Prediction of breast cancer risk based on profiling with common genetic variants
Research output: Contribution to journal › Journal article › Research › peer-review
Nasim Mavaddat, Paul D P Pharoah, Kyriaki Michailidou, Jonathan Tyrer, Mark N Brook, Manjeet K Bolla, Qin Wang, Joe Dennis, Alison M Dunning, Mitul Shah, Robert Luben, Judith Brown, Stig E Bojesen, Børge G Nordestgaard, Sune F Nielsen, Henrik Flyger, Kamila Czene, Hatef Darabi, Mikael Eriksson, Julian Peto & 192 others
BACKGROUND: Data for multiple common susceptibility alleles for breast cancer may be combined to identify women at different levels of breast cancer risk. Such stratification could guide preventive and screening strategies. However, empirical evidence for genetic risk stratification is lacking.
METHODS: We investigated the value of using 77 breast cancer-associated single nucleotide polymorphisms (SNPs) for risk stratification, in a study of 33 673 breast cancer cases and 33 381 control women of European origin. We tested all possible pair-wise multiplicative interactions and constructed a 77-SNP polygenic risk score (PRS) for breast cancer overall and by estrogen receptor (ER) status. Absolute risks of breast cancer by PRS were derived from relative risk estimates and UK incidence and mortality rates.
RESULTS: There was no strong evidence for departure from a multiplicative model for any SNP pair. Women in the highest 1% of the PRS had a three-fold increased risk of developing breast cancer compared with women in the middle quintile (odds ratio [OR] = 3.36, 95% confidence interval [CI] = 2.95 to 3.83). The ORs for ER-positive and ER-negative disease were 3.73 (95% CI = 3.24 to 4.30) and 2.80 (95% CI = 2.26 to 3.46), respectively. Lifetime risk of breast cancer for women in the lowest and highest quintiles of the PRS were 5.2% and 16.6% for a woman without family history, and 8.6% and 24.4% for a woman with a first-degree family history of breast cancer.
CONCLUSIONS: The PRS stratifies breast cancer risk in women both with and without a family history of breast cancer. The observed level of risk discrimination could inform targeted screening and prevention strategies. Further discrimination may be achievable through combining the PRS with lifestyle/environmental factors, although these were not considered in this report.
|Journal||National Cancer Institute. Journal (Print)|
|Number of pages||15|
|Publication status||Published - May 2015|
- Adult, Aged, Biomarkers, Tumor, Breast Neoplasms, Europe, Female, Gene Expression Profiling, Gene Expression Regulation, Neoplastic, Genetic Predisposition to Disease, Genotype, Humans, Middle Aged, Odds Ratio, Polymorphism, Single Nucleotide, Predictive Value of Tests, Receptors, Estrogen, Risk Assessment, Risk Factors