Low penetrance breast cancer susceptibility loci are associated with specific breast tumor subtypes: findings from the Breast Cancer Association Consortium

Abstract

Breast cancers demonstrate substantial biological, clinical and etiological heterogeneity. We investigated breast cancer risk associations of eight susceptibility loci identified in GWAS and two putative susceptibility loci in candidate genes in relation to specific breast tumor subtypes. Subtypes were defined by five markers (ER, PR, HER2, CK5/6, EGFR) and other pathological and clinical features. Analyses included up to 30 040 invasive breast cancer cases and 53 692 controls from 31 studies within the Breast Cancer Association Consortium. We confirmed previous reports of stronger associations with ER+ than ER- tumors for six of the eight loci identified in GWAS: rs2981582 (10q26) (P-heterogeneity = 6.1 × 10(-18)), rs3803662 (16q12) (P = 3.7 × 10(-5)), rs13281615 (8q24) (P = 0.002), rs13387042 (2q35) (P = 0.006), rs4973768 (3p24) (P = 0.003) and rs6504950 (17q23) (P = 0.002). The two candidate loci, CASP8 (rs1045485, rs17468277) and TGFB1 (rs1982073), were most strongly related with the risk of PR negative tumors (P = 5.1 × 10(-6) and P = 4.1 × 10(-4), respectively), as previously suggested. Four of the eight loci identified in GWAS were associated with triple negative tumors (P ≤ 0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35); however, only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (P ≤ 0.002). These analyses are consistent with different biological origins of breast cancers, and indicate that tumor stratification might help in the identification and characterization of novel risk factors for breast cancer subtypes. This may eventually result in further improvements in prevention, early detection and treatment.

Heterogeneity of epidemiological factors by breast tumor subtypes in Korean women: A case-case study

“…27 These heterogeneities were supported by the associations of epidemiological and genetic factors including copy number, gene expression and genetic variants with distinct tumor subtypes. 24,[28][29][30] Consistently, our study provides evidence on the epidemiological heterogeneity within breast tumor subtypes, supporting that the well-known risk factors of breast cancer are more frequent in HR1 HER22 but not in the other subtypes.…”

Unbiased analysis of potential targets of breast cancer susceptibility loci by Capture Hi-C

“…rs13387042 (2q35), rs13281615 (8q24.21), and rs865686 (9q32.1) are all strongly associated with predisposition to estrogen receptor (ER)-positive disease (Broeks et al 2011;Warren et al 2012); they are less strongly associated with ER-negative disease and have not been shown to be associated with disease progression (Fasching et al 2012). We therefore selected BT483 cells (Lasfargues et al 1978), because, unlike most breast cancer cell lines that are derived from (metastatic) pleural effusions, BT483 cells are derived from a primary invasive ductal carcinoma.…”

Breast cancer genome-wide association studies: there is strength in numbers

“…Four loci were associated with triple negative tumors (Pp0.016): rs3803662 (16q12), rs889312 (5q11), rs3817198 (11p15) and rs13387042 (2q35) but only two of them (16q12 and 2q35) were associated with tumors with the core basal phenotype (Pp0.002). This study identifying novel risk factors associated with BC subtypes could allow a better tumor stratification resulting in prevention, early detection and treatment improvement (Broeks et al, 2011).…”