The Genetic and Molecular Analyses of RAD51C and RAD51D Identifies Rare Variants Implicated in Hereditary Ovarian Cancer from a Genetically Unique Population

Wejdan M Alenezi; Larissa Milano; Caitlin T Fierheller; Corinne Serruya; Timothée Revil; Kathleen K Oros; Supriya Behl; Suzanna L Arcand; Porangana Nayar; Dan Spiegelman; Simon Gravel; Anne-Marie Mes-Masson; Diane Provencher; William D Foulkes; Zaki El Haffaf; Guy Rouleau; Luigi Bouchard; Celia M T Greenwood; Jean-Yves Masson; Jiannis Ragoussis; Patricia N Tonin

doi:10.3390/cancers14092251

The Genetic and Molecular Analyses of RAD51C and RAD51D Identifies Rare Variants Implicated in Hereditary Ovarian Cancer from a Genetically Unique Population

Cancers (Basel). 2022 Apr 30;14(9):2251. doi: 10.3390/cancers14092251.

Authors

Wejdan M Alenezi^{1

2

3}, Larissa Milano^{4

5}, Caitlin T Fierheller^{1

2}, Corinne Serruya², Timothée Revil^{1

6}, Kathleen K Oros⁷, Supriya Behl^{1

2}, Suzanna L Arcand², Porangana Nayar^{2

8}, Dan Spiegelman^{1

9}, Simon Gravel^{1

6}, Anne-Marie Mes-Masson^{10

11}, Diane Provencher^{10

12}, William D Foulkes^{1

2

7

13

14

15}, Zaki El Haffaf^{10

16}, Guy Rouleau^{1

9}, Luigi Bouchard^{17

18

19}, Celia M T Greenwood^{1

7

15

20}, Jean-Yves Masson^{4

5}, Jiannis Ragoussis^{1

6}, Patricia N Tonin^{1

2

14}

Affiliations

¹ Department of Human Genetics, McGill University, Montreal, QC H3A0C7, Canada.
² Cancer Research Program, Centre for Translational Biology, The Research Institute of McGill University Health Centre, Montreal, QC H4A3J1, Canada.
³ Department of Medical Laboratory Technology, Taibah University, Medina 42353, Saudi Arabia.
⁴ Department of Molecular Biology, Medical Biochemistry and Pathology, Laval University, Quebec City, QC G1V0A6, Canada.
⁵ Genome Stability Laboratory, Centre de Recherche du Centre Hospitalier de l'Université de Québec, HDQ Pavilion, Oncology Axis, Quebec City, QC G1R2J6, Canada.
⁶ McGill Genome Centre, McGill University, Montreal, QC H3A0G1, Canada.
⁷ Lady Davis Institute for Medical Research, Jewish General Hospital, Montreal, QC H3T1E2, Canada.
⁸ Institute of Parasitology, McGill University, Montreal, QC H9X3V9, Canada.
⁹ Montreal Neurological Institute, McGill University, Montreal, QC H3A2B4, Canada.
¹⁰ Institut du Cancer de Montréal, Centre de Recherche du Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X0A9, Canada.
¹¹ Département de Médecine, Université de Montréal, Montreal, QC H3T1J4, Canada.
¹² Division of Gynecologic Oncology, Université de Montréal, Montreal, QC H4A3J1, Canada.
¹³ Department of Medical Genetics, McGill University Health Centre, Montreal, QC H4A3J1, Canada.
¹⁴ Department of Medicine, McGill University, Montreal, QC H3G2M1, Canada.
¹⁵ Gerald Bronfman Department of Oncology, McGill University, Montreal, QC H3A1G5, Canada.
¹⁶ Service de Médecine Geénique, Centre Hospitalier de l'Université de Montréal, Montreal, QC H2X0A9, Canada.
¹⁷ Department of Biochemistry and Functional Genomics, Université de Sherbrooke, Sherbrooke, QC J1K2R1, Canada.
¹⁸ Department of Medical Biology, Centres Intégrés Universitaires de Santé et de Services Sociaux du Saguenay-Lac-Saint-Jean Hôpital Universitaire de Chicoutimi, Saguenay, QC G7H7K9, Canada.
¹⁹ Centre de Recherche du Centre Hospitalier l'Université de Sherbrooke, Sherbrooke, QC J1H5N4, Canada.
²⁰ Department of Epidemiology, Biostatistics and Occupational Health, McGill University, Montreal, QC H3A1A2, Canada.

Abstract

To identify candidate variants in RAD51C and RAD51D ovarian cancer (OC) predisposing genes by investigating French Canadians (FC) exhibiting unique genetic architecture. Candidates were identified by whole exome sequencing analysis of 17 OC families and 53 early-onset OC cases. Carrier frequencies were determined by the genetic analysis of 100 OC or HBOC families, 438 sporadic OC cases and 1025 controls. Variants of unknown function were assayed for their biological impact and/or cellular sensitivity to olaparib. RAD51C c.414G>C;p.Leu138Phe and c.705G>T;p.Lys235Asn and RAD51D c.137C>G;p.Ser46Cys, c.620C>T;p.Ser207Leu and c.694C>T;p.Arg232Ter were identified in 17.6% of families and 11.3% of early-onset cases. The highest carrier frequency was observed in OC families (1/44, 2.3%) and sporadic cases (15/438, 3.4%) harbouring RAD51D c.620C>T versus controls (1/1025, 0.1%). Carriers of c.620C>T (n = 7), c.705G>T (n = 2) and c.137C>G (n = 1) were identified in another 538 FC OC cases. RAD51C c.705G>T affected splicing by skipping exon four, while RAD51D p.Ser46Cys affected protein stability and conferred olaparib sensitivity. Genetic and functional assays implicate RAD51C c.705G>T and RAD51D c.137C>G as likely pathogenic variants in OC. The high carrier frequency of RAD51D c.620C>T in FC OC cases validates previous findings. Our findings further support the role of RAD51C and RAD51D in hereditary OC.

Keywords: French Canadian; RAD51C; RAD51D; genetic drift; ovarian cancer predisposing genes.

Grants and funding

PJT-156124/CAPMC/ CIHR/Canada