e13015 Background: Imbalance in DNA methylation/demethylation cycles due to mutations in TET1, TET2, TET3, and TDG has been implicated in the onset and progression of breast cancer. However, few studies have assessed the relationship between genetic variants in the TET-related DNA demethylation pathway and breast cancer risk, particularly among women of African ancestry. Methods: We investigated 4095 single-nucleotide polymorphisms (SNPs) in four TET-related DNA demethylation pathway genes in the ROOT consortium, which includes women of African ancestry, in 1657 cases [403 estrogen receptor-positive (ER+) and 374 ER-negative (ER-)] and 2029 controls. Pathway and gene-level analyses were conducted using the adaptive rank truncated product (ARTP) test for 925 SNPs that were not highly correlated (r2 < 0.8), and SNP-level analyses were conducted with logistic regression, which was used to estimate the odds ratio (OR) and 95 % confidence intervals (CI). Results: The Tet-related DNA demethylation pathway was significantly associated with ER-negative breast cancer (pathway level P = 0.049). Gene-level analyses showed that TET1 was the candidate gene responsible for the association at the pathway level ( P = 0.008). SNP TET1 rs10998376 (OR = 1.21, 95% CI = 1.02-1.42, Padj = 0.0032) was statistically significant even after gene-level correction for multiple comparisons, and was associated with increased risk. There were no SNPs in genes with P > 0.05 in the ARTP tests that were significant after Boferroni correction. Conclusions: In conclusion, specific TET-related DNA demethylation pathway genes may contribute to breast cancer risk, in particular, to risk of ER-negative tumors in women of African ancestry.
Association between common variation in 120 candidate genes and breast cancer risk
