TP53 R249S Mutations, Exposure to Aflatoxin, and Occurrence of Hepatocellular Carcinoma in a Cohort of Chronic Hepatitis B Virus Carriers from Qidong, China

Abstract

Hepatocellular carcinoma (HCC) has a high mortality in East Asia and Sub-Saharan Africa, two regions where the main etiologic factors are chronic infections with hepatitis B virus and dietary exposure to aflatoxin. A single base substitution at the third nucleotide of codon 249 of TP53 (R249S) is common in HCC in these regions and has been associated with aflatoxin-DNA adducts. To determine whether R249S may be detected in plasma DNA before HCC diagnosis, we conducted a case-control study nested in a cohort of adult chronic hepatitis B virus carriers from Qidong County, People's Republic of China. Of the 234 plasma specimens that yielded adequate DNA, only 2 (0.9%) were positive for R249S by restriction fragment length polymorphisms, and both of them were controls. Of the 249 subjects tested for aflatoxin-albumin adducts, 168 (67%) were positive, with equal distribution between cases and controls. Aflatoxin-albumin adduct levels were low in the study, suggesting an overall low ongoing exposure to aflatoxin in this cohort. The R249S mutation was detected in 11 of 18 (61%) available tumor tissues. To assess whether low levels of mutant DNA were detectable in pre-diagnosis plasma, 14 plasma specimens from these patients were analyzed by short oligonucleotide mass analysis. Nine of them (64%) were found to be positive. Overall, these results suggest that HCC containing R249S can occur in the absence of significant recent exposure to aflatoxins. The use of short oligonucleotide mass analysis in the context of low ongoing aflatoxin exposure may allow the detection of R249S in plasma several months ahead of clinical diagnosis. (Cancer Epidemiol Biomarkers Prev 2009;18(5):1638 -43)

Exposure to organochlorine pesticides is independent risk factor of hepatocellular carcinoma: A case–control study

“…HBV and the dietary aflatoxins have been suggested as the most important HCC hazard factors in China (Li et al, 2001), where HBV infection is almost a prerequisite for the onset of HCC in the high-risk regions (Yeh et al, 1989;Shen et al, 1991). Dietary exposure to aflatoxin B1 (AFB1) (Li et al, 2001;Wang et al, 2001;Wang and Liu, 2007) may associate with HCC risk in Chinese cohorts due to enhancement of the mutation frequency of the third nucleotide of codon 249 of TP53 (Deng et al, 1997;Kirk et al, 2000;Szymanska et al, 2009) and oxidative stress (Wu et al, 2008). However, among R e t r a c t e d individuals at very high risk of liver cancer due to infection with HBV and AFB1 exposure, only 20% eventually develop liver cancers.…”

Hepatitis B Virus Genetic Variation and TP53 R249S Mutation in Patients with Hepatocellular Carcinoma in Thailand

“…First, the method using RFLP assay might not be sensitive for detecting R249S mutation in some specimens containing trace amounts of the mutant DNA. In this regard, it has been shown that, at high blood levels of R249S mutation, RFLP provides good results in agreement with more sensitive methods such as short oligonucleotide mass analysis (SOMA) (Szymanska et al, 2009). At low levels, however, the signals generated by RFLP are below the detection threshold and might be responsible for the false-negative results.…”

Genome-scale mutational signatures of aflatoxin in cells, mice, and human tumors

“…We integrated the experimental results from cell lines and mice with somatic-mutation spectra from newly sequenced HCCs from Qidong, China, a region of well-studied high aflatoxin exposure (Szymanska et al 2009;Kensler et al 2011). The HCCs from Qidong were also selected for somatic TP53 R249S mutations, which is considered indicative of AFB1 exposure (Hollstein et al 1991;Montesano et al 1997;Sun et al 2011).…”