ONCOmmunity

Performance of breast cancer polygenic risk scores in 760 female CHEK2 germline mutation carriers.

By: 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

Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
2020-05-14; doi: 10.1093/jnci/djaa203

Abstract

Background

Genome-wide association studies (GWAS) 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 GWAS-independent clinical cohorts is poorly studied in individuals carrying mutations in moderately penetrant BC predisposition genes such as CHEK2.

Methods

760 female CHEK2 mutation carriers were included; 561 women were affected with BC, of whom 74 developed metachronous contralateral BC (mCBC). For PRS calculations, two 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 two-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 (HR) of 1.71 per standard deviation of the PRS was observed (95% confidence interval [CI] = 1.36 to 2.15, p = 3.87x10-6). 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 HR =: 1.23, 95%CI = 0.86 to 1.78, p = .26).

Conclusion

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.