Ability to predict breast cancer in Asian women using a polygenic susceptibility model

Recently identified susceptibility alleles from Genome-Wide Association Studies (GWAS) for breast cancer provide an option to stratify women for their breastcancer risk based on these alleles. This may allow greater precision in targeting preventive efforts at genetically highrisk groups. Given the variation in allele frequencies between populations, the utility of such risk-stratification may vary in different populations. We examined the possibility for individualized disease risk stratification based on common breast cancer risk alleles, and its potential impact on population-based screening in a population of Asian women. We assigned allele frequencies based on available data from the Singapore Genome Variation project and tested the utility of 13 previously validated single nucleotide polymorphisms in predicting risk using simulation and originally reported relative risks. We also tested how these markers performed collectively in distinguishing risk groups and evaluated their possible use for individualized mammography screening. Our analysis suggests that the risk profile generated by 13 single nucleotide polymorphisms as identified through GWAS provides different risk profiles between ethnic groups (population genetic mean relative risk = 0.698, 0.617, 0.661, 0.743 for Caucasians, Singapore Chinese, Singaporean Malays, and Singaporean Indians, respectively) but that it does not provide sufficient discrimination to be useful in individualized prevention. Furthermore, these markers are not useful in risk stratification for population-based screening programs due to both cost and under-diagnosis of breast cancers in the general population. The clinical use of single, common, low-penetrance genes for breast cancer risk prediction in an Asian setting is currently limited