Universität zu Köln

Borde, Julika, Laitman, Yael, Bluemcke, Britta, Niederacher, Dieter, Weber-Lassalle, Konstantin, Sutter, Christian, Rump, Andreas, Arnold, Norbert ORCID: 0000-0003-4523-8808, Wang-Gohrke, Shan, Horvath, Judit, Gehrig, Andrea, Schmidt, Gunnar, Dutrannoy, Veronique, Ramser, Juliane, Hentschel, Julia, Meindl, Alfons, Schroeder, Christopher, Wappenschmidt, Barbara, Engel, Christoph ORCID: 0000-0002-7247-282X, Kuchenbaecker, Karoline, Schmutzler, Rita K., Friedman, Eitan, Hahnen, Eric and Ernst, Corinna (2022). Polygenic risk scores indicate extreme ages at onset of breast cancer in female BRCA1/2 pathogenic variant carriers. BMC Cancer, 22 (1). LONDON: BMC. ISSN 1471-2407

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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.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Borde, Julika UNSPECIFIED UNSPECIFIED UNSPECIFIED Laitman, Yael UNSPECIFIED UNSPECIFIED UNSPECIFIED Bluemcke, Britta UNSPECIFIED UNSPECIFIED UNSPECIFIED Niederacher, Dieter UNSPECIFIED UNSPECIFIED UNSPECIFIED Weber-Lassalle, Konstantin UNSPECIFIED UNSPECIFIED UNSPECIFIED Sutter, Christian UNSPECIFIED UNSPECIFIED UNSPECIFIED Rump, Andreas UNSPECIFIED UNSPECIFIED UNSPECIFIED Arnold, Norbert UNSPECIFIED orcid.org/0000-0003-4523-8808 UNSPECIFIED Wang-Gohrke, Shan UNSPECIFIED UNSPECIFIED UNSPECIFIED Horvath, Judit UNSPECIFIED UNSPECIFIED UNSPECIFIED Gehrig, Andrea UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmidt, Gunnar UNSPECIFIED UNSPECIFIED UNSPECIFIED Dutrannoy, Veronique UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramser, Juliane UNSPECIFIED UNSPECIFIED UNSPECIFIED Hentschel, Julia UNSPECIFIED UNSPECIFIED UNSPECIFIED Meindl, Alfons UNSPECIFIED UNSPECIFIED UNSPECIFIED Schroeder, Christopher UNSPECIFIED UNSPECIFIED UNSPECIFIED Wappenschmidt, Barbara UNSPECIFIED UNSPECIFIED UNSPECIFIED Engel, Christoph UNSPECIFIED orcid.org/0000-0002-7247-282X UNSPECIFIED Kuchenbaecker, Karoline UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmutzler, Rita K. UNSPECIFIED UNSPECIFIED UNSPECIFIED Friedman, Eitan UNSPECIFIED UNSPECIFIED UNSPECIFIED Hahnen, Eric UNSPECIFIED UNSPECIFIED UNSPECIFIED Ernst, Corinna UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-696472
DOI:	10.1186/s12885-022-09780-1
Journal or Publication Title:	BMC Cancer
Volume:	22
Number:	1
Date:	2022
Publisher:	BMC
Place of Publication:	LONDON
ISSN:	1471-2407
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language HEREDITARY BREAST; FAMILY-HISTORY; OVARIAN; MUTATIONS; ASSOCIATION; PREDICTION; MODIFIERS; WOMEN; LIFE Multiple languages Oncology Multiple languages
URI:	http://kups.ub.uni-koeln.de/id/eprint/69647