We explored the risk factors for gallbladder cancer and explanations for its sharp and constant incidence increase in Chile since the 1970s. We compared 114 consecutive patients with verified gallbladder cancer, diagnosed 1992-1995, to 114 matched hospital patients with gallstones, using conditional logistic regression analysis. Low education showed a nonsignificant positive relationship with gallbladder cancer [odds ratio (OR) ‫؍‬ 2.3, 95% confidence interval (CI) 0.8 -6.2], and low socioeconomic level showed a significant relationship (OR ‫؍‬ 5.0, 95% CI 1.5-17.3). A very long history of gallstone disease was significantly more prevalent among cases (OR ‫؍‬ 11.0, 95% CI 1.4 -85.2). Significant red chili pepper consumption was observed in gallbladder cancer patients (OR ‫؍‬ 2.9, 95% CI 1.6 -5.2). Low intake of both fresh fruit and sugar as soft drinks was associated with gallbladder cancer, with ORs of 6.4 (95% CI 1.4 -30.3) and 3.6 (95% CI 1.3-10.1), respectively. Multivariate analysis kept only a very low socioeconomic status and red chili pepper consumption as significant independent risk factors for gallbladder cancer, ORs of 6.3 (95% CI 1.7-23.0) and 3.2 (95% CI 1.7-5.9). Longstanding gallstone cases were removed from the multivariate model because all were in the low and very low socioeconomic groups, reinforcing the association. Patients with gallbladder cancer differed from matched controls by exhibiting lower socioeconomic levels, having a much longer history of gallstone disease and presenting a dietary pattern characterized by high red chili pepper consumption and low fresh fruit intake.

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Purpose: Mutations in the mitochondrial DNA (mtDNA) have been observed frequently in human neoplasia, in both coding and noncoding regions. A mononucleotide repeat (poly-C) between 303 and 315 nucleotides (D310) within the regulatory displacement loop has been identified recently as a frequent hot spot of deletion/insertion mutations in tumors. We investigated the frequency and pattern of D310 abnormalities in the pathogenesis of gallbladder carcinoma (GBC).Experimental Design: DNA extracted from neoplastic and nonneoplastic archival gallbladder tissue including 123 tumors, 53 dysplastic areas, and 90 histologically normal epithelia adjacent to GBC, chronic cholecystitis, and 15 normal gallbladders were examined by PCR-based assay for D310 mutations, followed by sequencing in a subset of cases.Results: D310 mutation was a relatively frequent (47 of 123; 38%) abnormality in GBC. A very high frequency of mutations were detected in dysplastic (8 of 14; 57%) and normal-appearing gallbladder epithelia (10 of 22; 46%) accompanying GBC, showing a clonal relationship compared with the corresponding tumors. D310 mutations were also detected in dysplastic (8 of 39; 21%) and normal (17 of 68; 25%) epithelia obtained from chronic cholecystitis. A single case of 15 normal gallbladders showed a D310 abnormality. Overall, deletions (67 of 91; 74%) at D310 were more frequent than insertions.Conclusions: D310 mutation at the mtDNA displacement loop is a relatively frequent and early event in the sequential pathogenesis of GBC, being detected in normalappearing epithelium from chronic cholecystitis. Our findings suggest that mtDNA mutations should be additionally investigated in GBC pathogenesis, and D310 mononucleotide abnormalities could be included in a panel of molecular biomarkers for GBC early detection strategy.

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Genetic variants involved in gallstone formation such as the apolipoprotein B rs693 and CETP rs708272 polymorphisms may be related to the risk of developing GBC in Chilean women.