Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers

Borde, Julika; Ernst, Corinna; Wappenschmidt, Barbara; Niederacher, Dieter; Weber-Lassalle, Konstantin; Schmidt, Gunnar; Hauke, Jan; Quante, Anne S.; Weber-Lassalle, Nana; Horvath, Judit; Pohl-Rescigno, Esther; Arnold, Norbert; Rump, Andreas; Gehrig, Andrea; Hentschel, Julia; Faust, Ulrike; Dutrannoy, Veronique; 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 und Hahnen, Eric (2021): Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers. In: Jnci-Journal of the National Cancer Institute, Bd. 113, Nr. 7, djaa203: S. 893-899

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 x 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 x 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.

• Dokumententyp: Zeitschriftenartikel
• Fakultät: Medizin
• Themengebiete: 600 Technik, Medizin, angewandte Wissenschaften > 610 Medizin und Gesundheit
• ISSN: 0027-8874
• Sprache: Englisch