The Somatic Mutation Landscape of UDP-Glycosyltransferase (UGT) Genes in Human Cancers

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.

Cytochrome P450 and Other Drug-Metabolizing Enzymes As Therapeutic Targets

“…For example, various UGTs are involved in the glucuronidation of androgens, estrogens, and lipids, molecules with established roles in tumor growth. Further, numerous groups have shown associations between UGT expression levels and cancer prognoses, suggesting the potential to use UGT profiles as predictive and/or prognostic biomarkers (Desai et al, 2003;Dalhoff et al, 2005;Allain et al, 2020a;Hu et al, 2022). Multiple studies have suggested a role for UGT2B17 in affecting the outcome of chronic lymphocytic leukemia treatments, either due to its role in regulating endogenous steroids or through a nonenzymatic mechanism (Gruber et al, 2013;Bhoi et al, 2016;Allain et al, 2019;Allain et al, 2020b).…”

Overexpression of SmUGGT1 Confers Imidacloprid Resistance to Sitobion miscanthi (Takahashi)

“…41−43 Posttranscriptional regulation will be performed when the miRNAs combine with 3′UTRs regulating the UGT gene expression. 44 For example, the expression of UGT2B was regulated by miR-216b-5p related to liver cancer, 45 and the expression of UGT2A1 was mediated by miR-196b-5p or miR-196a-5p related to the detoxification of some hydrocarbons; 46 the expression of UGT1A1 was mediated by miR-486−3p or miR-214−5p related to the development or progression of liver fibrosis/cirrhosis. 47 Though UGTs play a crucial role in insecticide metabolism in insects, the molecular mechanism affected by insecticides remains unclear in S. miscanthi.…”

“…UGT expression could be mediated at both transcriptional and post-transcriptional levels where microRNAs (miRNAs) can act on post-transcriptional regulation by combining with 5′UTRs and 3′UTRs or coding sequences (CDs). − Post-transcriptional regulation will be performed when the miRNAs combine with 3′UTRs regulating the UGT gene expression . For example, the expression of UGT2B was regulated by miR-216b-5p related to liver cancer, and the expression of UGT2A1 was mediated by miR-196b-5p or miR-196a-5p related to the detoxification of some hydrocarbons; the expression of UGT1A1 was mediated by miR-486–3p or miR-214–5p related to the development or progression of liver fibrosis/cirrhosis …”