Polygenic risk scores indicate extreme ages at onset of breast cancer in female BRCA1/2 pathogenic variant carriers

BMC Cancer

Barbara Wappenschmidt¹  Eric Hahnen¹  Konstantin Weber-Lassalle¹  Britta Blümcke¹  Corinna Ernst¹  Rita K. Schmutzler¹  Julika Borde¹  Juliane Ramser²  Alfons Meindl³  Dieter Niederacher⁴  Shan Wang-Gohrke⁵  Karoline Kuchenbaecker⁶  Judit Horváth⁷  Christoph Engel⁸  Andreas Rump⁹  Norbert Arnold^1,10  Gunnar Schmidt^1,11  Andrea Gehrig^1,12  Christian Sutter^1,13  Julia Hentschel^1,14  Christopher Schroeder^1,15  Véronique Dutrannoy^1,16  Eitan Friedman^1,17  Yael Laitman^1,17 

[1] Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne;Department for Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich;Department of Gynaecology and Obstetrics, LMU Munich, University Hospital Munich;Department of Gynaecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University;Department of Gynaecology and Obstetrics, University Hospital Ulm;Division of Psychiatry, University College London;Institute for Human Genetics, University Hospital Muenster;Institute for Medical Informatics, Statistics and Epidemiology (IMISE);Institute of Clinical Genetics, Technische Universitaet Dresden;Institute of Clinical Molecular Biology, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel;Institute of Human Genetics, Hannover Medical School;Institute of Human Genetics, Julius-Maximilians University;Institute of Human Genetics, University of Heidelberg;Institute of Human Genetics, University of Leipzig Hospitals and Clinics;Institute of Medical Genetics and Applied Genomics, University of Tübingen;Institute of Medical and Human Genetics, Charité Universitaetsmedizin;Oncogenetics Unit, Sheba Medical Center;

关键词: Breast cancer;    Polygenic risk score;    PRS;    Risk assessment;    BRCA1;    BRCA2;   

DOI  :  10.1186/s12885-022-09780-1

来源: DOAJ

【 摘 要 】

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.

【 授权许可】

Unknown