Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 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

doi:10.1093/jnci/djaa203

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

J Natl Cancer Inst. 2021 Jul 1;113(7):893-899. doi: 10.1093/jnci/djaa203.

Authors

Julika Borde¹, Corinna Ernst¹, Barbara Wappenschmidt¹, Dieter Niederacher², Konstantin Weber-Lassalle¹, Gunnar Schmidt³, Jan Hauke¹, Anne S Quante⁴, Nana Weber-Lassalle¹, Judit Horváth⁵, Esther Pohl-Rescigno¹, Norbert Arnold⁶, Andreas Rump⁷, Andrea Gehrig⁸, Julia Hentschel⁹, Ulrike Faust¹⁰, Véronique Dutrannoy¹¹, Alfons Meindl¹², Maria Kuzyakova¹³, Shan Wang-Gohrke¹⁴, Bernhard H F Weber^{15

16}, Christian Sutter¹⁷, Alexander E Volk¹⁸, Olga Giannakopoulou^{19

20}, Andrew Lee²¹, Christoph Engel²², Marjanka K Schmidt²³, Antonis C Antoniou²¹, Rita K Schmutzler¹, Karoline Kuchenbaecker^{19

20}, Eric Hahnen¹

Affiliations

¹ Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
² Department of Gynecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University Duesseldorf, Duesseldorf, Germany.
³ Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
⁴ Department of Gynecology and Obstetrics, Technical University Munich, University Hospital Rechts der Isar, Munich, Germany.
⁵ Institute for Human Genetics, University Hospital Muenster, Muenster, Germany.
⁶ Institute of Clinical Molecular Biology, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
⁷ Institute for Clinical Genetics, Technische Universitaet Dresden, Dresden, Germany.
⁸ Institute of Human Genetics, Julius-Maximilians-Universität Würzburg, Würzburg, Germany.
⁹ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
¹⁰ Institute of Medical Genetics and Applied Genomics, University Hospital Tuebingen, Tuebingen, Germany.
¹¹ Institute of Medical and Human Genetics, Charité Universitätsmedizin Berlin, Berlin, Germany.
¹² Department of Gynecology and Obstetrics, Ludwig-Maximilians-University Munich, University Hospital Munich, Munich, Germany.
¹³ Institute of Human Genetics, University Medical Center, Georg August University, Goettingen, Germany.
¹⁴ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
¹⁵ Institute of Human Genetics, University of Regensburg, Regensburg, Germany.
¹⁶ Institute of Clinical Human Genetics, University Hospital Regensburg, Regensburg, Germany.
¹⁷ Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
¹⁸ Institute of Human Genetics, University Medical Center Hamburg-Eppendorf, Hamburg, Germany.
¹⁹ Division of Psychiatry, University College London, London, UK.
²⁰ UCL Genetics Institute, University College London, London, UK.
²¹ Department of Public Health and Primary Care, Centre for Cancer Genetic Epidemiology, University of Cambridge, Cambridge, UK.
²² Institute for Medical Informatics, Statistics and Epidemiology, University of Leipzig, Leipzig, Germany.
²³ Division of Molecular Pathology, Netherlands Cancer Institute, Amsterdam, The Netherlands.

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.

Publication types

Research Support, Non-U.S. Gov't

MeSH terms

Breast Neoplasms* / epidemiology
Breast Neoplasms* / genetics
Checkpoint Kinase 2 / genetics
Female
Genetic Predisposition to Disease
Genome-Wide Association Study
Germ-Line Mutation
Humans
Mutation
Risk Factors

Substances

Checkpoint Kinase 2
CHEK2 protein, human

Grants and funding

20861/CRUK_/Cancer Research UK/United Kingdom