A Comprehensive cis-eQTL Analysis Revealed Target Genes in Breast Cancer Susceptibility Loci Identified in Genome-wide Association Studies

Abstract

Genome-wide association studies (GWASs) have identified more than 150 common genetic loci for breast cancer risk. However, the target genes and underlying mechanisms remain largely unknown. We conducted a cis-expression quantitative trait loci (cis-eQTL) analysis using normal or tumor breast transcriptome data from the Molecular Taxonomy of Breast Cancer International Consortium (METABRIC), The Cancer Genome Atlas (TCGA), and the Genotype-Tissue Expression (GTEx) project. We identified a total of 101 genes for 51 lead variants after combing the results of a meta-analysis of METABRIC and TCGA, and the results from GTEx at a Benjamini-Hochberg (BH)-adjusted p < 0.05. Using luciferase reporter assays in both estrogen-receptor positive (ER) and negative (ER) cell lines, we showed that alternative alleles of potential functional single-nucleotide polymorphisms (SNPs), rs11552449 (DCLRE1B), rs7257932 (SSBP4), rs3747479 (MRPS30), rs2236007 (PAX9), and rs73134739 (ATG10), could significantly change promoter activities of their target genes compared to reference alleles. Furthermore, we performed in vitro assays in breast cancer cell lines, and our results indicated that DCLRE1B, MRPS30, and ATG10 played a vital role in breast tumorigenesis via certain disruption of cell behaviors. Our findings revealed potential target genes for associations of genetic susceptibility risk loci and provided underlying mechanisms for a better understanding of the pathogenesis of breast cancer.

Primo: integration of multiple GWAS and omics QTL summary statistics for elucidation of molecular mechanisms of trait-associated SNPs and detection of pleiotropy in complex traits

“…Application I: Understanding the mechanisms of breast cancer susceptibility loci With over 100,000 breast cancer cases and a similar number of controls from a total of 78 breast cancer studies, BCAC [35] has recently reported 174 common genetic variants associated with breast cancer risk. In order to understand the underlying mechanisms of those susceptibility risk loci and their potential cis target genes, a recent study [45] conducted cis-eQTL analysis using both normal and tumor breast transcriptome data and identified multiple genes likely to play important roles in breast tumorgenesis.…”

“…At the 80% probability cutoff and after conditional association analysis (estimated FDR of 3.8, 6.2, 12.2, and 8.5%), there were 49, 18, 7 and 1 susceptibility loci associated with at least 1, 2, 3 or 4 omics traits, respectively. The three GWAS SNPs (rs11552449, rs3747479, and rs73134739) in the three genes (DCLRE1B, MRPS30, and ATG10, respectively) reported in Guo, et al (2018) [45] had high probabilities of being an eQTL in both tumor and normal tissues (with probabilities of 59.7, >99.9, and >99.9%, respectively). In the KLHDC7A gene region, the GWAS SNP rs2992756 (indicated by red dot in Figure 3) is associated with the expression, methylation and global protein abundance levels of the cis-gene KLHDC7A.…”

Variable expression quantitative trait loci analysis of breast cancer risk variants

“…No significant associations were observed in the kidney analysis. By comparison, the number of observed eQTL in breast (155), ovary (19) and lung (123) were greater, similarly there were no significant kidney eQTL. The majority of veQTL and eQTL associations were trans and acted over distances greater than 1 Mb or between chromosomes.…”

“…The effects of genetic variation on gene expression variability has been recently described in human derived lymphoblastoid cell lines from HapMap individuals 8 and in the TwinsUK cohort 16,17 . 4 Breast cancer risk variants associated with eQTL, based on mean gene expression, have been investigated in both breast tissue (tumour and normal), and non-breast tissue 5,[18][19][20] . However, the mechanisms underlying breast cancer risk for the majority of variants remains to be uncovered.…”

Discovery of rare coding variants in OGDHL and BRCA2 in relation to breast cancer risk in Chinese women

“…5,7,11 The missing heritability could be partially attributed to risk-associated rare coding variants (MAF < 0.5%), which typically have large effect sizes, as demonstrated in multiple hereditary breast cancer genes, such as BRCA1, BRCA2, ATM, TP53, CHEK2, PALB2, CDH1, STK11, NF1 and PTEN. [12][13][14][15][16][17][18][19][20][21][22][23][24][25] Two recent case-control association studies conducted in European-ancestry populations discovered many new pathogenic coding variants by sequencing known cancer predisposition genes. 22,23 However, rare coding variants in known breast cancer susceptibility genes and other less well-characterized genes have not been adequately investigated in Asian populations.…”