of Medical Biology, Centres Intégrés Universitaires de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean Hôpital Universitaire de Chicoutimi, Saguenay, QC G7H 7K9, Canada.; Centre de Recherche du Centre Hospitalier l'Université de Sherbrooke, Sherbrooke, QC J1K 2R1, Canada., Provencher D; Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Montreal, QC H2X 0A9, Canada.; Division of Gynecologic Oncology, Université de Montréal, Montreal, QC H3T 1J4, Canada., Foulkes WD; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.; Department of Medicine, McGill University, Montreal, QC H3G 2M1, Canada., El Haffaf Z; Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X 0A9, Canada., Mes-Masson AM; Centre de Recherche du Centre Hospitalier de l'Université de Montréal and Institut du Cancer de Montréal, Montreal, QC H2X 0A9, Canada.; Department of Medicine, Université de Montréal, Montreal, QC H3T 1J4, Canada., Tischkowitz M; Department of Medical Genetics, National Institute for Health Research Cambridge Biomedical Research Centre, University of Cambridge, Cambridge CB2 1TN, UK., Campbell IG; Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC 3000, Australia.; Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC 3010, Australia., Pugh TJ; Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2C1, Canada., Greenwood CMT; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T 1E2, Canada.; Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H4A 3T2, Canada.; Department of Epidemiology, Biostatistics & Occupational Health, McGill University, Montreal, QC H3A 1Y7, Canada., Ragoussis J; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; McGill Genome Centre, McGill University, Montreal, QC H3A 0G1, Canada., Tonin PN; Department of Human Genetics, McGill University, Montreal, QC H3A 0C7, Canada.; Cancer Research Program, The Research Institute of the McGill University Health Centre, Montreal, QC H4A 3J1, Canada.; Department of Medicine, McGill University, Montreal, QC H3G 2M1, Canada.
Jazyk: angličtina
Zdroj: Genes [Genes (Basel)] 2023 Jan 20; Vol. 14 (2). Date of Electronic Publication: 2023 Jan 20.
DOI: 10.3390/genes14020277
Abstrakt: FANCI was recently identified as a new candidate ovarian cancer (OC)-predisposing gene from the genetic analysis of carriers of FANCI c.1813C>T; p.L605F in OC families. Here, we aimed to investigate the molecular genetic characteristics of FANCI, as they have not been described in the context of cancer. We first investigated the germline genetic landscape of two sisters with OC from the discovery FANCI c.1813C>T; p.L605F family (F1528) to re-affirm the plausibility of this candidate. As we did not find other conclusive candidates, we then performed a candidate gene approach to identify other candidate variants in genes involved in the FANCI protein interactome in OC families negative for pathogenic variants in BRCA1 , BRCA2 , BRIP1 , RAD51C , RAD51D , and FANCI , which identified four candidate variants. We then investigated FANCI in high-grade serous ovarian carcinoma (HGSC) from FANCI c.1813C>T carriers and found evidence of loss of the wild-type allele in tumour DNA from some of these cases. The somatic genetic landscape of OC tumours from FANCI c.1813C>T carriers was investigated for mutations in selected genes, copy number alterations, and mutational signatures, which determined that the profiles of tumours from carriers were characteristic of features exhibited by HGSC cases. As other OC-predisposing genes such as BRCA1 and BRCA2 are known to increase the risk of other cancers including breast cancer, we investigated the carrier frequency of germline FANCI c.1813C>T in various cancer types and found overall more carriers among cancer cases compared to cancer-free controls ( p = 0.007). In these different tumour types, we also identified a spectrum of somatic variants in FANCI that were not restricted to any specific region within the gene. Collectively, these findings expand on the characteristics described for OC cases carrying FANCI c.1813C>T; p.L605F and suggest the possible involvement of FANCI in other cancer types at the germline and/or somatic level.
Databáze: MEDLINE