The Expression Profiles and Deregulation of UDP-Glycosyltransferase (UGT) Genes in Human Cancers and Their Association with Clinical Outcomes

SIMPLE SUMMARY: The human UDP-glycosyltransferase (UGT) superfamily plays a critical role in the metabolism of numerous endogenous and exogenous small lipophilic compounds, including carcinogens, drugs, and bioactive molecules with pro- or anti-cancer activity. Previous studies have documented the expression of UGT genes in several cancers derived from drug-metabolizing organs (e.g., liver, colon, kidney). The present study represents the first to comprehensively assess the expression profiles of UGT genes and their impact on patient survival in nearly 30 different cancers primarily derived from non-drug-metabolizing organs. Briefly, our comprehensive analysis of the transcriptomic (RNAseq) and clinical datasets of 9514 patients from 33 different cancers shows the widespread expression of UGT genes, indicative of active drug metabolism within the tumor through the UGT conjugation pathway. We further identified the UGT genes whose intratumoral expression was associated with patient survival, highlighting the potential of UGT genes as prognostic biomarkers and therapeutic targets in various cancers. ABSTRACT: The human UDP-glycosyltransferase (UGTs) superfamily has 22 functional enzymes that play a critical role in the metabolism of small lipophilic compounds, including carcinogens, drugs, steroids, lipids, fatty acids, and bile acids. The expression profiles of UGT genes in human cancers and their impact on cancer patient survival remains to be systematically investigated. In the present study, a comprehensive analysis of the RNAseq and clinical datasets of 9514 patients from 33 different TCGA (the Genome Cancer Atlas) cancers demonstrated cancer-specific UGT expression profiles with high interindividual variability among and within individual cancers. Notably, cancers derived from drug metabolizing tissues (liver, kidney, gut, pancreas) expressed the largest number of UGT genes (COAD, KIRC, KIRP, LIHC, PAAD); six UGT genes (1A6, 1A9, 1A10, 2A3, 2B7, UGT8) showed high expression in five or more different cancers. Kaplan–Meier plots and logrank tests revealed that six UGT genes were significantly associated with increased overall survival (OS) rates [UGT1A1 (LUSC), UGT1A6 (ACC), UGT1A7 (ACC), UGT2A3 (KIRC), UGT2B15 (BLCA, SKCM)] or decreased OS rates [UGT2B15 (LGG), UGT8 (UVM)] in specific cancers. Finally, differential expression analysis of 611 patients from 12 TCGA cancers identified 16 UGT genes (1A1, 1A3, 1A6, 1A7, 1A8, 1A9, 1A10, 2A1, 2A3, 2B4, 2B7, 2B11, 2B15, 3A1, 3A2, UGT8) that were up/downregulated in at least one cancer relative to normal tissues. In conclusion, our data show widespread expression of UGT genes in cancers, highlighting the capacity for intratumoural drug metabolism through the UGT conjugation pathway. The data also suggests the potentials for specific UGT genes to serve as prognostic biomarkers or therapeutic targets in cancers.