AI Article Synopsis

  • - GWAS has found over 180 genetic variants linked to breast cancer risk, but their functional impacts remain unclear; the researchers propose that gene expression variability might highlight key susceptibility genes.
  • - The study conducted veQTL analysis using GTEx data, identifying 70 significant associations, with 55 specific to breast tissue, pointing to a connection between genetic variants and gene expression in breast cancer.
  • - Four key genes involved in hormone biosynthesis were found to have increased variability linked to a specific high-risk breast cancer allele (A/A) in the FTO gene, suggesting this genetic variant might disrupt hormonal regulation and increase breast cancer risk.

Article Abstract

Genome wide association studies (GWAS) have identified more than 180 variants associated with breast cancer risk, however the underlying functional mechanisms and biological pathways which confer disease susceptibility remain largely unknown. As gene expression traits are under genetic regulation we hypothesise that differences in gene expression variability may identify causal breast cancer susceptibility genes. We performed variable expression quantitative trait loci (veQTL) analysis using tissue-specific expression data from the Genotype-Tissue Expression (GTEx) Common Fund Project. veQTL analysis identified 70 associations (p < 5 × 10) consisting of 60 genes and 27 breast cancer risk variants, including 55 veQTL that were observed in breast tissue only. Pathway analysis of genes associated with breast-specific veQTL revealed an enrichment of four genes (CYP11B1, CYP17A1 HSD3B2 and STAR) involved in the C21-steroidal biosynthesis pathway that converts cholesterol to breast-related hormones (e.g. oestrogen). Each of these four genes were significantly more variable in individuals homozygous for rs11075995 (A/A) breast cancer risk allele located in the FTO gene, which encodes an RNA demethylase. The A/A allele was also found associated with reduced expression of FTO, suggesting an epi-transcriptomic mechanism may underlie the dysregulation of genes involved in hormonal biosynthesis leading to an increased risk of breast cancer. These findings provide evidence that genetic variants govern high levels of expression variance in breast tissue, thus building a more comprehensive insight into the underlying biology of breast cancer risk loci.

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Source
http://www.ncbi.nlm.nih.gov/pmc/articles/PMC8009949PMC
http://dx.doi.org/10.1038/s41598-021-86690-5DOI Listing

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