Common Genetic Variants for Breast Cancer: 32 Largely Refuted Candidates and Larger Prospects

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Abstract
Many common diseases, including most cancers ( 1 ) , may have a component of inheritance that is due to low-penetrance, common genetic variants. However, identifying these variants has been a challenge. In this issue of the Journal, the Breast Cancer Association Consortium reports an impressive collaborative effort—the large-scale evaluation of 16 single nucleotide polymorphisms (SNPs) that have been previously hypothesized to modify susceptibility to breast cancer ( 2 ) . Despite accumulated genotype information on 12 000–32 000 breast cancer case and control subjects for each SNP, results are largely null. No SNP shows an association with P <.0031, the threshold required after adjusting for 16 tests. Five variants with P values between .009 and .06 require further testing, but the odds ratios (ORs) are already hovering at around 0.9–1.1. For the other 11 SNPs, results are even more conclusively null. Extensive subgroup analyses largely reinforce these conclusions.