SlowN‐acetylation as a possible contributor to bladder carcinogenesis

Abstract

Bladder cancer (BCa) is an exophytic tumor that presents as either noninvasive confined to the mucosa (NMIBC) or invading the detrusor muscle (MIBC), and was recently further subgrouped into molecular subtypes. Arylamines, major BCa environmental and occupational risk factors, are mainly metabolized by the genetically polymorphic N‐acetyltransferases 1, NAT1 and NAT2. In this study, we investigated the association between N‐acetyltransferases genetic polymorphism and key MIBC and NMIBC tumor biomarkers and subtypes. A cohort of 250 males with histologically confirmed urothelial BCa was identified. Tumors were genotyped for NAT1 and NAT2 using real‐time polymerase chain reaction (PCR), and characterized for mutations in TP53, RB1, and FGFR3 by PCR‐restriction fragment length polymorphism. Pathology data and patients' smoking status were obtained from medical records. Pearson χ2 and Fisher exact tests were used to check for associations and interactions. Results show that NAT1 G560A polymorphism is significantly associated with higher muscle‐invasiveness (MIBC vs NMIBC; P = .001), higher tumor grade (high grade vs low grade; P = .011), and higher FGFR3 mutation frequency within the MIBC subgroup (P = .042; .027). NAT2 G857A polymorphism is also found to be significantly associated with higher muscle‐invasiveness (MIBC vs NMIBC; P = .041). Our results indicate that slow N‐acetylation is a contributor to bladder carcinogenesis and muscle‐invasiveness. These findings highlight NAT1 as a biomarker candidate in BCa and a potential target for drug development.

Disinfection By-Products in Drinking Water and Bladder Cancer: Evaluation of Risk Modification by Common Genetic Polymorphisms in Two Case–Control Studies

“…In this analysis, we report on potential risk modification of the relation between THM exposure and 16 loci associated with bladder cancer. Although there is evidence that -acetyltransferase 1 (NAT1) also plays a role in bladder carcinogenesis, 26 SNPs in NAT1 genotyped as part of our GWAS did not show strong evidence of association with bladder cancer risk and therefore is not presented in these results. We found the strongest evidence of such an association for rs907611 ( LSP1 region), with a suggestion of interaction in both New England and Spain.…”

560G>A (rs4986782) (R187Q) Single Nucleotide Polymorphism in Arylamine N-Acetyltransferase 1 Increases Affinity for the Aromatic Amine Carcinogens 4-Aminobiphenyl and N-Hydroxy-4-Aminobiphenyl: Implications for Cancer Risk Assessment

“…Notably, the incidence of urinary bladder cancer has increased markedly in Lebanon and is currently the second most incident cancer among males ( Shamseddine et al, 2004 ). The frequency of 560G > A (rs4986782) (R187Q) is 7-fold higher among urinary bladder cases than controls in Lebanon ( Yassine et al, 2012 ) and is significantly associated with higher muscle-invasiveness and higher tumor grade of urinary bladder tumors ( El Kawak et al, 2020 ). In the current study 560G > A (rs4986782) (R187Q) caused a 4 to 5-fold increase ( p < 0.05) in affinity for both ABP and N-OH-ABP.…”

“…Most of these focus on associations between NAT1*10 and/or NAT1*11 and cancer risk, two variant alleles that possess SNPs in the 3′-UTR region outside of the coding exon. Urinary bladder cancer is most frequently associated with NAT1 genetic polymorphism ( Cascorbi et al, 2001 ; Yassine et al, 2012 ; Dhaini et al, 2018 ; El-Kawak et al, 2020 ).…”

The role of protein acetylation in carcinogenesis and targeted drug discovery

“…Studies have shown that N-acetylation mainly affects protein-membrane binding and protein stability ( 16 ). N-acetylation is also one of many factors contributing to tumor progression; for example, slow N-acetylation is a factor in bladder carcinogenesis and muscle invasiveness, and NAT1 is recognized as a biomarker candidate in bladder cancer and a potential target for drug development point ( 17 ).…”