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Borde J, Ernst C, Wappenschmidt B, et al. Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers. J Natl Cancer Inst. 2021;113(7):893-899doi: 10.1093/jnci/djaa203.
Borde, J., Ernst, C., Wappenschmidt, B., Niederacher, D., Weber-Lassalle, K., Schmidt, G., Hauke, J., Quante, A. S., Weber-Lassalle, N., Horváth, J., Pohl-Rescigno, E., Arnold, N., Rump, A., Gehrig, A., Hentschel, J., Faust, U., Dutrannoy, V., Meindl, A., Kuzyakova, M., Wang-Gohrke, S., Weber, B. H. F., Sutter, C., Volk, A. E., Giannakopoulou, O., Lee, A., Engel, C., Schmidt, M. K., Antoniou, A. C., Schmutzler, R. K., Kuchenbaecker, K., & Hahnen, E. (2021). Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers. Journal of the National Cancer Institute, 113(7), 893-899. https://doi.org/10.1093/jnci/djaa203
Borde, Julika, et al. "Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers." Journal of the National Cancer Institute vol. 113,7 (2021): 893-899. doi: https://doi.org/10.1093/jnci/djaa203
Borde J, Ernst C, Wappenschmidt B, Niederacher D, Weber-Lassalle K, Schmidt G, Hauke J, Quante AS, Weber-Lassalle N, Horváth J, Pohl-Rescigno E, Arnold N, Rump A, Gehrig A, Hentschel J, Faust U, Dutrannoy V, Meindl A, Kuzyakova M, Wang-Gohrke S, Weber BHF, Sutter C, Volk AE, Giannakopoulou O, Lee A, Engel C, Schmidt MK, Antoniou AC, Schmutzler RK, Kuchenbaecker K, Hahnen E. Performance of Breast Cancer Polygenic Risk Scores in 760 Female CHEK2 Germline Mutation Carriers. J Natl Cancer Inst. 2021 Jul 01;113(7):893-899. doi: 10.1093/jnci/djaa203. PMID: 33372680; PMCID: PMC8246885.
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J Natl Cancer Inst. 2021 Jul 01;113(7):893-899. doi: 10.1093/jnci/djaa203.

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

Journal of the National Cancer Institute

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

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.

PMID: 33372680 PMCID: PMC8246885 DOI: 10.1093/jnci/djaa203

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.

© The Author(s) 2020. Published by Oxford University Press. All rights reserved. For permissions, please email: [email protected].

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