Our results indicate that both aflatoxin and PAH exposures are common in US HCC cases. Although it is estimated that 0.7% of US HCC show evidence of aflatoxin exposure from the Cancer Genome Atlas analysis,6 we observed that ~ 46% of HCC cases had detectable aflatoxin adducts. Our study provides additional evidence that environmental exposure including to aflatoxin might partially explain the increase in the incidence of HCC in the US.5
Aflatoxin, a genotoxic hepatocarcinogen, can induce G→T mutations, in particular at codon 249 p53.7 A significant racial difference in P53R249S mutations, a hallmark of aflatoxin-related HCC, in tumors from HCC cases in South Texas was also observed; The prevalence of TP53R249S mutations was highest in Asians (72.7%), followed by Blacks (18.2%), and Hispanics (9.1%).8 In our study, we did not see any racial difference in AFB1-albumin adducts. However, measuring AFB1-DNA adducts and p53 mutations in HCC tumors, we previously observed that AFB1-DNA adducts were associated with p53 DNA mutation.7 As adducts serve as a biomarker of exposure, examining the mutational spectrum of tumors might assist in the better understanding of racial differences in mechanisms of AFB1 carcinogenesis.
A strong interaction between aflatoxin and HBV was reported.9 In our case-control study nested in a community-based cohort, we found that HCC risks was 6-fold higher for individuals with chronic HCV infection and low AFB1-albumin adduct, and 20-fold for individuals with both chronic HCV infection and high adducts compared to those with low adducts and no HCV infection.10 In the present study, we observed that individuals with detectable AFB1-albumin adduct were more likely to be HCV positive. Further study is needed to better understand the molecular mechanism involved in AFB1 promoting hepatocarcinogenesis in HCV-infected liver.
We found AFB1-albumin adducts were associated with blood markers including total bilirubin, albumin, plasma LINE-1 methylation and adiponectin. Adiponectin is known to regulate inflammation, tumor microenvironment and behavior.11 A study of HCC tissues found that increased adiponectin significantly correlated with tumor size, indicating its possible role in prediction of poor prognosis.12 We previously reported lower plasma levels of LINE-1 methylation was associated with worse survival in HCC patients.13 Both animal and human studies found aflatoxin is immunosuppressive by impairing and suppressing normal immune function.14 Further study is need to understand the potential effects of aflatoxin exposure on HCC prognosis.
Analyzing plasma banked up to 12 years before diagnosis, we demonstrated a 2-fold increased risk for development of HCC with increased PAH-albumin adducts independent of viral status.4 In the present study, we found that about half of the HCC cases had detectable PAH-albumin adducts and those with adducts were more likely to be ever smokers. Previous studies have suggested a role for smoking in development of HCC.15 That the correlation of PAH-albumin adduct and smoking suggest that PAH-albumin adducts can be used a biomarker for validating smoking cessation in HCC prevention.
Study strengths include using biomarker measurement to quantify environmental exposure at the individual level. The limitations of this study are small sample size and case only study design. A larger study will be needed to identify individuals at high risk of aflatoxin exposure which will useful for HCC prevention.