Universität zu Köln

Kuchenbaecker, Karoline B., McGuffog, Lesley, Barrowdale, Daniel ORCID: 0000-0003-1661-3939, Lee, Andrew, Soucy, Penny, Dennis, Joe, Domchek, Susan M., Robson, Mark, Spurdle, Amanda B., Ramus, Susan J., Mavaddat, Nasim, Terry, Mary Beth, Neuhausen, Susan L., Schmutzler, Rita Katharina, Simard, Jacques, Pharoah, Paul D. P., Offit, Kenneth, Couch, Fergus J., Chenevix-Trench, Georgia ORCID: 0000-0002-1878-2587, Easton, Douglas F. and Antoniou, Antonis C. (2017). Evaluation of Polygenic Risk Scores for Breast and Ovarian Cancer Risk Prediction in BRCA1 and BRCA2 Mutation Carriers. JNCI-J. Natl. Cancer Inst., 109 (7). CARY: OXFORD UNIV PRESS INC. ISSN 1460-2105

Full text not available from this repository.

Abstract

Background: Genome-wide association studies (GWAS) have identified 94 common single-nucleotide polymorphisms (SNPs) associated with breast cancer (BC) risk and 18 associated with ovarian cancer (OC) risk. Several of these are also associated with risk of BC or OC for women who carry a pathogenic mutation in the high-risk BC and OC genes BRCA1 or BRCA2. The combined effects of these variants on BC or OC risk for BRCA1 and BRCA2 mutation carriers have not yet been assessed while their clinical management could benefit from improved personalized risk estimates. Methods: We constructed polygenic risk scores (PRS) using BC and OC susceptibility SNPs identified through population-based GWAS: for BC (overall, estrogen receptor [ER]-positive, and ER-negative) and for OC. Using data from 15 252 female BRCA1 and 8211 BRCA2 carriers, the association of each PRS with BC or OC risk was evaluated using a weighted cohort approach, with time to diagnosis as the outcome and estimation of the hazard ratios (HRs) per standard deviation increase in the PRS. Results: The PRS for ER-negative BC displayed the strongest association with BC risk in BRCA1 carriers (HR = 1.27, 95% confidence interval [CI] = 1.23 to 1.31, P = 8.2 x 10(53)). In BRCA2 carriers, the strongest association with BC risk was seen for the overall BC PRS (HR = 1.22, 95% CI = 1.17 to 1.28, P = 7.2 x 10(-20)). The OC PRS was strongly associated with OC risk for both BRCA1 and BRCA2 carriers. These translate to differences in absolute risks (more than 10% in each case) between the top and bottom deciles of the PRS distribution; for example, the OC risk was 6% by age 80 years for BRCA2 carriers at the 10th percentile of the OC PRS compared with 19% risk for those at the 90th percentile of PRS. Conclusions: BC and OC PRS are predictive of cancer risk in BRCA1 and BRCA2 carriers. Incorporation of the PRS into risk prediction models has promise to better inform decisions on cancer risk management.

Item Type:	Journal Article
Creators:	Creators Email ORCID ORCID Put Code Kuchenbaecker, Karoline B. UNSPECIFIED UNSPECIFIED UNSPECIFIED McGuffog, Lesley UNSPECIFIED UNSPECIFIED UNSPECIFIED Barrowdale, Daniel UNSPECIFIED orcid.org/0000-0003-1661-3939 UNSPECIFIED Lee, Andrew UNSPECIFIED UNSPECIFIED UNSPECIFIED Soucy, Penny UNSPECIFIED UNSPECIFIED UNSPECIFIED Dennis, Joe UNSPECIFIED UNSPECIFIED UNSPECIFIED Domchek, Susan M. UNSPECIFIED UNSPECIFIED UNSPECIFIED Robson, Mark UNSPECIFIED UNSPECIFIED UNSPECIFIED Spurdle, Amanda B. UNSPECIFIED UNSPECIFIED UNSPECIFIED Ramus, Susan J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Mavaddat, Nasim UNSPECIFIED UNSPECIFIED UNSPECIFIED Terry, Mary Beth UNSPECIFIED UNSPECIFIED UNSPECIFIED Neuhausen, Susan L. UNSPECIFIED UNSPECIFIED UNSPECIFIED Schmutzler, Rita Katharina UNSPECIFIED UNSPECIFIED UNSPECIFIED Simard, Jacques UNSPECIFIED UNSPECIFIED UNSPECIFIED Pharoah, Paul D. P. UNSPECIFIED UNSPECIFIED UNSPECIFIED Offit, Kenneth UNSPECIFIED UNSPECIFIED UNSPECIFIED Couch, Fergus J. UNSPECIFIED UNSPECIFIED UNSPECIFIED Chenevix-Trench, Georgia UNSPECIFIED orcid.org/0000-0002-1878-2587 UNSPECIFIED Easton, Douglas F. UNSPECIFIED UNSPECIFIED UNSPECIFIED Antoniou, Antonis C. UNSPECIFIED UNSPECIFIED UNSPECIFIED
URN:	urn:nbn:de:hbz:38-226668
DOI:	10.1093/jnci/djw302
Journal or Publication Title:	JNCI-J. Natl. Cancer Inst.
Volume:	109
Number:	7
Date:	2017
Publisher:	OXFORD UNIV PRESS INC
Place of Publication:	CARY
ISSN:	1460-2105
Language:	English
Faculty:	Unspecified
Divisions:	Unspecified
Subjects:	no entry
Uncontrolled Keywords:	Keywords Language EARLY BILATERAL OOPHORECTOMY; WIDE ASSOCIATION ANALYSIS; SUSCEPTIBILITY ALLELES; FUNCTIONAL VARIANTS; LOCUS; WOMEN; IDENTIFICATION; MORTALITY; MODIFIERS; COHORT Multiple languages Oncology Multiple languages
Refereed:	Yes
URI:	http://kups.ub.uni-koeln.de/id/eprint/22666