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Region Hovedstaden - en del af Københavns Universitetshospital
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Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers

Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

DOI

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  2. BRCA2 Polymorphic Stop Codon K3326X and the Risk of Breast, Prostate, and Ovarian Cancers

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  3. Height and Breast Cancer Risk: Evidence From Prospective Studies and Mendelian Randomization

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  4. Immune Regulation by Self-Recognition: Novel Possibilities for Anticancer Immunotherapy

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  5. Peripheral blood leukocyte telomere length and mortality among 64,637 individuals from the general population

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

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  2. Breast cancer survival in Nordic BRCA2 mutation carriers-unconventional association with oestrogen receptor status

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

    Publikation: Bidrag til tidsskriftTidsskriftartikelForskningpeer review

  • Studygroup,Thomas van Overeem Hansen, Anne-Marie Gerdes, members)
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Background: Genome-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.

Methods: We 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.

Results: The 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.

Conclusions: BC 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.

OriginalsprogEngelsk
TidsskriftJournal of the National Cancer Institute
Vol/bind109
Udgave nummer7
Sider (fra-til)djw302
ISSN0027-8874
DOI
StatusUdgivet - 1 jul. 2017

ID: 52702813