Identification of low-frequency variants of UGT1A3 associated with bladder cancer risk by next-generation sequencing

Abstract

Although genome-wide association studies (GWASs) have successfully revealed many common risk variants for bladder cancer, the heritability is still largely unexplained. We hypothesized that low-frequency variants involved in bladder cancer risk could reveal the unexplained heritability. Next-generation sequencing of 113 patients and 118 controls was conducted on 81 genes/ regions of known bladder cancer GWAS loci. A two-stage validation comprising 3,350 cases and 4,005 controls was performed to evaluate the effects of low-frequency variants on bladder cancer risk. Biological experiments and techniques, including electrophoretic mobility shift assays, CRISPR/Cas9, RNA-Seq, and bioinformatics approaches, were performed to assess the potential functions of low-frequency variants. The low-frequency variant rs28898617 was located in the first exon of UGT1A3 and was significantly associated with increased bladder cancer risk (odds ratio = 1.50, P = 3.10 × 10 −6). Intriguingly, rs28898617 was only observed in the Asian population, but monomorphism was observed in the European population. The risk-associated G allele of rs28898617 increased UGT1A3 expression, facilitated UGT1A3 transcriptional activity, and enhanced the binding activity. In addition, UGT1A3 deletion significantly inhibited the proliferation, invasion, and migration of bladder cancer cells and xenograft tumor growth. Mechanistically, UGT1A3 induced LAMC2 expression by binding CBP and promoting histone acetylation, which remarkably promoted the progression of bladder cancer. This is the first targeted sequencing study to reveal that the novel lowfrequency variant rs28898617 and its associated gene UGT1A3 are involved in bladder cancer development, providing new insights into the genetic architecture of bladder cancer.

Susceptibility Loci in SLC15A1, UGT1A3, and CWC27 Genes Associated with Bladder Cancer in the Northeast Chinese Population

“…UGT1A3 encodes a vital protein of the human UDP-glucuronosyltransferase (UGT) superfamily performing a key role in endobiotic and xenobiotic metabolism. Many studies showed that UGT1A3 was related to many kinds of cancers including pancreatic cancer [ 34 ], bladder cancer [ 16 ], thyroid cancer [ 35 ], stomach cancer [ 36 ], colorectal cancer, colon cancer [ 37 ], and lung adenocarcinoma [ 38 ]. Zheng et al [ 16 ] first revealed that a low-frequency variant rs28898617 in UGT1A3 was significantly associated with the increased risk of BCa.…”

“…Many studies showed that UGT1A3 was related to many kinds of cancers including pancreatic cancer [ 34 ], bladder cancer [ 16 ], thyroid cancer [ 35 ], stomach cancer [ 36 ], colorectal cancer, colon cancer [ 37 ], and lung adenocarcinoma [ 38 ]. Zheng et al [ 16 ] first revealed that a low-frequency variant rs28898617 in UGT1A3 was significantly associated with the increased risk of BCa. However, in this study, we failed to replicate the association between SNPs of UGT1A3 and BCa in the Chinese Northeast population.…”

“…SCL15A1 is one of the important molecules during cancer development. Zheng et al reported that low-frequency variants of UGT1A3 are related with bladder cancer development [ 16 ]. Also, UTG1A3 polymorphisms are also associated with patients' drug metabolism [ 17 , 18 ].…”

Cannabis Pharmacogenomics: A Path to Personalized Medicine

“…This allele was only observed in the Asian population, but monomorphism was also observed in the Europeans. The total allele frequency was estimated to be 0.003 [ 253 ].…”

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.…”