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

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.

SUBMITTER: Chen Z

PROVIDER: S-EPMC6731359 | biostudies-literature | 2019 Sep

REPOSITORIES: biostudies-literature

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

Chen Zhishan Z Wen Wanqing W Beeghly-Fadiel Alicia A Shu Xiao-Ou XO Díez-Obrero Virginia V Long Jirong J Bao Jiandong J Wang Jing J Liu Qi Q Cai Qiuyin Q Moreno Victor V Zheng Wei W Guo Xingyi X

American journal of human genetics 20190808 3

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, lu ...[more]

PMID: 31402092

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Project description:Simple Summary The human UDP-glycosyltransferase (UGT) superfamily is involved in the metabolism of numerous anticancer drugs and endobiotic signaling molecules with pro/anti-cancer activities. Previous studies have shown abundant expression of UGT genes in many human cancers, indicative of the active intratumoral metabolism of drugs and endobiotics through the UGT conjugation pathway. Mutations of UGT genes in tumors that can affect this pathway have not yet been reported. In the present study, our analysis of somatic mutations in 10,069 tumors from 33 different cancer types identified 3427 somatic mutations in UGT genes, over half of which have been predicted to code for variant UGT proteins with no or reduced activity. As a result, somatic mutations of UGT genes may reduce the capacity of cancer cells to metabolize anticancer drugs and pro/anti-cancer endobiotics, and hence, they are likely to alter therapeutic efficacy and cancer growth, highlighting their potential utility as biomarkers predicting therapeutic efficacy and clinical outcomes. Abstract The human UDP-glycosyltransferase (UGTs) superfamily has a critical role in the metabolism of anticancer drugs and numerous pro/anti-cancer molecules (e.g., steroids, lipids, fatty acids, bile acids and carcinogens). Recent studies have shown wide and abundant expression of UGT genes in human cancers. However, the extent to which UGT genes acquire somatic mutations within tumors remains to be systematically investigated. In the present study, our comprehensive analysis of the somatic mutation profiles of 10,069 tumors from 33 different TCGA cancer types identified 3427 somatic mutations in UGT genes. Overall, nearly 18% (1802/10,069) of the assessed tumors had mutations in UGT genes with huge variations in mutation frequency across different cancer types, ranging from over 25% in five cancers (COAD, LUAD, LUSC, SKCM and UCSC) to less than 5% in eight cancers (LAML, MESO, PCPG, PAAD, PRAD, TGCT, THYM and UVM). All 22 UGT genes showed somatic mutations in tumors, with UGT2B4, UGT3A1 and UGT3A2 showing the largest number of mutations (289, 307 and 255 mutations, respectively). Nearly 65% (2260/3427) of the mutations were missense, frame-shift and nonsense mutations that have been predicted to code for variant UGT proteins. Furthermore, about 10% (362/3427) of the mutations occurred in non-coding regions (5′ UTR, 3′ UTR and splice sites) that may be able to alter the efficiency of translation initiation, miRNA regulation or the splicing of UGT transcripts. In conclusion, our data show widespread somatic mutations of UGT genes in human cancers that may affect the capacity of cancer cells to metabolize anticancer drugs and endobiotics that control pro/anti-cancer signaling pathways. This highlights their potential utility as biomarkers for predicting therapeutic efficacy and clinical outcomes.

Dataset Information

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

Publications

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

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