Frontiers in Oncology (Mar 2023)
Genetic analyses of DNA repair pathway associated genes implicate new candidate cancer predisposing genes in ancestrally defined ovarian cancer cases
- Wejdan M. Alenezi,
- Wejdan M. Alenezi,
- Wejdan M. Alenezi,
- Caitlin T. Fierheller,
- Caitlin T. Fierheller,
- Corinne Serruya,
- Timothée Revil,
- Timothée Revil,
- Kathleen K. Oros,
- Deepak N. Subramanian,
- Jeffrey Bruce,
- Dan Spiegelman,
- Dan Spiegelman,
- Trevor Pugh,
- Trevor Pugh,
- Trevor Pugh,
- Ian G. Campbell,
- Ian G. Campbell,
- Anne-Marie Mes-Masson,
- Anne-Marie Mes-Masson,
- Diane Provencher,
- Diane Provencher,
- William D. Foulkes,
- William D. Foulkes,
- William D. Foulkes,
- William D. Foulkes,
- William D. Foulkes,
- William D. Foulkes,
- Zaki El Haffaf,
- Zaki El Haffaf,
- Guy Rouleau,
- Guy Rouleau,
- Luigi Bouchard,
- Luigi Bouchard,
- Luigi Bouchard,
- Celia M. T. Greenwood,
- Celia M. T. Greenwood,
- Celia M. T. Greenwood,
- Celia M. T. Greenwood,
- Jiannis Ragoussis,
- Jiannis Ragoussis,
- Patricia N. Tonin,
- Patricia N. Tonin,
- Patricia N. Tonin
Affiliations
- Wejdan M. Alenezi
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Wejdan M. Alenezi
- Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC, Canada
- Wejdan M. Alenezi
- Department of Medical Laboratory Technology, Taibah University, Medina, Saudi Arabia
- Caitlin T. Fierheller
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Caitlin T. Fierheller
- Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC, Canada
- Corinne Serruya
- Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC, Canada
- Timothée Revil
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Timothée Revil
- McGill Genome Centre, McGill University, Montreal, QC, Canada
- Kathleen K. Oros
- Lady Davis Institute for Medical Research of the Jewish General Hospital, Montreal, QC, Canada
- Deepak N. Subramanian
- Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Jeffrey Bruce
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Dan Spiegelman
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Dan Spiegelman
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- Trevor Pugh
- Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada
- Trevor Pugh
- Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
- Trevor Pugh
- 0Ontario Institute for Cancer Research, Toronto, ON, Canada
- Ian G. Campbell
- Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia
- Ian G. Campbell
- 1Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia
- Anne-Marie Mes-Masson
- 2Centre de recherche du Centre hospitalier de l’Université de Montréal and Institut du cancer de Montréal, Montreal, QC, Canada
- Anne-Marie Mes-Masson
- 3Departement of Medicine, Université de Montréal, Montreal, QC, Canada
- Diane Provencher
- 2Centre de recherche du Centre hospitalier de l’Université de Montréal and Institut du cancer de Montréal, Montreal, QC, Canada
- Diane Provencher
- 4Division of Gynecologic Oncology, Université de Montréal, Montreal, QC, Canada
- William D. Foulkes
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- William D. Foulkes
- Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC, Canada
- William D. Foulkes
- Lady Davis Institute for Medical Research of the Jewish General Hospital, Montreal, QC, Canada
- William D. Foulkes
- 5Department of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada
- William D. Foulkes
- 6Department of Medicine, McGill University, Montreal, QC, Canada
- William D. Foulkes
- 7Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada
- Zaki El Haffaf
- 2Centre de recherche du Centre hospitalier de l’Université de Montréal and Institut du cancer de Montréal, Montreal, QC, Canada
- Zaki El Haffaf
- 8Service de Médecine Génique, Centre Hospitalier de l’Université de Montréal, Montreal, QC, Canada
- Guy Rouleau
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Guy Rouleau
- Montreal Neurological Institute, McGill University, Montreal, QC, Canada
- Luigi Bouchard
- 9Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, QC, Canada
- Luigi Bouchard
- 0Department of Medical Biology, Centres intégrés universitaires de santé et de services sociaux du Saguenay-Lac-Saint-Jean hôpital Universitaire de Chicoutimi, Saguenay, QC, Canada
- Luigi Bouchard
- 1Centre de Recherche du Centre hospitalier l’Université de Sherbrooke, Sherbrooke, QC, Canada
- Celia M. T. Greenwood
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Celia M. T. Greenwood
- Lady Davis Institute for Medical Research of the Jewish General Hospital, Montreal, QC, Canada
- Celia M. T. Greenwood
- 7Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada
- Celia M. T. Greenwood
- 2Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada
- Jiannis Ragoussis
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Jiannis Ragoussis
- McGill Genome Centre, McGill University, Montreal, QC, Canada
- Patricia N. Tonin
- Department of Human Genetics, McGill University, Montreal, QC, Canada
- Patricia N. Tonin
- Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC, Canada
- Patricia N. Tonin
- 6Department of Medicine, McGill University, Montreal, QC, Canada
- DOI
- https://doi.org/10.3389/fonc.2023.1111191
- Journal volume & issue
-
Vol. 13
Abstract
Not all familial ovarian cancer (OC) cases are explained by pathogenic germline variants in known risk genes. A candidate gene approach involving DNA repair pathway genes was applied to identify rare recurring pathogenic variants in familial OC cases not associated with known OC risk genes from a population exhibiting genetic drift. Whole exome sequencing (WES) data of 15 OC cases from 13 families tested negative for pathogenic variants in known OC risk genes were investigated for candidate variants in 468 DNA repair pathway genes. Filtering and prioritization criteria were applied to WES data to select top candidates for further analyses. Candidates were genotyped in ancestry defined study groups of 214 familial and 998 sporadic OC or breast cancer (BC) cases and 1025 population-matched controls and screened for additional carriers in 605 population-matched OC cases. The candidate genes were also analyzed in WES data from 937 familial or sporadic OC cases of diverse ancestries. Top candidate variants in ERCC5, EXO1, FANCC, NEIL1 and NTHL1 were identified in 5/13 (39%) OC families. Collectively, candidate variants were identified in 7/435 (1.6%) sporadic OC cases and 1/566 (0.2%) sporadic BC cases versus 1/1025 (0.1%) controls. Additional carriers were identified in 6/605 (0.9%) OC cases. Tumour DNA from ERCC5, NEIL1 and NTHL1 variant carriers exhibited loss of the wild-type allele. Carriers of various candidate variants in these genes were identified in 31/937 (3.3%) OC cases of diverse ancestries versus 0-0.004% in cancer-free controls. The strategy of applying a candidate gene approach in a population exhibiting genetic drift identified new candidate OC predisposition variants in DNA repair pathway genes.
Keywords
- germline variants
- familial ovarian cancer
- cancer predisposing genes
- whole exome sequencing
- DNA repair pathways
- Genetic drift
