Polygenic risk scores indicate extreme ages at onset of breast cancer in female BRCA1/2 pathogenic variant carriers
Julika Borde,
Yael Laitman,
Britta Blümcke,
Dieter Niederacher,
Konstantin Weber-Lassalle,
Christian Sutter,
Andreas Rump,
Norbert Arnold,
Shan Wang-Gohrke,
Judit Horváth,
Andrea Gehrig,
Gunnar Schmidt,
Véronique Dutrannoy,
Juliane Ramser,
Julia Hentschel,
Alfons Meindl,
Christopher Schroeder,
Barbara Wappenschmidt,
Christoph Engel,
Karoline Kuchenbaecker,
Rita K. Schmutzler,
Eitan Friedman,
Eric Hahnen,
Corinna Ernst
Affiliations
Julika Borde
Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne
Yael Laitman
Oncogenetics Unit, Sheba Medical Center
Britta Blümcke
Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne
Dieter Niederacher
Department of Gynaecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University
Konstantin Weber-Lassalle
Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne
Christian Sutter
Institute of Human Genetics, University of Heidelberg
Andreas Rump
Institute of Clinical Genetics, Technische Universitaet Dresden
Norbert Arnold
Institute of Clinical Molecular Biology, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel
Shan Wang-Gohrke
Department of Gynaecology and Obstetrics, University Hospital Ulm
Judit Horváth
Institute for Human Genetics, University Hospital Muenster
Andrea Gehrig
Institute of Human Genetics, Julius-Maximilians University
Gunnar Schmidt
Institute of Human Genetics, Hannover Medical School
Véronique Dutrannoy
Institute of Medical and Human Genetics, Charité Universitaetsmedizin
Juliane Ramser
Department for Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich
Julia Hentschel
Institute of Human Genetics, University of Leipzig Hospitals and Clinics
Alfons Meindl
Department of Gynaecology and Obstetrics, LMU Munich, University Hospital Munich
Christopher Schroeder
Institute of Medical Genetics and Applied Genomics, University of Tübingen
Barbara Wappenschmidt
Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne
Christoph Engel
Institute for Medical Informatics, Statistics and Epidemiology (IMISE)
Karoline Kuchenbaecker
Division of Psychiatry, University College London
Rita K. Schmutzler
Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne
Eitan Friedman
Oncogenetics Unit, Sheba Medical Center
Eric Hahnen
Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne
Corinna Ernst
Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne
Abstract Background Clinical management of women carrying a germline pathogenic variant (PV) in the BRCA1/2 genes demands for accurate age-dependent estimators of breast cancer (BC) risks, which were found to be affected by a variety of intrinsic and extrinsic factors. Here we assess the contribution of polygenic risk scores (PRSs) to the occurrence of extreme phenotypes with respect to age at onset, namely, primary BC diagnosis before the age of 35 years (early diagnosis, ED) and cancer-free survival until the age of 60 years (late/no diagnosis, LD) in female BRCA1/2 PV carriers. Methods Overall, estrogen receptor (ER)-positive, and ER-negative BC PRSs as developed by Kuchenbaecker et al. for BC risk discrimination in female BRCA1/2 PV carriers were employed for PRS computation in a curated sample of 295 women of European descent carrying PVs in the BRCA1 (n=183) or the BRCA2 gene (n=112), and did either fulfill the ED criteria (n=162, mean age at diagnosis: 28.3 years, range: 20 to 34 years) or the LD criteria (n=133). Binomial logistic regression was applied to assess the association of standardized PRSs with either ED or LD under adjustment for patient recruitment criteria for germline testing and localization of BRCA1/2 PVs in the corresponding BC or ovarian cancer (OC) cluster regions. Results For BRCA1 PV carriers, the standardized overall BC PRS displayed the strongest association with ED (odds ratio (OR) = 1.62; 95% confidence interval (CI): 1.16–2.31, p<0.01). Additionally, statistically significant associations of selection for the patient recruitment criteria for germline testing and localization of pathogenic PVs outside the BRCA1 OC cluster region with ED were observed. For BRCA2 PV carriers, the standardized PRS for ER-negative BC displayed the strongest association (OR = 2.27, 95% CI: 1.45–3.78, p<0.001). Conclusions PRSs contribute to the development of extreme phenotypes of female BRCA1/2 PV carriers with respect to age at primary BC diagnosis. Construction of optimized PRS SNP sets for BC risk stratification in BRCA1/2 PV carriers should be the task of future studies with larger, well-defined study samples. Furthermore, our results provide further evidence, that localization of PVs in BC/OC cluster regions might be considered in BC risk calculations for unaffected BRCA1/2 PV carriers.
