Genetic analyses of DNA repair pathway associated genes implicate new candidate cancer predisposing genes in ancestrally defined ovarian cancer cases

Wejdan M Alenezi; Caitlin T Fierheller; Corinne Serruya; Timothée Revil; Kathleen K Oros; Deepak N Subramanian; Jeffrey Bruce; Dan Spiegelman; Trevor Pugh; Ian G Campbell; Anne-Marie Mes-Masson; Diane Provencher; William D Foulkes; Zaki El Haffaf; Guy Rouleau; Luigi Bouchard; Celia M T Greenwood; Jiannis Ragoussis; Patricia N Tonin

doi:10.3389/fonc.2023.1111191

Genetic analyses of DNA repair pathway associated genes implicate new candidate cancer predisposing genes in ancestrally defined ovarian cancer cases

Front Oncol. 2023 Mar 8:13:1111191. doi: 10.3389/fonc.2023.1111191. eCollection 2023.

Authors

Wejdan M Alenezi^{1

2

3}, Caitlin T Fierheller^{1

2}, Corinne Serruya², Timothée Revil^{1

4}, Kathleen K Oros⁵, Deepak N Subramanian⁶, Jeffrey Bruce⁷, Dan Spiegelman^{1

8}, Trevor Pugh^{7

9

10}, Ian G Campbell^{6

11}, Anne-Marie Mes-Masson^{12

13}, Diane Provencher^{12

14}, William D Foulkes^{1

2

5

15

16

17}, Zaki El Haffaf^{12

18}, Guy Rouleau^{1

8}, Luigi Bouchard^{19

20

21}, Celia M T Greenwood^{1

5

17

22}, Jiannis Ragoussis^{1

4}, Patricia N Tonin^{1

2

16}

Affiliations

¹ Department of Human Genetics, McGill University, Montreal, QC, Canada.
² Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC, Canada.
³ Department of Medical Laboratory Technology, Taibah University, Medina, Saudi Arabia.
⁴ McGill Genome Centre, McGill University, Montreal, QC, Canada.
⁵ Lady Davis Institute for Medical Research of the Jewish General Hospital, Montreal, QC, Canada.
⁶ Cancer Genetics Laboratory, Peter MacCallum Cancer Centre, Melbourne, VIC, Australia.
⁷ Princess Margaret Cancer Centre, University Health Network, Toronto, ON, Canada.
⁸ Montreal Neurological Institute, McGill University, Montreal, QC, Canada.
⁹ Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada.
¹⁰ Ontario Institute for Cancer Research, Toronto, ON, Canada.
¹¹ Sir Peter MacCallum Department of Oncology, University of Melbourne, Melbourne, VIC, Australia.
¹² Centre de recherche du Centre hospitalier de l'Université de Montréal and Institut du cancer de Montréal, Montreal, QC, Canada.
¹³ Departement of Medicine, Université de Montréal, Montreal, QC, Canada.
¹⁴ Division of Gynecologic Oncology, Université de Montréal, Montreal, QC, Canada.
¹⁵ Department of Medical Genetics, McGill University Health Centre, Montreal, QC, Canada.
¹⁶ Department of Medicine, McGill University, Montreal, QC, Canada.
¹⁷ Gerald Bronfman Department of Oncology, McGill University, Montreal, QC, Canada.
¹⁸ Service de Médecine Génique, Centre Hospitalier de l'Université de Montréal, Montreal, QC, Canada.
¹⁹ Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, QC, Canada.
²⁰ Department of Medical Biology, Centres intégrés universitaires de santé et de services sociaux du Saguenay-Lac-Saint-Jean hôpital Universitaire de Chicoutimi, Saguenay, QC, Canada.
²¹ Centre de Recherche du Centre hospitalier l'Université de Sherbrooke, Sherbrooke, QC, Canada.
²² Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC, Canada.

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: DNA repair pathways; Genetic drift; cancer predisposing genes; familial ovarian cancer; germline variants; whole exome sequencing.

Grants and funding

The work was supported in part by the Department of Medicine, McGill University to PT; Saudi Arabian Cultural Bureau to PT and WA; The Canadian Institute for Health Research (CIHR) operating grants (PCC-156736 to PT, CG and JR) and (PJT-156124 to PT and JR); Cancer Research Society and Ovarian Cancer Canada partnership grant (21123 to PT); Department of Medicine, McGill University Grant to PT; the Fond de la recherche du Québec en santé (FRQS) and Quebec Breast Cancer Foundation network grants to PT; Compute Canada resource allocation project wst-164 and Genome Canada Genome Technology Platform award to JR; Institut du cancer de Montréal Fonds Défi Spyder and Anne-Marie Chagnon which covers funds from platform to DP and A-MM-M; Gen3G has been supported over the time by FRQS grant (20697 to Marie-France Hivert); CIHR grant (MOP-115071 to Dr. Marie-France Hivert) and (PJT-152989 to LB); American Diabetes Association (ADA) accelerator award (1-15-ACE-26 to Marie-France Hivert). LB is a senior research scholar from FRQS. The sequencing of the Gen3G offspring has been sponsored by Fonds de recherche du Québec, McGill University and Université de Sherbrooke. Ovarian tumour banking was supported by the Banque de tissus et de données of the Réseau de recherche sur le cancer of the FRQS affiliated with the Canadian Tumour Repository Network (CTRNet). WA was supported by a Scholarship Award by Ministry of Education in Saudi Arabia and CF was supported in part by RI-MUHC Scholarship Award and James O and Maria Meadows Award.