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Ovarian and Breast Cancer Risks Associated With Pathogenic Variants in RAD51C and RAD51D.

Accepted version
Peer-reviewed

Type

Article

Change log

Authors

Yang, Xin 
Song, Honglin 
Engel, Christoph 
Hahnen, Eric 

Abstract

BACKGROUND: The purpose of this study was to estimate precise age-specific tubo-ovarian carcinoma (TOC) and breast cancer (BC) risks for carriers of pathogenic variants in RAD51C and RAD51D. METHODS: We analyzed data from 6178 families, 125 with pathogenic variants in RAD51C, and 6690 families, 60 with pathogenic variants in RAD51D. TOC and BC relative and cumulative risks were estimated using complex segregation analysis to model the cancer inheritance patterns in families while adjusting for the mode of ascertainment of each family. All statistical tests were two-sided. RESULTS: Pathogenic variants in both RAD51C and RAD51D were associated with TOC (RAD51C: relative risk [RR] = 7.55, 95% confidence interval [CI] = 5.60 to 10.19; P = 5 × 10-40; RAD51D: RR = 7.60, 95% CI = 5.61 to 10.30; P = 5 × 10-39) and BC (RAD51C: RR = 1.99, 95% CI = 1.39 to 2.85; P = 1.55 × 10-4; RAD51D: RR = 1.83, 95% CI = 1.24 to 2.72; P = .002). For both RAD51C and RAD51D, there was a suggestion that the TOC relative risks increased with age until around age 60 years and decreased thereafter. The estimated cumulative risks of developing TOC to age 80 years were 11% (95% CI = 6% to 21%) for RAD51C and 13% (95% CI = 7% to 23%) for RAD51D pathogenic variant carriers. The estimated cumulative risks of developing BC to 80 years were 21% (95% CI = 15% to 29%) for RAD51C and 20% (95% CI = 14% to 28%) for RAD51D pathogenic variant carriers. Both TOC and BC risks for RAD51C and RAD51D pathogenic variant carriers varied by cancer family history and could be as high as 32-36% for TOC, for carriers with two first-degree relatives diagnosed with TOC, or 44-46% for BC, for carriers with two first-degree relatives diagnosed with BC. CONCLUSIONS: These estimates will facilitate the genetic counseling of RAD51C and RAD51D pathogenic variant carriers and justify the incorporation of RAD51C and RAD51D into cancer risk prediction models.

Description

Keywords

Adolescent, Adult, Aged, Aged, 80 and over, Breast Neoplasms, DNA-Binding Proteins, Female, Genetic Association Studies, Genetic Predisposition to Disease, Genetic Testing, Germ-Line Mutation, Heterozygote, Humans, Middle Aged, Ovarian Neoplasms, Risk Factors, Young Adult

Journal Title

J Natl Cancer Inst

Conference Name

Journal ISSN

0027-8874
1460-2105

Volume Title

112

Publisher

Oxford University Press (OUP)

Rights

All rights reserved
Sponsorship
Cancer Research UK (20861)
European Research Council (310018)
Cancer Research UK (via Institute of Cancer Research (ICR)) (DGECATAAL)
National Cancer Institute (R01CA178535)
European Commission Horizon 2020 (H2020) Societal Challenges (634935)