Oxidative stress and deregulations in base excision repair pathway as contributors to gallbladder anomalies and carcinoma - a study involving North-East Indian population.

Gallbladder cancer (GBC) is a fatal condition with dismal prognosis and aggressive local invasiveness; and with uncharacterised molecular pathology relating to non-specific therapeutic modalities. Given the importance of oxidative stress in chronic diseases and carcinogenesis, and the lacunae in literature regarding its role in gallbladder diseases, this study aimed to study the involvement of oxidative stress and deregulation in the base excision repair (BER) pathway in the pathogenesis of gallbladder diseases including GBC. This study involved patients from the North-East Indian population, where the numbers of reported cases are increasing rapidly and alarmingly. Oxidative stress, based on 8-OH-dG levels, was found to be significantly higher in gallbladder anomalies (cholelithiasis [CL] and cholecystitis [CS]) and GBC at the plasma and DNA level, and was associated with GBC severity. The expressions of key BER pathway genes were downregulated in gallbladder anomalies and GBC compared to controls, and in GBC compared to both non-neoplastic controls and gallbladder anomalies. Expression of and was significantly associated with both susceptibility and severity of GBC. The polymorphism was associated with disease susceptibility; and significantly higher oxidative stress was observed in genotypic variants. The genomes of GBC patients were found to be more hypermethylated compared to controls, with the promoters of and being hypermethylated and, therefore, being silenced. This study underlined the prognostic significance of the oxidative stress marker 8-OH-dG and BER pathway genes, especially and in gallbladder anomalies and GBC, as well as stated their potential for therapeutic targeting.