Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers. (29th December 2020)

• Record Type: Journal Article
• 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; Weber, Bernhard H. F; Sutter, Christian; Volk, Alexander E; Giannakopoulou, Olga; Lee, Andrew; Engel, Christoph; Schmidt, Marjanka K; Antoniou, Antonis C; Schmutzler, Rita K; Kuchenbaecker, Karoline; Hahnen, Eric;
• Is Part Of: Journal of the National Cancer Institute. Volume 113:Number 7(2021)
• Page Start: 893
• Page End: 899
• Publication Date: 2020-12-29
• Subjects: Cancer -- Periodicals; Cancer -- Research -- Periodicals; 616.994
• DOI: 10.1093/jnci/djaa203
• Languages: English
• ISSNs: 0027-8874

Abstract

Abstract: Background: 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 . Methods: 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. Results: 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). Conclusions: 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.