We found a match
Your institution may have rights to this item. Sign in to continue.
- Title
Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers.
- Authors
Borde, Julika; Ernst, Corinna; Wappenschmidt, Barbara; Niederacher, Dieter; Weber-Lassalle, Konstantin; Schmidt, Gunnar; Hauke, Jan; Quante, Anne S; Weber-Lassalle, Nana; Horváth, Judit; Pohl-Rescigno, Esther; Arnold, Norbert; Rump, Andreas; Gehrig, Andrea; Hentschel, Julia; Faust, Ulrike; Dutrannoy, Véronique; Meindl, Alfons; Kuzyakova, Maria; Wang-Gohrke, Shan
- Abstract
<bold>Background: </bold>Genome-wide association studies suggest that the combined effects of breast cancer (BC)-associated single nucleotide polymorphisms (SNPs) can improve BC risk stratification using polygenic risk scores (PRSs). The performance of PRSs in genome-wide association studies-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2.<bold>Methods: </bold>A total of 760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, 2 SNP sets covering 77 (SNP set 1, developed for BC risk stratification in women unselected for their BRCA1/2 germline mutation status) and 88 (SNP set 2, developed for BC risk stratification in female BRCA1/2 mutation carriers) BC-associated SNPs were used. All statistical tests were 2-sided.<bold>Results: </bold>Both SNP sets provided concordant PRS results at the individual level (r = 0.91, P < 2.20 × 10-16). Weighted cohort Cox regression analyses revealed statistically significant associations of PRSs with the risk for first BC. For SNP set 1, a hazard ratio of 1.71 per SD of the PRS was observed (95% confidence interval = 1.36 to 2.15, P = 3.87 × 10-6). PRSs identify a subgroup of CHEK2 mutation carriers with a predicted lifetime risk for first BC that exceeds the surveillance thresholds defined by international guidelines. Association of PRS with mCBC was examined via Cox regression analysis (SNP set 1 hazard ratio = 1.23, 95% confidence interval = 0.86 to 1.78, P = .26).<bold>Conclusions: </bold>PRSs may be used to personalize risk-adapted preventive measures for women with CHEK2 mutations. Larger studies are required to assess the role of PRSs in mCBC predisposition.
- Subjects
DISEASE risk factors; GENOME-wide association studies; SINGLE nucleotide polymorphisms; BREAST cancer; GERM cells; PROTEIN kinases; GENETIC mutation; SEQUENCE analysis; DISEASE susceptibility; RESEARCH funding; BREAST tumors
- Publication
JNCI: Journal of the National Cancer Institute, 2021, Vol 113, Issue 7, p893
- ISSN
0027-8874
- Publication type
journal article
- DOI
10.1093/jnci/djaa203