TP53 R249S mutations, exposure to aflatoxin, and occurrence of hepatocellular carcinoma in a cohort of chronic hepatitis B virus carriers from Qidong, China.
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.
Szymañska
Katarzyna
K
IARC, Lyon Cedex 08, France.
Chen
Jian-Guo
JG
Cui
Yan
Y
Gong
Yun Yun
YY
Turner
Paul Craig
PC
Villar
Stéphanie
S
Wild
Christopher Paul
CP
Parkin
Donald Maxwell
DM
Hainaut
Pierre
P
D000328:Adult; D000348:Aflatoxins / Q000633:toxicity*; D000418:Albumins; D006528:Carcinoma, Hepatocellular / Q000453:epidemiology / Q000209:etiology / Q000235:genetics*; D002353:Carrier State; D002681:China / Q000453:epidemiology; D003043:Cocarcinogenesis; D003062:Codon; D005260:Female; D005506:Food Contamination; D005838:Genotype; D019694:Hepatitis B, Chronic / Q000150:complications / Q000453:epidemiology / Q000235:genetics; D006801:Humans; D008113:Liver Neoplasms / Q000453:epidemiology / Q000209:etiology* / Q000235:genetics*; D016015:Logistic Models; D008297:Male; D008875:Middle Aged; D009154:Mutation; D012150:Polymorphism, Restriction Fragment Length; D016159:Tumor Suppressor Protein p53 / Q000235:genetics*
D000348:Aflatoxins; D000418:Albumins; D003062:Codon; C495901:TP53 protein, human; D016159:Tumor Suppressor Protein p53; C098408:aflatoxin-albumin adduct