Abstract
There are significant inter-individual differences in the levels of gene expression. Through modulation of gene expression, cis-acting variants represent an important source of phenotypic variation. Consequently, cis-regulatory SNPs associated with differential allelic expression are functional candidates for further investigation as disease-causing variants. To investigate whether common variants associated with differential allelic expression were involved in breast cancer susceptibility, a list of genes was established on the basis of their involvement in cancer related pathways and/or mechanisms. Thereafter, using data from a genome-wide map of allelic expression associated SNPs, 313 genetic variants were selected and their association with breast cancer risk was then evaluated in 46,451 breast cancer cases and 42,599 controls of European ancestry ascertained from 41 studies participating in the Breast Cancer Association Consortium. The associations were evaluated with overall breast cancer risk and with estrogen receptor negative and positive disease. One novel breast cancer susceptibility locus on 4q21 (rs11099601) was identified (OR = 1.05, P = 5.6x10-6). rs11099601 lies in a 135 kb linkage disequilibrium block containing several genes, including, HELQ, encoding the protein HEL308 a DNA dependant ATPase and DNA Helicase involved in DNA repair, MRPS18C encoding the Mitochondrial Ribosomal Protein S18C and FAM175A (ABRAXAS), encoding a BRCA1 BRCT domain-interacting protein involved in DNA damage response and double-strand break (DSB) repair. Expression QTL analysis in breast cancer tissue showed rs11099601 to be associated with HELQ (P = 8.28x10-14), MRPS18C (P = 1.94x10-27) and FAM175A (P = 3.83x10-3), explaining about 20%, 14% and 1%, respectively of the variance inexpression of these genes in breast carcinomas.
Highlights
Breast cancer is a complex disease with a strong heritable component
For the one hundred seventy-five selected genes involved in cancer-related pathways, we identified a set of 355 genetic variants showing evidence of association with www.impactjournals.com/oncotarget
We have shown HELQ to be differentially expressed between normal breast and tumor tissue and to be significantly down regulated in basal-like breast tumors compared to estrogen receptor (ER) positive tumors, suggesting that altered gene expression levels, potentially mediated through the effect of regulatory variants, could be one of the mechanisms contributing to breast cancer susceptibility
Summary
Breast cancer is a complex disease with a strong heritable component. Great efforts have been made during the last decades to elucidate the underlying etiology of this disease. Recent evidence has suggested that differences in gene expression play a critical role in the underlying phenotypic variation associated with many complex genetic diseases [48]. A recent study has shown that close to half of the known risk alleles for estrogen receptor (ER)-positive breast cancer are eQTLs acting upon major determinants of gene expression in tumors [50]. These results suggest that additional cancer susceptibility loci may be identified through studying genetic variants affecting regulation of gene expression
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