High enzyme activity UGT1A1 or low activity UGT1A8 and UGT2B4 genotypes increase esophageal cancer risk

Dura, Polat; Salomon, Jody; Morsche, R.H.M. te; Roelofs, Hennie M.J.; Kristinsson, Jakob; Wobbes, Theo; Witteman, Ben J.M.; Tan, Adriaan C.; Drenth, Joost P.H.; Peters, Wilbert H.M.

doi:10.3892/ijo.2012.1385

Cited by 17 publications

(23 citation statements)

References 42 publications

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“…In previous studies, the polymorphic variants of UGT1A8 at codons 173 and 277 have been associated with altered glucuronidation activity (48) and cancer risk (49). A functional effect by these variants was also observed in the present study.…”

Section: Discussionmentioning

confidence: 99%

Characterization of Raloxifene Glucuronidation: Potential Role of UGT1A8 Genotype on Raloxifene Metabolism In Vivo

Sun

Jones

Manni

et al. 2013

Cancer Prevention Research

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Raloxifene is a 2nd-generation selective estrogen receptor modulator used for the prevention and treatment of osteoporosis and the prevention of breast cancer in postmenopausal women. Raloxifene is extensively metabolized by glucuronidation to form raloxifene-6-glucuronide (ral-6-Gluc) and raloxifene-4′-glucuronide (ral-4′-Gluc). The goal of the present study was to determine whether functional polymorphisms in active UGTs could play a role in altered raloxifene glucuronidation in vivo. Using homogenates from HEK293 UGT-overexpressing cell lines, raloxifene was shown to be glucuronidated primarily by the hepatic UGTs 1A1 and 1A9 and the extra-hepatic UGTs 1A8 and 1A10; no detectable raloxifene glucuronidation activity was found for UGT2B enzymes. Functional UGT1A1 transcriptional promoter genotypes were significantly (ptrend=0.005) associated with ral-6-Gluc formation in human liver microsomes, and, consistent with the decreased raloxifene glucuronidation activities observed in vitro with cell line over-expressing UGT1A8 variants, the UGT1A8*2 variant was significantly (p=0.023) correlated with total raloxifene glucuronide formation in human jejunum homogenates. While ral-4′-Gluc exhibited 1/100th the anti-estrogenic activity of raloxifene itself as measured by binding to the estrogen receptor, raloxifene glucuronides comprised ∼99% of the circulating raloxifene dose in raloxifene-treated subjects, with ral-4′-Gluc comprising ∼70% of raloxifene glucuronides. Plasma ral-6-Gluc (ptrend=0.0025), ral-4′-Gluc (ptrend=0.001), and total raloxifene glucuronides (ptrend=0.001) were increased in raloxifene-treated subjects who were predicted slow metabolizers [UGT1A8 (*1/*3)] vs intermediate metabolizers [UGT1A8 (*1/*1) or UGT1A8 (*1/*2)] vs fast metabolizers [UGT1A8 (*2/*2). These data suggest that raloxifene metabolism may be dependent on UGT1A8 genotype and that UGT1A8 genotype may play an important role in overall response to raloxifene.

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Section: Discussionmentioning

confidence: 99%

Characterization of Raloxifene Glucuronidation: Potential Role of UGT1A8 Genotype on Raloxifene Metabolism In Vivo

Sun

Jones

Manni

et al. 2013

Cancer Prevention Research

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“…UGT2B4 genotypes associated with decreased enzyme activities are found to increase the risk of esophageal squamous cell carcinoma [43].…”

Section: Discovering Rare Driver Genesmentioning

confidence: 99%

DriverFinder: A Gene Length-Based Network Method to Identify Cancer Driver Genes

Wei

Zhang

et al. 2017

Complexity

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Integration of multi-omics data of cancer can help people to explore cancers comprehensively. However, with a large volume of different omics and functional data being generated, there is a major challenge to distinguish functional driver genes from a sea of inconsequential passenger genes that accrue stochastically but do not contribute to cancer development. In this paper, we present a gene length-based network method, named DriverFinder, to identify driver genes by integrating somatic mutations, copy number variations, gene-gene interaction network, tumor expression, and normal expression data. To illustrate the performance of DriverFinder, it is applied to four cancer types from The Cancer Genome Atlas including breast cancer, head and neck squamous cell carcinoma, thyroid carcinoma, and kidney renal clear cell carcinoma. Compared with some conventional methods, the results demonstrate that the proposed method is effective. Moreover, it can decrease the influence of gene length in identifying driver genes and identify some rare mutated driver genes.

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“…Only patients with a diagnosis of esophageal carcinoma, as confirmed by a pathologist, were included in the study. Tissue, blood and DNA were stored, and DNA isolation was performed as previously described [11]. …”

Section: Methodsmentioning

confidence: 99%

No role for glutathione S-transferase genotypes in Caucasian esophageal squamous cell or adenocarcinoma etiology: an European case–control study

et al. 2013

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BackgroundIdentifying and monitoring high-risk patients can aid the prevention of esophageal cancer (EC). The interaction of environmental risk factor exposure and genetic susceptibility may contribute to the etiology of EC. Biotransformation enzymes such as Glutathione S-Transferases (GSTs ) detoxify mutagenic and genotoxic compounds and therefore control the rate of detoxification of carcinogens. Functional polymorphisms in the genes coding for GSTs alter their enzyme activity in vitro, and were reported to modify EC risk in Asians. We hypothesized that altered enzyme activity GST genotypes influence the susceptibility for esophageal adeno- (EAC) and squamous cell carcinoma (ESCC) in Caucasians.MethodsWe performed a case–control study including 440 Caucasian patients with EC and 592 healthy Caucasian controls matched for age and sex. Functional polymorphisms were selected and genotypes were determined in GST classes Alpha, Mu, Theta and Pi by means of polymerase chain reaction. Genotypes were classified into predicted high, intermediate and low enzyme activity categories based on in vitro activity data. The distribution of the activity genotypes were compared between patients with EAC or ESCC, and controls. Odds ratios (OR) with 95% confidence intervals (CI) were calculated by logistic regression analyses. Gene-gene interactions were tested and for comparison purposes, the predicted low and intermediate activity genotypes were combined. Genotypes with similar risks for EAC or ESCC were combined and analyzed for multiplicative effects.ResultsOur analyses includes 327 patients with EAC and 106 patients with ESCC. Low or intermediate activity enzyme genotypes for GSTM1, GSTA1, GSTP1 I105V and A114V as well as for GSTT1, did not significantly modify the risk for ESCC or EAC in our Dutch population.ConclusionFunctional genotypes in GST genes are not involved in EAC or ESCC susceptibility in Caucasians, in contrast to results on ESCC from Asia or Africa.

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High enzyme activity UGT1A1 or low activity UGT1A8 and UGT2B4 genotypes increase esophageal cancer risk

Cited by 17 publications

References 42 publications

Characterization of Raloxifene Glucuronidation: Potential Role of UGT1A8 Genotype on Raloxifene Metabolism In Vivo

Characterization of Raloxifene Glucuronidation: Potential Role of UGT1A8 Genotype on Raloxifene Metabolism In Vivo

DriverFinder: A Gene Length-Based Network Method to Identify Cancer Driver Genes

No role for glutathione S-transferase genotypes in Caucasian esophageal squamous cell or adenocarcinoma etiology: an European case–control study

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