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

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  • Additional Information
    • Source:
      Publisher: Cell Press Country of Publication: United States NLM ID: 0370475 Publication Model: Print Cited Medium: Internet ISSN: 1537-6605 (Electronic) Linking ISSN: 00029297 NLM ISO Abbreviation: Am J Hum Genet Subsets: MEDLINE
    • Publication Information:
      Publication: 2008- : [Cambridge, MA] : Cell Press
      Original Publication: Baltimore, American Society of Human Genetics.
    • Subject Terms:
      Genes, Neoplasm* ; Genome-Wide Association Study*; Breast Neoplasms/*genetics ; Quantitative Trait Loci/*genetics; Alleles ; Cell Line, Tumor ; Chromatin/metabolism ; Female ; Gene Expression Regulation, Neoplastic ; Genes, Reporter ; Humans ; Luciferases/metabolism ; Polymorphism, Single Nucleotide/genetics ; Promoter Regions, Genetic/genetics ; Risk Factors
    • 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.
      (Copyright © 2018 American Society of Human Genetics. Published by Elsevier Inc. All rights reserved.)
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    • Grant Information:
      P30 CA068485 United States CA NCI NIH HHS; R01 CA148667 United States CA NCI NIH HHS
    • Contributed Indexing:
      Keywords: GWAS; bioinformatics; breast cancer; cell behavior; cis-eQTL; functional SNP; functional genomics; gene expression; risk variant; susceptibility gene
    • Accession Number:
      0 (Chromatin)
      EC 1.13.12.- (Luciferases)
    • Publication Date:
      Date Created: 20180505 Date Completed: 20181211 Latest Revision: 20200824
    • Publication Date:
      20221213
    • Accession Number:
      PMC5986971
    • Accession Number:
      10.1016/j.ajhg.2018.03.016
    • Accession Number:
      29727689