Genome-wide association and transcriptome studies identify target genes and risk loci for breast cancer

Abstract

Genome-wide association studies (GWAS) have identified more than 170 breast cancer susceptibility loci. Here we hypothesize that some risk-associated variants might act in non-breast tissues, specifically adipose tissue and immune cells from blood and spleen. Using expression quantitative trait loci (eQTL) reported in these tissues, we identify 26 previously unreported, likely target genes of overall breast cancer risk variants, and 17 for estrogen receptor (ER)-negative breast cancer, several with a known immune function. We determine the directional effect of gene expression on disease risk measured based on single and multiple eQTL. In addition, using a gene-based test of association that considers eQTL from multiple tissues, we identify seven (and four) regions with variants associated with overall (and ER-negative) breast cancer risk, which were not reported in previous GWAS. Further investigation of the function of the implicated genes in breast and immune cells may provide insights into the etiology of breast cancer.

Sjögren syndrome/scleroderma autoantigen 1 is a direct Tankyrase binding partner in cancer cells

“…In particular, the locus 11q13 where SSSCA1 is located has been shown to be rearranged and amplified in multiple human cancers by numerous genetic mechanisms including deletions, translocations, loss of heterozygosity and allelic amplifications [46][47][48][49][50] . This could be one of the reasons why SSSCA1 has been shown to be overexpressed in colorectal adenocarcinomas 10,11 , identified as a target gene in breast cancer [12][13][14] , and associated with disease progression and genomic instability in both metastatic oral squamous cell carcinoma 15 and pediatric metastatic neuroblastoma 16 . It is tempting to speculate that the reason could be that the oncogene c-MYC, altered in a variety of cancers, also regulates SSSCA1.…”

“…In colorectal adenocarcinomas, SSSCA1 shows increased mRNA expression levels and has been identified as a key genetic marker for stroma activation and for upregulated pathway activity in colorectal adenoma-to-carcinoma progression 10,11 . Recently, SSSCA1 has been highlighted in numerous studies as a potential target gene and putative biomarker for breast cancer [12][13][14] . It has been associated with genomic instability at 11q and poor survival in both metastatic oral squamous cell carcinoma 15 and pediatric metastatic neuroblastoma 16 .…”

Supervariants identification for breast cancer

“…Genome‐wide association studies (GWAS) have been popular in detecting association between single‐nucleotide polymorphisms (SNPs) and disease, where the association is usually determined via the test of the marginal effect of an SNP. This has led to successful findings for many complex diseases including breast cancer and type 2 diabetes (Ferreira et al, 2019; Xue et al, 2018). However, the risk attributed to genetic factors is still far from satisfactory; for instance, the common genetic variation only explains 18% of the twofold familial relative risk for breast cancer (Ferreira et al, 2019).…”

Variable expression quantitative trait loci analysis of breast cancer risk variants

“…Gene expression traits are under genetic regulation and the heritability of differences in genotypes have been extensively described 4 . For example, identification of expression quantitative trait loci (eQTL) has been a key approach for investigating tissue-specific effects of breast cancer risk variants under the hypothesis that non-breast tissue may be involved in breast cancer risk 5 . Gene expression patterns are often explored assuming genetic control of mean expression level, however the variability of gene expression is also genetically controlled [6][7][8][9] .…”

“…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.…”