Slow N-acetylation as a possible contributor to bladder carcinogenesis
2020
El Kawak, Michelle | Dhaini, Hassan R. | Jabbour, Michel Elias | Moussa, Mohamad Ahmad | El-Asmar, Khalil | Aoun, Mona | Environmental Health (ENHL) | Epidemiology and Population Health (EPHD) | Faculty of Medicine (FM) | Faculty of Health Sciences (FHS) | American University of Beirut
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. © 2020 Wiley Periodicals LLC
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