Association of Aflatoxin and Gallbladder Cancer

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.

Keywords: Biliary Tract Cancer; Carcinogen; Epidemiology; Etiology.

Figure 1

Normalized distribution of detectable (≥0.5 pg aflatoxin–lysine/mg albumin) aflatoxin B1-lysine adduct levels in the A) Shanghai Biliary Tract Cancer Case–control Study and the B) previously-published gallbladder cancer study in Chile.