Dataset Information

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.

SUBMITTER: Yang X

PROVIDER: S-EPMC7735771 | biostudies-literature | 2020 Dec

REPOSITORIES: biostudies-literature

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Publications

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

Yang Xin X Song Honglin H Leslie Goska G Engel Christoph C Hahnen Eric E Auber Bernd B Horváth Judit J Kast Karin K Niederacher Dieter D Turnbull Clare C Houlston Richard R Hanson Helen H Loveday Chey C Dolinsky Jill S JS LaDuca Holly H Ramus Susan J SJ Menon Usha U Rosenthal Adam N AN Jacobs Ian I Gayther Simon A SA Dicks Ed E Nevanlinna Heli H Aittomäki Kristiina K Pelttari Liisa M LM Ehrencrona Hans H Borg Åke Å Kvist Anders A Rivera Barbara B Hansen Thomas V O TVO Djursby Malene M Lee Andrew A Dennis Joe J Bowtell David D DD Traficante Nadia N Diez Orland O Balmaña Judith J Gruber Stephen B SB Chenevix-Trench Georgia G Investigators kConFab K Jensen Allan A Kjær Susanne K SK Høgdall Estrid E Castéra Laurent L Garber Judy J Janavicius Ramunas R Osorio Ana A Golmard Lisa L Vega Ana A Couch Fergus J FJ Robson Mark M Gronwald Jacek J Domchek Susan M SM Culver Julie O JO de la Hoya Miguel M Easton Douglas F DF Foulkes William D WD Tischkowitz Marc M Meindl Alfons A Schmutzler Rita K RK Pharoah Paul D P PDP Antoniou Antonis C AC

Journal of the National Cancer Institute 20201201 12

<h4>Background</h4>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.<h4>Methods</h4>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 ad ...[more]

PMID: 32107557

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Project description:BackgroundClinical management of Asian BRCA1 and BRCA2 pathogenic variants (PV) carriers remains challenging due to imprecise age-specific breast (BC) and ovarian cancer (OC) risks estimates. We aimed to refine these estimates using six multi-ethnic studies in Asia.MethodsData were collected on 271 BRCA1 and 301 BRCA2 families from Malaysia and Singapore, ascertained through population/hospital-based case-series (88%) and genetic clinics (12%). Age-specific cancer risks were estimated using a modified segregation analysis method, adjusted for ascertainment.FindingsBC and OC relative risks (RRs) varied across age groups for both BRCA1 and BRCA2. The age-specific RR estimates were similar across ethnicities and country of residence. For BRCA1 carriers of Malay, Indian and Chinese ancestry born between 1950 and 1959 in Malaysia, the cumulative risk (95% CI) of BC by age 80 was 40% (36%-44%), 49% (44%-53%) and 55% (51%-60%), respectively. The corresponding estimates for BRCA2 were 29% (26-32%), 36% (33%-40%) and 42% (38%-45%). The corresponding cumulative BC risks for Singapore residents from the same birth cohort, where the underlying population cancer incidences are higher compared to Malaysia, were higher, varying by ancestry group between 57 and 61% for BRCA1, and between 43 and 47% for BRCA2 carriers. The cumulative risk of OC by age 80 was 31% (27-36%) for BRCA1 and 12% (10%-15%) for BRCA2 carriers in Malaysia born between 1950 and 1959; and 42% (34-50%) for BRCA1 and 20% (14-27%) for BRCA2 carriers of the same birth cohort in Singapore. There was evidence of increased BC and OC risks for women from >1960 birth cohorts (p-value = 3.6 × 10-5 for BRCA1 and 0.018 for BRCA2).InterpretationThe absolute age-specific cancer risks of Asian carriers vary depending on the underlying population-specific cancer incidences, and hence should be customised to allow for more accurate cancer risk management.FundingWellcome Trust [grant no: v203477/Z/16/Z]; CRUK (PPRPGM-Nov20∖100002).

Dataset Information

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

Background

Methods

Results

Conclusions

Publications

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

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