Jill Koshiol1, Yu-Tang Gao2, Michael Dean3, Patricia Egner4, Chirag Nepal5, Kristine Jones6, Bingsheng Wang7, Asif Rashid8, Wen Luo6, Alison L Van Dyke9, Catterina Ferreccio10, Michael Malasky6, Ming-Chang Shen11, Bin Zhu12, Jesper B Andersen5, Allan Hildesheim9, Ann W Hsing13, John Groopman4. 1. Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. Electronic address: koshiolj@mail.nih.gov. 2. Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China. 3. Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 4. Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland. 5. Biotech Research & Innovation Centre, Department of Health and Medical Sciences, University of Copenhagen, Copenhagen, Denmark. 6. Cancer Genomics Research Laboratory, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 7. Department of General Surgery, Zhongshan Hospital, School of Medicine, Fudan University, Shanghai, China. 8. Department of Pathology, M.D. Anderson Cancer Center, Houston, Texas. 9. Infections and Immunoepidemiology Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 10. Pontificia Universidad Católica, Fondap Advanced Center for Chronic Diseases, Santiago, Chile. 11. Department of Pathology, Shanghai Cancer Center, Fudan University, Shanghai, China. 12. Biostatistics Branch, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Bethesda, Maryland. 13. Stanford Cancer Institute, Stanford University, Stanford, California.
Abstract
BACKGROUND & AIMS: Aflatoxin, which causes hepatocellular carcinoma, may also cause gallbladder cancer. We investigated whether patients with gallbladder cancer have higher exposure to aflatoxin than patients with gallstones. METHODS: We measured aflatoxin B1 (AFB1)-lysine adducts in plasma samples from the Shanghai Biliary Tract Cancer case-control study, conducted from 1997 through 2001. We calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) and the population-attributable fraction for 209 patients with gallbladder cancer and gallstones vs 250 patients with gallstones without cancer (controls). In 54 patients with gallbladder cancer, tumor tissue was examined for the R249S mutation in TP53, associated with aflatoxin exposure, through targeted sequencing. RESULTS: The AFB1-lysine adduct was detected in 67 (32%) of 209 patients with gallbladder cancer and 37 (15%) of the 250 controls (χ2 P < .0001), almost threefold more patients with gallbladder cancer than controls (OR, 2.71; 95% CI, 1.70-4.33). Among participants with detectable levels of AFB1-lysine, the median level of AFB1-lysine was 5.4 pg/mg in those with gallbladder cancer, compared with 1.2 pg/mg in controls. For patients in the fourth quartile of AFB1-lysine level vs the first quartile, the OR for gallbladder cancer was 7.61 (95% CI, 2.01-28.84). None of the 54 gallbladder tumors sequenced were found to have the R249S mutation in TP53. The population-attributable fraction for cancer related to aflatoxin was 20% (95% CI, 15%-25%). CONCLUSIONS: In a case-control study of patients with gallbladder cancer and gallstones vs patients with gallstones without cancer, we associated exposure to aflatoxin (based on plasma level of AFB1-lysine) with gallbladder cancer. Gallbladder cancer does not appear associate with the R249S mutation in TP53. If aflatoxin is a cause of gallbladder cancer, it may have accounted for up to 20% of the gallbladder cancers in Shanghai, China, during the study period, and could account for an even higher proportion in high-risk areas. If our findings are verified, reducing aflatoxin exposure might reduce the incidence of gallbladder cancer.
BACKGROUND & AIMS:Aflatoxin, which causes hepatocellular carcinoma, may also cause gallbladder cancer. We investigated whether patients with gallbladder cancer have higher exposure to aflatoxin than patients with gallstones. METHODS: We measured aflatoxin B1 (AFB1)-lysine adducts in plasma samples from the Shanghai Biliary Tract Cancer case-control study, conducted from 1997 through 2001. We calculated age- and sex-adjusted odds ratios (ORs) and 95% confidence intervals (CIs) and the population-attributable fraction for 209 patients with gallbladder cancer and gallstones vs 250 patients with gallstones without cancer (controls). In 54 patients with gallbladder cancer, tumor tissue was examined for the R249S mutation in TP53, associated with aflatoxin exposure, through targeted sequencing. RESULTS: The AFB1-lysine adduct was detected in 67 (32%) of 209 patients with gallbladder cancer and 37 (15%) of the 250 controls (χ2 P < .0001), almost threefold more patients with gallbladder cancer than controls (OR, 2.71; 95% CI, 1.70-4.33). Among participants with detectable levels of AFB1-lysine, the median level of AFB1-lysine was 5.4 pg/mg in those with gallbladder cancer, compared with 1.2 pg/mg in controls. For patients in the fourth quartile of AFB1-lysine level vs the first quartile, the OR for gallbladder cancer was 7.61 (95% CI, 2.01-28.84). None of the 54 gallbladder tumors sequenced were found to have the R249S mutation in TP53. The population-attributable fraction for cancer related to aflatoxin was 20% (95% CI, 15%-25%). CONCLUSIONS: In a case-control study of patients with gallbladder cancer and gallstones vs patients with gallstones without cancer, we associated exposure to aflatoxin (based on plasma level of AFB1-lysine) with gallbladder cancer. Gallbladder cancer does not appear associate with the R249S mutation in TP53. If aflatoxin is a cause of gallbladder cancer, it may have accounted for up to 20% of the gallbladder cancers in Shanghai, China, during the study period, and could account for an even higher proportion in high-risk areas. If our findings are verified, reducing aflatoxin exposure might reduce the incidence of gallbladder cancer.
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Authors: Chirag Nepal; Bin Zhu; Colm J O'Rourke; Deepak Kumar Bhatt; Donghyuk Lee; Lei Song; Difei Wang; Alison L Van Dyke; Hyoyoung Choo-Wosoba; Zhiwei Liu; Allan Hildesheim; Alisa M Goldstein; Michael Dean; Juan LaFuente-Barquero; Scott Lawrence; Karun Mutreja; Mary E Olanich; Justo Lorenzo Bermejo; Catterina Ferreccio; Juan Carlos Roa; Asif Rashid; Ann W Hsing; Yu-Tang Gao; Stephen J Chanock; Juan Carlos Araya; Jesper B Andersen; Jill Koshiol Journal: J Hepatol Date: 2020-12-01 Impact factor: 25.083