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

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.

Rare Germline Genetic Variants and the Risks of Epithelial Ovarian Cancer

“…Prospective population-based studies, which have been used to provide gold-standard estimates of lifetime cancer risk in BRCA1 , BRCA2 , and the mismatch repair genes, would provide more accurate risk estimates for moderate penetrance ovarian cancer genes, but are costly, and require long-term investment. Segregation analysis from large international consortia has been used to calculate ovarian cancer risks in RAD51C , RAD51D , and PALB2 , and could be applied to other moderate risk ovarian cancer genes [ 10 , 12 ].…”

“…More recently, Yang et al performed a study of 125 families with pathogenic variants in RAD51C and 60 families with pathogenic variants in RAD51D and confirmed an increased risk of ovarian cancer associated with pathogenic variants in both genes ( RAD51C , RR 7.55, 95% CI 5.6–10.2 and RAD51D , RR 7.6, 95% CI 5.6–10.3) [ 10 ]. The cumulative risk of having ovarian cancer by age 80 was estimated to be 11% (95% CI 6–21%) for RAD51C and 13% (95% CI 7–23%) for RAD51D based on their segregation analysis [ 10 ] ( Table 3 ). RAD51C/D were also shown to be associated with breast cancer with cumulative risk of 21% (95% CI 15–29%) and 20% (95% CI 14–28%) for these genes by the age of 80 years, respectively [ 10 ].…”

“…The cumulative risk of having ovarian cancer by age 80 was estimated to be 11% (95% CI 6–21%) for RAD51C and 13% (95% CI 7–23%) for RAD51D based on their segregation analysis [ 10 ] ( Table 3 ). RAD51C/D were also shown to be associated with breast cancer with cumulative risk of 21% (95% CI 15–29%) and 20% (95% CI 14–28%) for these genes by the age of 80 years, respectively [ 10 ].…”

“…EOC BRCA1/2 from ref [ 33 ], MMR from ref [ 33 ], BRIP1 from ref [ 11 ], RAD51C/D from ref [ 48 ], PALB2 from ref [ 54 ]. BC BRCA1/2 from ref [ 9 ], RAD51C/D from ref [ 10 ], PALB2 from ref [ 12 ], CHEK2/ATM/NBN from ref [ 84 ]. $ BRCA1/2 from refs [ 39 , 85 ], MMR from ref [ 13 ], BRIP1/RAD51C/D from ref [ 49 ], PALB2/CHEK2/ATM/NBN from refs [ 77 , 84 ].…”

“…BRCA1 and BRCA2 have been confirmed as highly penetrant predisposition genes for EOC [ 9 ]. Several other genes— BRIP1 , RAD51C , RAD51D , and PALB2 , recently described as moderate risk genes, are also part of this pathway [ 10 , 11 , 12 ]. The mismatch repair genes MLH1 , MSH2 , MSH6 , and PSM2 are also confirmed moderate risk EOC susceptibility genes [ 13 ].…”