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

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.

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

“…All raw data used for analysis in this section are provided in Table S9 . We obtained clinicopathological parameters such as tumor stages for 488 tumors and overall survival (OS) times for 495 patients from the TCGA Pan-Cancer Clinical Data Resources (TCGA-CDR), as we recently reported [ 39 ]. Figure 8 shows the numbers of tumors with or without UGT mutations at four different tumor stages (I, II, II and IV).…”

“…We recently reported highly variable expression of UGT genes in LUAD tumors and a lack of expression of one or multiple UGT genes in many LUAD tumors [ 39 ]. Mutations in UGT genes might have an impact on clinicopathological parameters only if they occur in tumors that express the corresponding UGT gene.…”

“…UGT genes are also widely expressed in many non-drug-metabolizing tissues, supporting their role in drug metabolism by peripheral tissues [ 4 , 31 , 35 , 36 , 37 , 38 ]. Many studies have further shown abundant expression of UGT genes in a variety of human cancers and their associations with tumor progression and recurrence as well as patient survival, highlighting the impact of the intratumoral metabolism of anticancer drugs and other pro/anti-cancer signaling molecules through the UGT conjugation pathway [ 22 , 29 , 30 , 39 , 40 , 41 , 42 , 43 , 44 , 45 , 46 ]. The deregulation of UGT gene expression and somatic mutations that alter UGT activity within cancer cells could affect this pathway.…”

The Glycosyltransferase Pathway: An Integrated Analysis of the Cell Metabolome

“…Multiple recent reports have highlighted that the expression of UGT enzymes and alternative variants is frequently perturbed in disease conditions and especially in tumors [ 20 , 21 , 22 , 23 , 24 , 25 , 26 ]. In fact, metabolic alterations constitute one well documented strategy exploited by cancer cells to sustain rapid cell proliferation and evasion.…”

“…In addition, several specific UGTs emerge as prognostic markers in multiple cancer types (leukemia, lung, prostate, colon, breast, bladder, etc.) and as predictive markers of drug responses, including in treatment-naïve patients [ 3 , 14 , 21 , 25 , 28 , 29 , 30 , 31 , 32 ]. However, the impact of UGT enzymes and alt.…”