This study shows that reproductive factors and BMI are most clearly associated with hormone receptor-positive tumors and suggest that triple-negative or CBP tumors may have distinct etiology.
Analysis of 4,405 variants in 89,050 European subjects from 41 case-control studies identified three independent association signals for estrogen-receptor-positive tumors at 11q13. The strongest signal maps to a transcriptional enhancer element in which the G allele of the best candidate causative variant rs554219 increases risk of breast cancer, reduces both binding of ELK4 transcription factor and luciferase activity in reporter assays, and may be associated with low cyclin D1 protein levels in tumors. Another candidate variant, rs78540526, lies in the same enhancer element. Risk association signal 2, rs75915166, creates a GATA3 binding site within a silencer element. Chromatin conformation studies demonstrate that these enhancer and silencer elements interact with each other and with their likely target gene, CCND1.
GWAS have identified a breast cancer susceptibility locus on 2q35. Here we report the
fine mapping of this locus using data from 101,943 subjects from 50 case-control
studies. We genotype 276 SNPs using the ‘iCOGS’ genotyping
array and impute genotypes for a further 1,284 using 1000 Genomes Project data. All
but two, strongly correlated SNPs (rs4442975 G/T and rs6721996 G/A) are excluded as
candidate causal variants at odds against >100:1. The best functional
candidate, rs4442975, is associated with oestrogen
receptor positive (ER+) disease with an odds ratio (OR) in Europeans of 0.85 (95%
confidence interval=0.84−0.87; P=1.7 ×
10−43) per t-allele. This SNP flanks a
transcriptional enhancer that physically interacts with the promoter of
IGFBP5 (encoding insulin-like growth factor-binding protein 5)
and displays allele-specific gene expression, FOXA1 binding and chromatin looping. Evidence suggests that the
g-allele confers increased breast cancer susceptibility through relative
downregulation of IGFBP5, a
gene with known roles in breast cell biology.
A tumorigenic role of the nonhomologous end-joining (NHEJ) pathway for the repair of DNA double-strand breaks (DSBs) has been suggested by the finding of a significant association between increased breast cancer risk and a cooperative effect of single nucleotide polymorphisms (SNPs) in NHEJ genes. However, the lack of an association between hereditary breast cancer and defective NHEJ genes prevents conclusions from being drawn about a link between NHEJ and breast cancer development. Recently, BRCA1-deficient mouse embryonic fibroblasts were found to have significantly reduced NHEJ activity, suggesting an accessory role of BRCA1 in NHEJ. The present study was performed to confirm this observation in human breast cancer cell lines and to examine whether the interaction between BRCA1 and NHEJ was of tumorigenic significance. Support for this hypothesis came from the findings that (a) a case-control study (469 breast cancer patients and 740 healthy controls) showed that the breast cancer risk associated with high-risk genotypes of NHEJ genes was significantly modified by the BRCA1 genotype. A significant increase in the cancer risk associated either with harboring one additional putative high-risk NHEJ genotype or with the joint effect of having reproductive risk factors (reflected by an interval of >12 years between menarche and first full-term pregnancy) and a higher number of high-risk genotypes of the NHEJ genes was only seen in women with at least one variant BRCA1 allele (i.e., the Glu/Gly or Gly/Gly forms of BRCA1 Glu 1038 Gly); and (b) a phenotype-based study measuring in vitro and in vivo NHEJ capacity showed that the precise end-joining capacity was different in breast cancer cell lines with different BRCA1 statuses being higher in BRCA1-expressing MCF-7 cells than in HCC1937 cells (defective BRCA1 expression). Furthermore, this end-joining capacity was decreased in MCF-7 cells in which BRCA1 expression was blocked using small interfering RNA and increased in HCC1937 transfected with full-length BRCA1. Because BRCA1 is a well-documented breast cancer susceptibility gene, this association between NHEJ and BRCA1 not only suggests a role of BRCA1 in NHEJ but also provides essential support for the tumorigenic contribution of NHEJ in breast cancer development.
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