Performance of Breast Cancer Polygenic Risk Scores in 760 Female<i>CHEK2</i>Germline Mutation Carriers
Julika Borde, Corinna Ernst, Barbara Wappenschmidt, Dieter Niederacher, Konstantin Weber‐Lassalle, Gunnar Schmidt, Jan Hauke, Anne S. Quante, Nana Weber‐Lassalle, Judit Horváth, Esther Pohl‐Rescigno, Norbert Arnold, Andreas Rump, Andrea Gehrig, Julia Hentschel, Ulrike Faust, Véronique Dutrannoy, Alfons Meindl, Maria Kuzyakova, Shan Wang‐Gohrke, Bernhard H. F. Weber, Christian Sutter, Alexander E. Volk, Olga Giannakopoulou, Andrew Lee, Christoph Engel, Marjanka K. Schmidt, Antonis C. Antoniou, Rita K. Schmutzler, Karoline Kuchenbaecker, Eric Hahnen
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.