Phase II Drug-Metabolizing Polymorphisms and Smoking Predict Recurrence of Non–Muscle-Invasive Bladder Cancer: A Gene–Smoking Interaction

Abstract

Cigarette smoking is the most important known risk factor for urinary bladder cancer. Selected arylamines in cigarette smoke are recognized human bladder carcinogens and undergo biotransformation through several detoxification pathways, such as the glutathione S-transferases (GST), and uridinediphospho-glucuronosyltransferases (UGT) pathways. GSTM1 deletion status and UGT1A1Ã 28 rs8175347 genotypes were assessed in 189 non-muscle-invasive bladder cancers (NMIBC) patients with pTa (77.2%) and pT1 (22.8%) tumors and a mean follow-up of 5.6 years, to investigate whether two common functional polymorphisms in GSTM1 and UGT1A1 genes and smoking history are associated with recurrence-free survival of patients with NMIBC. Ã 28 allele demonstrated a risk of recurrence of 4.95 (95% CI, 1.02-24.0) and 5.32 (95% CI, 2.07-13.7), respectively. This study establishes a connection between GSTM1, UGT1A1, and tobacco exposure as prognostic markers of NMIBC recurrence in bladder cancer patients. These findings warrant validation in larger cohorts. Cancer Prev Res; 9(2); 189-95. Ó2015 AACR.

Bilirubin is not associated with urinary bladder cancer risk and prognosis: A Mendelian Randomization Study in the UK Biobank

“…Mutations in the UGT1A cluster, located in 2q37.1, have been associated with UBC in previous genetic studies [3, 4, 21, 22], SNPs in UGT1A have shown both harmful [21] and protective effects for the risk of developing de novo UBC [4, 22], but there is uncertainty if UGT1A influences the disease course, especially in NMIBC. Lacombe et al evaluated the effect of UGT1A1*28 SNP rs8175347 in a group of 189 NMIBC cases [23] and concluded that it significantly increased the risk of recurrence, with a gene-smoking interaction present (higher recurrence risk for ever smokers). Nevertheless, the many strata in the study resulted in small subgroup sample sizes [23]; therefore, the findings must be replicated in other cohorts to establish validity.…”

“…Lacombe et al evaluated the effect of UGT1A1*28 SNP rs8175347 in a group of 189 NMIBC cases [23] and concluded that it significantly increased the risk of recurrence, with a gene-smoking interaction present (higher recurrence risk for ever smokers). Nevertheless, the many strata in the study resulted in small subgroup sample sizes [23]; therefore, the findings must be replicated in other cohorts to establish validity.…”

Association of Glutathione S-transferase gene polymorphism with bladder Cancer susceptibility

“…Smoking is a known risk factor for bladder cancer [ 113 ], and the products of GSTs help detoxify the polycyclic aromatic hydrocarbons found in tobacco smoke [ 114 ]. Our study suggests that the GSTM1-null genotype might play a role in such detoxification, but the GSTT1-null genotype does not.…”

The effect of α-solanine on the activity, gene expression, and kinetics of arylamine N-acetyltransferase in HepG2 cells

“…Their main function being to transfer the acetyl group from AcCoA onto the nitrogen or oxygen atom in such substances such as arylamines (17), hydrazines (18), arylhydroxylamines (19) or arylhydrazines (17). These enzymes play an important role in the metabolism of drugs (20) and toxins as well as in detoxification (21,22). Using 2-AF as an example, the process by which arylamines cause cancer is as follows: first, NATs in the cell transform 2-AF into N-acetyl-2-aminofluorene (2-AAF) (23), then 2-AAF is further activated by other enzymes such as glucuronyltransferase, deacylase, sulfotransferase and acyltransferase (24,25), and ultimately transformed in the end to carcinogens nitrenium ion and arylamidonium ion.…”