Mavaddat, N;
Michailidou, K;
Dennis, J;
Lush, M;
Fachal, L;
Lee, A;
Tyrer, JP;
... Easton, DF; + view all
(2019)
Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes.
American Journal of Human Genetics
, 104
(1)
pp. 21-34.
10.1016/j.ajhg.2018.11.002.
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Abstract
Stratification of women according to their risk of breast cancer based on polygenic risk scores (PRSs) could improve screening and prevention strategies. Our aim was to develop PRSs, optimized for prediction of estrogen receptor (ER)-specific disease, from the largest available genome-wide association dataset and to empirically validate the PRSs in prospective studies. The development dataset comprised 94,075 case subjects and 75,017 control subjects of European ancestry from 69 studies, divided into training and validation sets. Samples were genotyped using genome-wide arrays, and single-nucleotide polymorphisms (SNPs) were selected by stepwise regression or lasso penalized regression. The best performing PRSs were validated in an independent test set comprising 11,428 case subjects and 18,323 control subjects from 10 prospective studies and 190,040 women from UK Biobank (3,215 incident breast cancers). For the best PRSs (313 SNPs), the odds ratio for overall disease per 1 standard deviation in ten prospective studies was 1.61 (95%CI: 1.57-1.65) with area under receiver-operator curve (AUC) = 0.630 (95%CI: 0.628-0.651). The lifetime risk of overall breast cancer in the top centile of the PRSs was 32.6%. Compared with women in the middle quintile, those in the highest 1% of risk had 4.37- and 2.78-fold risks, and those in the lowest 1% of risk had 0.16- and 0.27-fold risks, of developing ER-positive and ER-negative disease, respectively. Goodness-of-fit tests indicated that this PRS was well calibrated and predicts disease risk accurately in the tails of the distribution. This PRS is a powerful and reliable predictor of breast cancer risk that may improve breast cancer prevention programs.
| Type: | Article |
|---|---|
| Title: | Polygenic Risk Scores for Prediction of Breast Cancer and Breast Cancer Subtypes |
| Location: | United States |
| Open access status: | An open access version is available from UCL Discovery |
| DOI: | 10.1016/j.ajhg.2018.11.002 |
| Publisher version: | http://doi.org/10.1016/j.ajhg.2018.11.002 |
| Language: | English |
| Additional information: | Copyright © 2018 American Society of Human Genetics. Open Access This article is published under Attribution-Non Commercial-NoDerivatives 4.0 International (CC BY-NC-ND 4.0) license. |
| Keywords: | breast, cancer, epidemiology, genetic, polygenic, prediction, risk, score, screening, stratification |
| UCL classification: | UCL UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Population Health Sciences > Inst of Clinical Trials and Methodology > MRC Clinical Trials Unit at UCL |
| URI: | https://discovery.ucl.ac.uk/id/eprint/10065044 |
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