Dataset Information

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

ABSTRACT:

Purpose

To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS₃₁₃) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.

Methods

We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 (CIMBA), a large international retrospective series. Cox regression analysis was performed to assess the association between overall and ER-specific PRS₃₁₃ and CBC risk.

Results

For BRCA1 heterozygotes the estrogen receptor (ER)-negative PRS₃₁₃ showed the largest association with CBC risk, hazard ratio (HR) per SD = 1.12, 95% confidence interval (CI) (1.06-1.18), C-index = 0.53; for BRCA2 heterozygotes, this was the ER-positive PRS₃₁₃, HR = 1.15, 95% CI (1.07-1.25), C-index = 0.57. Adjusting for family history, age at diagnosis, treatment, or pathological characteristics for the first BC did not change association effect sizes. For women developing first BC < age 40 years, the cumulative PRS₃₁₃ 5th and 95th percentile 10-year CBC risks were 22% and 32% for BRCA1 and 13% and 23% for BRCA2 heterozygotes, respectively.

Conclusion

The PRS₃₁₃ can be used to refine individual CBC risks for BRCA1/2 heterozygotes of European ancestry, however the PRS₃₁₃ needs to be considered in the context of a multifactorial risk model to evaluate whether it might influence clinical decision-making.

SUBMITTER: Lakeman IMM

PROVIDER: S-EPMC8460445 | biostudies-literature | 2021 Sep

REPOSITORIES: biostudies-literature

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Publications

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Lakeman Inge M M IMM van den Broek Alexandra J AJ Vos Juliën A M JAM Barnes Daniel R DR Adlard Julian J Andrulis Irene L IL Arason Adalgeir A Arnold Norbert N Arun Banu K BK Balmaña Judith J Barrowdale Daniel D Benitez Javier J Borg Ake A Caldés Trinidad T Caligo Maria A MA Chung Wendy K WK Claes Kathleen B M KBM Collée J Margriet JM Couch Fergus J FJ Daly Mary B MB Dennis Joe J Dhawan Mallika M Domchek Susan M SM Eeles Ros R Engel Christoph C Evans D Gareth DG Feliubadaló Lidia L Foretova Lenka L Friedman Eitan E Frost Debra D Ganz Patricia A PA Garber Judy J Gayther Simon A SA Gerdes Anne-Marie AM Godwin Andrew K AK Goldgar David E DE Hahnen Eric E Hake Christopher R CR Hamann Ute U Hogervorst Frans B L FBL Hooning Maartje J MJ Hopper John L JL Hulick Peter J PJ Imyanitov Evgeny N EN Isaacs Claudine C Izatt Louise L Jakubowska Anna A James Paul A PA Janavicius Ramunas R Jensen Uffe Birk UB Jiao Yue Y John Esther M EM Joseph Vijai V Karlan Beth Y BY Kets Carolien M CM Konstantopoulou Irene I Kwong Ava A Legrand Clémentine C Leslie Goska G Lesueur Fabienne F Loud Jennifer T JT Lubiński Jan J Manoukian Siranoush S McGuffog Lesley L Miller Austin A Gomes Denise Molina DM Montagna Marco M Mouret-Fourme Emmanuelle E Nathanson Katherine L KL Neuhausen Susan L SL Nevanlinna Heli H Yie Joanne Ngeow Yuen JNY Olah Edith E Olopade Olufunmilayo I OI Park Sue K SK Parsons Michael T MT Peterlongo Paolo P Piedmonte Marion M Radice Paolo P Rantala Johanna J Rennert Gad G Risch Harvey A HA Schmutzler Rita K RK Sharma Priyanka P Simard Jacques J Singer Christian F CF Stadler Zsofia Z Stoppa-Lyonnet Dominique D Sutter Christian C Tan Yen Yen YY Teixeira Manuel R MR Teo Soo Hwang SH Teulé Alex A Thomassen Mads M Thull Darcy L DL Tischkowitz Marc M Toland Amanda E AE Tung Nadine N van Rensburg Elizabeth J EJ Vega Ana A Wappenschmidt Barbara B Devilee Peter P van Asperen Christi J CJ Bernstein Jonine L JL Offit Kenneth K Easton Douglas F DF Rookus Matti A MA Chenevix-Trench Georgia G Antoniou Antonis C AC Robson Mark M Schmidt Marjanka K MK

Genetics in medicine : official journal of the American College of Medical Genetics 20210610 9

<h4>Purpose</h4>To evaluate the association between a previously published 313 variant-based breast cancer (BC) polygenic risk score (PRS<sub>313</sub>) and contralateral breast cancer (CBC) risk, in BRCA1 and BRCA2 pathogenic variant heterozygotes.<h4>Methods</h4>We included women of European ancestry with a prevalent first primary invasive BC (BRCA1 = 6,591 with 1,402 prevalent CBC cases; BRCA2 = 4,208 with 647 prevalent CBC cases) from the Consortium of Investigators of Modifiers of BRCA1/2 ( ...[more]

PMID: 34113011

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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.

Dataset Information

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Purpose

Methods

Results

Conclusion

Publications

The predictive ability of the 313 variant-based polygenic risk score for contralateral breast cancer risk prediction in women of European ancestry with a heterozygous BRCA1 or BRCA2 pathogenic variant.

Similar Datasets

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