Dataset Information

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

ABSTRACT:

Purpose

We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.

Methods

Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen receptor (ER)-negative, or ER-positive BC, and two PRS for overall or high-grade serous EOC. Associations were validated in a prospective cohort.

Results

The ER-negative PRS showed the strongest association with BC risk for BRCA1 carriers (hazard ratio [HR] per standard deviation?=?1.29 [95% CI 1.25-1.33], P?=?3×10^-72). For BRCA2, the strongest association was with overall BC PRS (HR?=?1.31 [95% CI 1.27-1.36], P?=?7×10^-50). HR estimates decreased significantly with age and there was evidence for differences in associations by predicted variant effects on protein expression. The HR estimates were smaller than general population estimates. The high-grade serous PRS yielded the strongest associations with EOC risk for BRCA1 (HR?=?1.32 [95% CI 1.25-1.40], P?=?3×10^-22) and BRCA2 (HR?=?1.44 [95% CI 1.30-1.60], P?=?4×10^-12) carriers. The associations in the prospective cohort were similar.

Conclusion

Population-based PRS are strongly associated with BC and EOC risks for BRCA1/2 carriers and predict substantial absolute risk differences for women at PRS distribution extremes.

SUBMITTER: Barnes DR

PROVIDER: S-EPMC7521995 | biostudies-literature | 2020 Oct

REPOSITORIES: biostudies-literature

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Publications

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Barnes Daniel R DR Rookus Matti A MA McGuffog Lesley L Leslie Goska G Mooij Thea M TM Dennis Joe J Mavaddat Nasim N Adlard Julian J Ahmed Munaza M Aittomäki Kristiina K Andrieu Nadine N Andrulis Irene L IL Arnold Norbert N Arun Banu K BK Azzollini Jacopo J Balmaña Judith J Barkardottir Rosa B RB Barrowdale Daniel D Benitez Javier J Berthet Pascaline P Białkowska Katarzyna K Blanco Amie M AM Blok Marinus J MJ Bonanni Bernardo B Boonen Susanne E SE Borg Åke Å Bozsik Aniko A Bradbury Angela R AR Brennan Paul P Brewer Carole C Brunet Joan J Buys Saundra S SS Caldés Trinidad T Caligo Maria A MA Campbell Ian I Christensen Lise Lotte LL Chung Wendy K WK Claes Kathleen B M KBM Colas Chrystelle C Collonge-Rame Marie-Agnès MA Cook Jackie J Daly Mary B MB Davidson Rosemarie R de la Hoya Miguel M de Putter Robin R Delnatte Capucine C Devilee Peter P Diez Orland O Ding Yuan Chun YC Domchek Susan M SM Dorfling Cecilia M CM Dumont Martine M Eeles Ros R Ejlertsen Bent B Engel Christoph C Evans D Gareth DG Faivre Laurence L Foretova Lenka L Fostira Florentia F Friedlander Michael M Friedman Eitan E Frost Debra D Ganz Patricia A PA Garber Judy J Gehrig Andrea A Gerdes Anne-Marie AM Gesta Paul P Giraud Sophie S Glendon Gord G Godwin Andrew K AK Goldgar David E DE González-Neira Anna A Greene Mark H MH Gschwantler-Kaulich Daphne D Hahnen Eric E Hamann Ute U Hanson Helen H Hentschel Julia J Hogervorst Frans B L FBL Hooning Maartje J MJ Horvath Judit J Hu Chunling C Hulick Peter J PJ Imyanitov Evgeny N EN Isaacs Claudine C Izatt Louise L Izquierdo Angel A Jakubowska Anna A James Paul A PA Janavicius Ramunas R John Esther M EM Joseph Vijai V Karlan Beth Y BY Kast Karin K Koudijs Marco M Kruse Torben A TA Kwong Ava A Laitman Yael Y Lasset Christine C Lazaro Conxi C Lester Jenny J Lesueur Fabienne F Liljegren Annelie A Loud Jennifer T JT Lubiński Jan J Mai Phuong L PL Manoukian Siranoush S Mari Véronique V Mebirouk Noura N Meijers-Heijboer Hanne E J HEJ Meindl Alfons A Mensenkamp Arjen R AR Miller Austin A Montagna Marco M Mouret-Fourme Emmanuelle E Mukherjee Semanti S Mulligan Anna Marie AM Nathanson Katherine L KL Neuhausen Susan L SL Nevanlinna Heli H Niederacher Dieter D Nielsen Finn Cilius FC Nikitina-Zake Liene L Noguès Catherine C Olah Edith E Olopade Olufunmilayo I OI Ong Kai-Ren KR O'Shaughnessy-Kirwan Aoife A Osorio Ana A Ott Claus-Eric CE Papi Laura L Park Sue K SK Parsons Michael T MT Pedersen Inge Sokilde IS Peissel Bernard B Peixoto Ana A Peterlongo Paolo P Pfeiler Georg G Phillips Kelly-Anne KA Prajzendanc Karolina K Pujana Miquel Angel MA Radice Paolo P Ramser Juliane J Ramus Susan J SJ Rantala Johanna J Rennert Gad G Risch Harvey A HA Robson Mark M Rønlund Karina K Salani Ritu R Schuster Hélène H Senter Leigha L Shah Payal D PD Sharma Priyanka P Side Lucy E LE Singer Christian F CF Slavin Thomas P TP Soucy Penny P Southey Melissa C MC Spurdle Amanda B AB Steinemann Doris D Steinsnyder Zoe Z Stoppa-Lyonnet Dominique D Sutter Christian C Tan Yen Yen YY Teixeira Manuel R MR Teo Soo Hwang SH Thull Darcy L DL Tischkowitz Marc M Tognazzo Silvia S Toland Amanda E AE Trainer Alison H AH Tung Nadine N van Engelen Klaartje K van Rensburg Elizabeth J EJ Vega Ana A Vierstraete Jeroen J Wagner Gabriel G Walker Lisa L Wang-Gohrke Shan S Wappenschmidt Barbara B Weitzel Jeffrey N JN Yadav Siddhartha S Yang Xin X Yannoukakos Drakoulis D Zimbalatti Dario D Offit Kenneth K Thomassen Mads M Couch Fergus J FJ Schmutzler Rita K RK Simard Jacques J Easton Douglas F DF Chenevix-Trench Georgia G Antoniou Antonis C AC

Genetics in medicine : official journal of the American College of Medical Genetics 20200715 10

<h4>Purpose</h4>We assessed the associations between population-based polygenic risk scores (PRS) for breast (BC) or epithelial ovarian cancer (EOC) with cancer risks for BRCA1 and BRCA2 pathogenic variant carriers.<h4>Methods</h4>Retrospective cohort data on 18,935 BRCA1 and 12,339 BRCA2 female pathogenic variant carriers of European ancestry were available. Three versions of a 313 single-nucleotide polymorphism (SNP) BC PRS were evaluated based on whether they predict overall, estrogen recepto ...[more]

PMID: 32665703

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Project description:BackgroundGenome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates.MethodsWe constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS.ResultsThe PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2×10 -53 ). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2×10 -20 ). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS.ConclusionsBC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Project description:BackgroundClinical management of women carrying a germline pathogenic variant (PV) in the BRCA1/2 genes demands for accurate age-dependent estimators of breast cancer (BC) risks, which were found to be affected by a variety of intrinsic and extrinsic factors. Here we assess the contribution of polygenic risk scores (PRSs) to the occurrence of extreme phenotypes with respect to age at onset, namely, primary BC diagnosis before the age of 35 years (early diagnosis, ED) and cancer-free survival until the age of 60 years (late/no diagnosis, LD) in female BRCA1/2 PV carriers.MethodsOverall, estrogen receptor (ER)-positive, and ER-negative BC PRSs as developed by Kuchenbaecker et al. for BC risk discrimination in female BRCA1/2 PV carriers were employed for PRS computation in a curated sample of 295 women of European descent carrying PVs in the BRCA1 (n=183) or the BRCA2 gene (n=112), and did either fulfill the ED criteria (n=162, mean age at diagnosis: 28.3 years, range: 20 to 34 years) or the LD criteria (n=133). Binomial logistic regression was applied to assess the association of standardized PRSs with either ED or LD under adjustment for patient recruitment criteria for germline testing and localization of BRCA1/2 PVs in the corresponding BC or ovarian cancer (OC) cluster regions.ResultsFor BRCA1 PV carriers, the standardized overall BC PRS displayed the strongest association with ED (odds ratio (OR) = 1.62; 95% confidence interval (CI): 1.16-2.31, p<0.01). Additionally, statistically significant associations of selection for the patient recruitment criteria for germline testing and localization of pathogenic PVs outside the BRCA1 OC cluster region with ED were observed. For BRCA2 PV carriers, the standardized PRS for ER-negative BC displayed the strongest association (OR = 2.27, 95% CI: 1.45-3.78, p<0.001).ConclusionsPRSs contribute to the development of extreme phenotypes of female BRCA1/2 PV carriers with respect to age at primary BC diagnosis. Construction of optimized PRS SNP sets for BC risk stratification in BRCA1/2 PV carriers should be the task of future studies with larger, well-defined study samples. Furthermore, our results provide further evidence, that localization of PVs in BC/OC cluster regions might be considered in BC risk calculations for unaffected BRCA1/2 PV carriers.

Project description:BACKGROUND:BRCA1 and BRCA2 mutations have been associated with prostate cancer (PCa) risk but a wide range of risk estimates have been reported that are based on retrospective studies. OBJECTIVE:To estimate relative and absolute PCa risks associated with BRCA1/2 mutations and to assess risk modification by age, family history, and mutation location. DESIGN, SETTING, AND PARTICIPANTS:This was a prospective cohort study of male BRCA1 (n = 376) and BRCA2 carriers (n = 447) identified in clinical genetics centres in the UK and Ireland (median follow-up 5.9 and 5.3?yr, respectively). OUTCOME MEASUREMENTS AND STATISTICAL ANALYSIS:Standardised incidence/mortality ratios (SIRs/SMRs) relative to population incidences or mortality rates, absolute risks, and hazard ratios (HRs) were estimated using cohort and survival analysis methods. RESULTS AND LIMITATIONS:Sixteen BRCA1 and 26 BRCA2 carriers were diagnosed with PCa during follow-up. BRCA2 carriers had an SIR of 4.45 (95% confidence interval [CI] 2.99-6.61) and absolute PCa risk of 27% (95% CI 17-41%) and 60% (95% CI 43-78%) by ages 75 and 85?yr, respectively. For BRCA1 carriers, the overall SIR was 2.35 (95% CI 1.43-3.88); the corresponding SIR at age <65?yr was 3.57 (95% CI 1.68-7.58). However, the BRCA1 SIR varied between 0.74 and 2.83 in sensitivity analyses to assess potential screening effects. PCa risk for BRCA2 carriers increased with family history (HR per affected relative 1.68, 95% CI 0.99-2.85). BRCA2 mutations in the region bounded by positions c.2831 and c.6401 were associated with an SIR of 2.46 (95% CI 1.07-5.64) compared to population incidences, corresponding to lower PCa risk (HR 0.37, 95% CI 0.14-0.96) than for mutations outside the region. BRCA2 carriers had a stronger association with Gleason score ?7 (SIR 5.07, 95% CI 3.20-8.02) than Gleason score ?6 PCa (SIR 3.03, 95% CI 1.24-7.44), and a higher risk of death from PCa (SMR 3.85, 95% CI 1.44-10.3). Limitations include potential screening effects for these known mutation carriers; however, the BRCA2 results were robust to multiple sensitivity analyses. CONCLUSIONS:The results substantiate PCa risk patterns indicated by retrospective analyses for BRCA2 carriers, including further evidence of association with aggressive PCa, and give some support for a weaker association in BRCA1 carriers. PATIENT SUMMARY:In this study we followed unaffected men known to carry mutations in the BRCA1 and BRCA2 genes to investigate whether they are at higher risk of developing prostate cancer compared to the general population. We found that carriers of BRCA2 mutations have a high risk of developing prostate cancer, particularly more aggressive prostate cancer, and that this risk varies by family history of prostate cancer and the location of the mutation within the gene.

Dataset Information

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

Purpose

Methods

Results

Conclusion

Publications

Polygenic risk scores and breast and epithelial ovarian cancer risks for carriers of BRCA1 and BRCA2 pathogenic variants.

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