To determine whether associations between estrogen pathway-related single nucleotide polymorphisms (SNPs) and breast cancer risk differ by molecular subtype, we evaluated associations between SNPs in cytochrome P450 family 19 subfamily A polypeptide 1 (CYP19A1), estrogen receptor (ESR1), 3-beta hydroxysteroid dehydrogenase type I (HSD3B1), 17-beta hydroxysteroid dehydrogenase type II (HSD17B2), progesterone receptor (PGR), and sex hormone-binding globulin (SHBG) and breast cancer risk in a case-control study in North Carolina.
Cases (N=1,972) were women 20–74 years old and diagnosed with breast cancer between 1993 and 2001. Population-based controls (N=1,776) were frequency-matched to cases by age and race. 195 SNPs were genotyped and linkage disequilibrium was evaluated using the r2 statistic. Odds ratios (ORs) and 95% confidence intervals (CIs) for associations with breast cancer overall and by molecular subtype were estimated using logistic regression. Monte Carlo methods were used to control for multiple comparisons; two-sided P values <3.3 × 10−4 were statistically significant. Heterogeneity tests comparing the two most common subtypes, luminal A (N=679) and basal-like (N=200), were based on the Wald statistic.
ESR1 rs6914211 (AA vs. AT+TT, OR=2.24, CI: 1.51, 3.33), ESR1 rs985191 (CC vs. AA, OR=2.11, CI: 1.43, 3.13), and PGR rs1824128 (TT+GT vs. GG, OR=1.33, CI: 1.14, 1.55) were associated with risk after accounting for multiple comparisons. Rs6914211 and rs985191 were in strong linkage disequilibrium among controls (African Americans r2=0.70; whites r2=0.95). There was no evidence of heterogeneity between luminal A and basal-like subtypes, and the three SNPs were also associated with elevated risk of the less common luminal B, HER2+/ER− and unclassified subtypes.
ESR1 and PGR SNPs were associated with risk, but lack of heterogeneity between subtypes suggests variants in hormone-related genes may play similar roles in the etiology of breast cancer molecular subtypes.