The Genetic and Molecular Analyses of RAD51C and RAD51D Identifies Rare Variants Implicated in Hereditary Ovarian Cancer from a Genetically Unique Population
by
, , , , , , , and
Wejdan M. Alenezi
1,2,3
,
Larissa Milano
4,5,
Caitlin T. Fierheller
1,2,
Corinne Serruya
2,
Timothée Revil
1,6,
Kathleen K. Oros
7,
Supriya Behl
1,2,
Suzanna L. Arcand
2,
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 and
Patricia N. Tonin
1,2,14,*add
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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
*
Author to whom correspondence should be addressed.
Cancers 2022, 14(9), 2251; https://doi.org/10.3390/cancers14092251
Submission received: 18 March 2022
/
Revised: 13 April 2022
/
Accepted: 20 April 2022
/
Published: 30 April 2022
(This article belongs to the Special Issue New Insights into Hereditary Cancer Syndromes)
Simple Summary
We have investigated RAD51C and RAD51D, hereditary ovarian cancer risk genes, in French Canadians of Quebec, Canada. This population of Western European origins exhibits a unique genetic landscape as shown by the frequency of carriers of specific rare pathogenic variants. As studying French Canadians could facilitate the identification and interpretation of clinically relevant variants, we performed genetic analyses of RAD51C and RAD51D in this population comprised of cases with a family history of ovarian cancer or those who developed it at a young age. We identified candidate variants and then investigated them in other French Canadian study groups. We performed biological assays and revealed possible mechanisms that would affect gene function. Using engineered cells expressing one of our protein variants, we also showed that they were more sensitive to a recently approved treatment for ovarian cancer. Our findings support the role of inherited variants in RAD51C and RAD51D in ovarian cancer.
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.
