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Am J Hum Genet. 2019 Sep 5;105(3):477-492. doi: 10.1016/j.ajhg.2019.07.006. Epub 2019 Aug 8.

Identifying Putative Susceptibility Genes and Evaluating Their Associations with Somatic Mutations in Human Cancers.

Author information

1
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA.
2
Unit of Biomarkers and Susceptibility, Oncology Data Analytics Program, Catalan Institute of Oncology, Barcelona 08908, Spain; Colorectal Cancer Group, ONCOBELL Program, Bellvitge Biomedical Research Institute, Barcelona 08908, Spain; Consortium for Biomedical Research in Epidemiology and Public Health, Barcelona 08908, Spain; Department of Clinical Sciences, Faculty of Medicine, University of Barcelona, Barcelona 08908, Spain.
3
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA; College of Life Sciences, Fujian Agriculture and Forestry University, Fuzhou 350002, Fujian, China.
4
Center for Quantitative Sciences, Vanderbilt University School of Medicine, Nashville, TN 37232, USA.
5
Division of Epidemiology, Department of Medicine, Vanderbilt Epidemiology Center, and Vanderbilt-Ingram Cancer Center, Vanderbilt University School of Medicine, Nashville, TN 37203, USA. Electronic address: xingyi.guo@vumc.org.

Abstract

Genome-wide association studies (GWASs) have identified hundreds of genetic risk variants for human cancers. However, target genes for the majority of risk loci remain largely unexplored. It is also unclear whether GWAS risk-loci-associated genes contribute to mutational signatures and tumor mutational burden (TMB) in cancer tissues. We systematically conducted cis-expression quantitative trait loci (cis-eQTL) analyses for 294 GWAS-identified variants for six major types of cancer-colorectal, lung, ovary, prostate, pancreas, and melanoma-by using transcriptome data from the Genotype-Tissue Expression (GTEx) Project, the Cancer Genome Atlas (TCGA), and other public data sources. By using integrative analysis strategies, we identified 270 candidate target genes, including 99 with previously unreported associations, for six cancer types. By analyzing functional genomic data, our results indicate that 180 genes (66.7% of 270) had evidence of cis-regulation by putative functional variants via proximal promoter or distal enhancer-promoter interactions. Together with our previously reported associations for breast cancer risk, our results show that 24 genes are shared by at least two cancer types, including four genes for both breast and ovarian cancer. By integrating mutation data from TCGA, we found that expression levels of 33 and 66 putative susceptibility genes were associated with specific mutational signatures and TMB of cancer-driver genes, respectively, at a Bonferroni-corrected p < 0.05. Together, these findings provide further insight into our understanding of how genetic risk variants might contribute to carcinogenesis through the regulation of susceptibility genes that are related to the biogenesis of somatic mutations.

KEYWORDS:

GWAS-identified variants; cancer driver genes; cis-eQTL; functional variants; gene expression; human cancers; mutational signature; susceptibility genes; tumor mutational burden

PMID:
31402092
PMCID:
PMC6731359
[Available on 2020-03-05]
DOI:
10.1016/j.ajhg.2019.07.006

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