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Table 1.  
Characteristics of Patients With Gallbladder Cancer Compared With 2 Control Groups
Characteristics of Patients With Gallbladder Cancer Compared With 2 Control Groups
Table 2.  
Association of Aflatoxin B1-Lysine Adducts in Patients With Gallbladder Cancer Compared With 2 Control Groupsa
Association of Aflatoxin B1-Lysine Adducts in Patients With Gallbladder Cancer Compared With 2 Control Groupsa
1.
Sieber  SM, Correa  P, Dalgard  DW, Adamson  RH.  Induction of osteogenic sarcomas and tumors of the hepatobiliary system in nonhuman primates with aflatoxin B1. Cancer Res. 1979;39(11):4545-4554.
PubMed
2.
Tsuchiya  Y, Terao  M, Okano  K,  et al.  Mutagenicity and mutagens of the red chili pepper as gallbladder cancer risk factor in Chilean women. Asian Pac J Cancer Prev. 2011;12(2):471-476.
PubMed
3.
Scholl  PF, Groopman  JD.  Long-term stability of human aflatoxin B1 albumin adducts assessed by isotope dilution mass spectrometry and high-performance liquid chromatography-fluorescence. Cancer Epidemiol Biomarkers Prev. 2008;17(6):1436-1439.
PubMedArticle
4.
Venniyoor  A.  Cholesterol gallstones and cancer of gallbladder (CAGB): molecular links. Med Hypotheses. 2008;70(3):646-653.
PubMedArticle
5.
Departamento de Epidemiologia. Informe anual 2011 hepatitis B. http://epi.minsal.cl/epi/html/bolets/reportes/HepatitisB/HepB_2011.pdf. Accessed September 22, 2014.
6.
Chen  JG, Egner  PA, Ng  D,  et al.  Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila). 2013;6(10):1038-1045.
PubMedArticle
Research Letter
May 26, 2015

Association of Aflatoxin With Gallbladder Cancer in Chile

Author Affiliations
  • 1Division of Cancer Epidemiology and Genetics, National Cancer Institute, Rockville, Maryland
  • 2School of Medicine, Pontificia Universidad Católica de Chile, Santiago, Chile
  • 3Department of Environmental Health Sciences, Johns Hopkins Bloomberg School of Public Health, Baltimore, Maryland
JAMA. 2015;313(20):2075-2077. doi:10.1001/jama.2015.4559

In Chile, gallbladder cancer is a leading cause of cancer death in women. Other than gallstones, gallbladder cancer etiology remains largely unclear. Exposure to aflatoxin, a liver carcinogen, is associated with bile duct epithelium proliferation in both animals and humans,1 and with gallbladder cancer in primates.1 Aflatoxin contamination has been identified in Chile, including in ají rojo (red chili peppers). Ají rojo is associated with gallbladder cancer2; however, the association of aflatoxin with gallbladder cancer in humans has not been directly evaluated.

Methods

We evaluated plasma aflatoxin-albumin adducts and gallbladder cancer in a pilot study conducted from April 2012 through August 2013. We recruited incident gallbladder cancer cases identified through rapid ascertainment at cancer referral hospitals in Santiago, Concepción, and Temuco, Chile. We initially recruited all cases consecutively and later recruited only surgical cases to provide tissue samples for future studies. We aimed at 1:1:1 matching by age and sex, as well as hospital for controls with gallstones (to ensure associations with gallbladder cancer were not solely due to gallstones) or study site for community controls. Pairing of controls with gallstones was limited by the small number of patients older than 50 years who underwent gallbladder surgery.

Community controls were selected from a random listing of the population enrolled in the same health center registry as the cases or through neighborhood sampling. Participants had to be previously cancer-free and covered by public health insurance (>90% of population). Chile and US institutional review board–approved written consent was obtained for data and blood collection at enrollment.

Aflatoxin forms adducts with albumin in peripheral blood that accumulate up to 30-fold higher with chronic vs single exposure.3 Using isotope dilution mass spectrometry,3 we assessed aflatoxin B1-lysine adduct (AFB1 adduct) detection (≥0.5 pg/mg of albumin) and level. Conditional and unconditional logistic regression models produced similar results. Therefore, we used polytomous logistic regression as the most powerful analytic approach. We evaluated variables in Table 1 as potential confounders. We retained questionnaire-derived ají rojo consumption (at least weekly), which changed the magnitude of the odds ratio (OR) for AFB1 adduct detection by greater than 10%. We assessed statistical significance at P < .05 using 2-sided tests. Analyses were conducted in SAS version 9.3 (SAS Institute Inc).

Results

Participation rates were similar for cases with gallbladder cancer (85%, 52/61) and controls with gallstones (86%, 37/43) but lower for community controls (57%, 50/88); male and younger potential community controls refused more often. However, age did not differ among community controls by aflatoxin status (median age, 66 vs 65 years) and none of the 8 males had detectable levels. We included all participants with available plasma: 36 cases (69%), 29 controls with gallstones (78%), and 47 community controls (94%). Cases and controls had similar characteristics except for ají rojo consumption (Table 1).

The AFB1-adducts were detected in 23 cases (64%), 7 controls with gallstones (18%), and 9 community controls (23%). Levels were highest in cases (median, 7.6 pg/mg; Table 1), who were more likely to have detectable AFB1 adducts than controls with gallstones (OR, 9.4; 95% CI, 2.8-37.2) or community controls (OR, 13.2; 95% CI, 4.3-47.9) (Table 2). Restricted to participants with AFB1 adducts, cases with gallbladder cancer had higher levels per change of 10 pg/mg of albumin than controls with gallstones (OR, 4.0; 95% CI, 1.0-78.0) or community controls (OR, 2.5; 95% CI, 1.0-16.7).

Discussion

Several lines of evidence support the biological plausibility of the association of gallbladder cancer with aflatoxin, including experimental, animal, and occupational data4; low hepatitis B virus prevalence in Chile2,5; and genetic variation that may affect xenobiotic excretion.4 In addition, AFB1 adduct plasma levels are similar to those associated with increased risk of hepatocellular carcinoma.6

Despite the small number of participants, the associations between aflatoxin exposure and gallbladder cancer were statistically significant. Recall bias may affect self-reported variables, but not exposure measurement. We cannot rule out reverse causation (ie, cancer may affect AFB1 adduct detection) using cross-sectional data. Larger and longitudinal efforts are needed to substantiate these preliminary findings (eg, by identifying aflatoxin-related TP53 mutations), obtain more precise effect estimates, and identify sources of aflatoxin. These findings, if confirmed, may have implications for cancer prevention.

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Article Information
Section Editor: Jody W. Zylke, MD, Deputy Editor.

Corresponding Author: Catterina Ferreccio, MD, MPH, Department of Public Health/Faculty of Medicine, Pontificia Universidad Católica de Chile, Marcoleta 434, Santiago, Chile (catferre@gmail.com).

Author Contributions: Dr Koshiol had full access to all of the data in the study and takes responsibility for the integrity of the data and the accuracy of the data analysis. Drs Nogueira, Foerster, Koshiol, and Ferreccio contributed equally to this work.

Study concept and design: Nogueira, Koshiol, Ferreccio.

Acquisition, analysis, or interpretation of data: Nogueira, Foerster, Groopman, Egner, Koshiol, Ferreccio.

Drafting of the manuscript: Nogueira, Foerster, Groopman, Koshiol.

Critical revision of the manuscript for important intellectual content: Nogueira, Foerster, Egner, Koshiol, Ferreccio.

Statistical analysis: Nogueira, Koshiol.

Obtained funding: Koshiol.

Administrative, technical, or material support: Foerster, Groopman, Egner, Koshiol.

Study supervision: Foerster, Koshiol, Ferreccio.

Conflict of Interest Disclosures: The authors have completed and submitted the ICMJE Form for Disclosure of Potential Conflicts of Interest and none were reported.

Funding/Support: This work was supported by general funds from the Intramural Research Program, National Institutes of Health, National Cancer Institute, Division of Cancer Epidemiology and Genetics (DCEG), CONICYT/FONDAP grant 15130011, and Fondo Nacional de Investigación y Desarrollo en Salud grant SA11I2205.

Role of the Funder/Sponsor: These funding sources had no role in the design and conduct of the study; collection, management, analysis, and interpretation of the data; preparation of the manuscript; and decision to submit the manuscript for publication. The DCEG did participate in the review and approval of the manuscript; however, the study authors functioned as investigators without direction or interference by DCEG.

Additional Information: The members of the Gallbladder Cancer Chile Working Group appear in the eList in the Supplement.

Correction: This article was corrected on June 9, 2015, to fix formatting in Table 2.

References
1.
Sieber  SM, Correa  P, Dalgard  DW, Adamson  RH.  Induction of osteogenic sarcomas and tumors of the hepatobiliary system in nonhuman primates with aflatoxin B1. Cancer Res. 1979;39(11):4545-4554.
PubMed
2.
Tsuchiya  Y, Terao  M, Okano  K,  et al.  Mutagenicity and mutagens of the red chili pepper as gallbladder cancer risk factor in Chilean women. Asian Pac J Cancer Prev. 2011;12(2):471-476.
PubMed
3.
Scholl  PF, Groopman  JD.  Long-term stability of human aflatoxin B1 albumin adducts assessed by isotope dilution mass spectrometry and high-performance liquid chromatography-fluorescence. Cancer Epidemiol Biomarkers Prev. 2008;17(6):1436-1439.
PubMedArticle
4.
Venniyoor  A.  Cholesterol gallstones and cancer of gallbladder (CAGB): molecular links. Med Hypotheses. 2008;70(3):646-653.
PubMedArticle
5.
Departamento de Epidemiologia. Informe anual 2011 hepatitis B. http://epi.minsal.cl/epi/html/bolets/reportes/HepatitisB/HepB_2011.pdf. Accessed September 22, 2014.
6.
Chen  JG, Egner  PA, Ng  D,  et al.  Reduced aflatoxin exposure presages decline in liver cancer mortality in an endemic region of China. Cancer Prev Res (Phila). 2013;6(10):1038-1045.
PubMedArticle
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