. 2022 Jun 27;22(1):706.

doi: 10.1186/s12885-022-09780-1.

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

Julika Borde¹, Yael Laitman^{2

3}, Britta Blümcke¹, Dieter Niederacher⁴, Konstantin Weber-Lassalle¹, Christian Sutter⁵, Andreas Rump⁶, Norbert Arnold⁷, Shan Wang-Gohrke⁸, Judit Horváth⁹, Andrea Gehrig¹⁰, Gunnar Schmidt¹¹, Véronique Dutrannoy¹², Juliane Ramser¹³, Julia Hentschel¹⁴, Alfons Meindl¹⁵, Christopher Schroeder¹⁶, Barbara Wappenschmidt¹, Christoph Engel¹⁷, Karoline Kuchenbaecker^{18

19}, Rita K Schmutzler^#¹, Eitan Friedman^#^{2

3}, Eric Hahnen^#¹, Corinna Ernst^#²⁰

Affiliations

¹ Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
² Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Israel.
³ Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.
⁴ Department of Gynaecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany.
⁵ Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
⁶ Institute of Clinical Genetics, Technische Universitaet Dresden, Dresden, Germany.
⁷ Institute of Clinical Molecular Biology, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
⁸ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
⁹ Institute for Human Genetics, University Hospital Muenster, Muenster, Germany.
¹⁰ Institute of Human Genetics, Julius-Maximilians University, Wuerzburg, Germany.
¹¹ Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
¹² Institute of Medical and Human Genetics, Charité Universitaetsmedizin, Berlin, Germany.
¹³ Department for Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
¹⁴ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
¹⁵ Department of Gynaecology and Obstetrics, LMU Munich, University Hospital Munich, Munich, Germany.
¹⁶ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
¹⁷ Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Leipzig, Germany.
¹⁸ Division of Psychiatry, University College London, London, UK.
¹⁹ UCL Genetics Institute, University College London, London, UK.
²⁰ Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany. corinna.ernst@uk-koeln.de.

^# Contributed equally.

PMID: 35761208
PMCID: PMC9238030
DOI: 10.1186/s12885-022-09780-1

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

Julika Borde et al. BMC Cancer. 2022.

. 2022 Jun 27;22(1):706.

doi: 10.1186/s12885-022-09780-1.

Authors

Affiliations

¹ Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany.
² Oncogenetics Unit, Sheba Medical Center, Tel Hashomer, Israel.
³ Sackler School of Medicine, Tel Aviv University, Tel-Aviv, Israel.
⁴ Department of Gynaecology and Obstetrics, University Hospital Duesseldorf, Heinrich-Heine University, Duesseldorf, Germany.
⁵ Institute of Human Genetics, University of Heidelberg, Heidelberg, Germany.
⁶ Institute of Clinical Genetics, Technische Universitaet Dresden, Dresden, Germany.
⁷ Institute of Clinical Molecular Biology, Department of Gynaecology and Obstetrics, University Hospital of Schleswig-Holstein, Campus Kiel, Christian-Albrechts University Kiel, Kiel, Germany.
⁸ Department of Gynaecology and Obstetrics, University Hospital Ulm, Ulm, Germany.
⁹ Institute for Human Genetics, University Hospital Muenster, Muenster, Germany.
¹⁰ Institute of Human Genetics, Julius-Maximilians University, Wuerzburg, Germany.
¹¹ Institute of Human Genetics, Hannover Medical School, Hannover, Germany.
¹² Institute of Medical and Human Genetics, Charité Universitaetsmedizin, Berlin, Germany.
¹³ Department for Gynaecology and Obstetrics, Division of Tumor Genetics, Klinikum rechts der Isar, Technical University Munich, Munich, Germany.
¹⁴ Institute of Human Genetics, University of Leipzig Hospitals and Clinics, Leipzig, Germany.
¹⁵ Department of Gynaecology and Obstetrics, LMU Munich, University Hospital Munich, Munich, Germany.
¹⁶ Institute of Medical Genetics and Applied Genomics, University of Tübingen, Tübingen, Germany.
¹⁷ Institute for Medical Informatics, Statistics and Epidemiology (IMISE), Leipzig, Germany.
¹⁸ Division of Psychiatry, University College London, London, UK.
¹⁹ UCL Genetics Institute, University College London, London, UK.
²⁰ Center for Familial Breast and Ovarian Cancer, Center for Integrated Oncology (CIO), Medical Faculty, University Hospital Cologne, Kerpener Straße 62, Cologne, 50937, Germany. corinna.ernst@uk-koeln.de.

^# Contributed equally.

PMID: 35761208
PMCID: PMC9238030
DOI: 10.1186/s12885-022-09780-1

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.

Keywords: BRCA1; BRCA2; Breast cancer; PRS; Polygenic risk score; Risk assessment.

PubMed Disclaimer

Conflict of interest statement

The authors declare that they have no competing interests.

Figures

**Fig. 1**
Standardized polygenic risk score (PRS) values per individual and Spearman’s rank correlation coefficients ρ. (Upper left) Overall breast cancer (BC) PRS versus estrogen receptor-positive (ER+) BC PRS in 183 *BRCA1* pathogenic variant (PV) carriers who were either diagnosed with BC before the age of 35 years (early diagnosis, ED) or were unaffected at least until the age of 60 years (late/no diagnosis, LD). (Upper right) Overall BC PRS versus estrogen receptor-negative (ER-) BC PRS in the same sample. (Lower left) Overall BC PRS versus ER+ BC PRS in 112 *BRCA2* PV carriers who belonged to either the LD or ED group. (Lower right) Overall BC PRS versus ER- BC PRS in the same sample

**Fig. 2**
Boxplots and two-sided Welch’s t-test p values of standardized polygenic risk scores (overall breast cancer (BC), estrogen receptor (ER)-positive BC (ER+), ER-negative BC (ER-) PRS) of 183 *BRCA1* and 112 *BRCA2* pathogenic variant carriers, who were either diagnosed with BC before the age of 35 years (early diagnosis, ED) or were unaffected at least until the age of 60 years (late/no diagnosis, LD)

See this image and copyright information in PMC

References

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

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

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Conflict of interest statement

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