Fig. 1

Overview of the analytic strategy and results from the investigation of 173 known breast cancer susceptibility variants for evidence of heterogeneity of effect according to the estrogen receptor (ER), progesterone receptor (PR), human epidermal growth factor receptor 2 (HER2), and grade. ^aWe evaluated 173 breast cancer risk variants identified in or replicated by prior BCAC GWAS [6, 7], see Methods and Additional file 3: Methods sections for more details. ^bModel 1 (primary analyses): Mixed-effect two-stage polytomous model (ER as fixed-effect, and PR, HER2 and grade as random-effects) for global heterogeneity tests (i.e. case-case comparisons from stage 2 of the two-stage model) between each individual risk variant and any of the tumor features (separate models were fit for each variant). ^cModel 2: Fixed-effect two-stage polytomous model for marker-specific tumor heterogeneity tests (i.e. case-case comparisons from stage 2 of the two-stage model) between each individual variant and each of the tumor features (ER, PR, HER2, and grade), mutually adjusted for each other (separate models were fit for each variant). ^dModel 3: Fixed effect two-stage polytomous model for risk associations with intrinsic-like subtypes (i.e. case–control comparisons from stage 1 of the two-stage model): luminal A-like, luminal B-like/HER2-negative, luminal B-like/HER2-positive, HER2-positive/non-luminal, and triple-negative. ^eModel 4: Fixed effect two-stage polytomous model for risk associations with tumor grade (i.e. case–control comparisons from stage 1 of the two-stage model) for the 12 variants associated at p < 0.05 only with grade in case-case comparisons (from model 2): grade 1, grade 2, and grade 3