Genetic susceptibility to triple-negative breast cancer

Abstract

Triple-negative breast cancers (TNBC), defined by the absence of estrogen receptor, progesterone receptor, and HER-2 expression, account for 12% to 24% of all breast cancers. TNBC is associated with early recurrence of disease and poor outcome. Germline mutations in the BRCA1 and BRCA2 breast cancer susceptibility genes have been associated with up to 15% of TNBC, and TNBC accounts for 70% of breast tumors arising in BRCA1 mutation carriers and 16% to 23% of breast tumors in BRCA2 carriers. Whether germline mutations in other breast cancer susceptibility genes also predispose to TNBC remains to be determined. Common variation in a subset of the 72 known breast cancer susceptibility loci identified through genome-wide association studies and other large-scale genotyping efforts have also been associated with risk of TNBC (TOX3, ESR1, RAD51L1, TERT, 19p13.1, 20q11, MDM4, 2p24.1, and FTO). Furthermore, variation in the 19p13.1 locus and the MDM4 locus has been associated with TNBC, but not other forms of breast cancer, suggesting that these are TNBC-specific loci. Thus, TNBC can be distinguished from other breast cancer subtypes by a unique pattern of common and rare germline predisposition alleles. Additional efforts to combine genetic and epidemiologic data are needed to better understand the etiology of this aggressive form of breast cancer, to identify prevention and therapeutic targets, and to impact clinical practice through the development of risk prediction models.

Figure 1. Triple negative breast cancer susceptibility loci across breast cancer subtypes

Forest plots for thirteen TNBC susceptibility variants are shown to provide visual comparison of the strength and direction of association between each SNP and risk of a) ER-positive breast cancer, b) ER-negative breast cancer, c) triple negative breast cancer, and d) BRCA1-related breast cancers. The thirteen SNPs are stratified by strength of evidence for association with TNBC risk (strong vs. marginal). For each breast cancer subtype, estimates (odds ratios (OR) and 95% confidence intervals (CIs)) are shown for each variant from largest study of each relevant breast cancer subtype. ORs are denoted by black boxes and 95% CIs are denoted by corresponding black lines. Box heights are inversely proportional to precision of the OR estimate as influenced by sample size, such that a larger OR box indicates larger sample size and better precision. A vertical grey line is shown at the null value of 1, such that ORs to the left of the null line are <1 and ORs to the right of the null line are >1. Estimates with confidence intervals that do not overlap the null line indicate significance at p<0.05. ^a ER-positive and ER-negative estimates from a GWAS of Asian women; TN and BRCA1 carrier estimates from studies of women of European ancestry. ^b Estimate shown for rs12662670 TNBC and for rs9397435 in ER-positives, ER-negatives, and BRCA1 carriers ^c Previously unpublished data from TNBCC ^d Estimate shown for rs10483813/rs999737 in ER-negatives and ER-positives, rs999737 in TNBC, and rs1801320 (HR for GG vs CC) in BRCA1 carriers ^e Estimate shown for rs17468277/rs1045485 in ER-negatives and ER-positives, rs17468277 in TNBC, and rs1045485 in BRCA1 carriers.