IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

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IARC MONOGRAPHS VOLUME 82
samples from Hong Kong and in 4/20 (20%) from Shanghai. This mutation was not
found in 16 samples from Japan and 17 from the USA, although there were other mutations
in exon 7 in the Japanese samples.
In areas of expected low aflatoxin exposure (including Japan, Republic of Korea,
Europe and North America), the prevalence of codon 249 mutations is extremely low
(< 1%) and even those that do occur tend to be at the second nucleotide rather than the
third. Oda et al. (1992) analysed 140 HCC tissue samples (128 Japanese, six Korean,
four Indonesian and two Taiwanese); of these, only one Japanese and one Indonesian
showed the specific 249 ser mutation. The limited information on residence and ethnicity
in many studies has been commented upon (Laskey & Magder, 1997).
Hollstein et al. (1993) measured serum aflatoxin–albumin adducts and liver aflatoxin
B 1–DNA adducts from 15 Thai patients, but only one had measurable concentrations
of albumin adducts in serum. In none of the samples were aflatoxin B 1–DNA
adducts found. Only one had the specific 249 ser mutation. In another study of 16 HCC
cases from Mexico (Soini et al., 1996), three tumours contained the 249 ser mutation; of
these, sera were available for two patients and both contained aflatoxin–albumin adducts.
Aflatoxin–albumin adducts were detected in sera from all of a further 14 patients without
the mutation in the corresponding HCC.
Since chronic HBV infection is a strong and specific risk factor for HCC and aflatoxin
exposure commonly co-occurs with viral infection, it is important to examine
whether the 249 ser mutation is seen only in the presence of chronic HBV infection.
Although it is clear from the studies summarized below of HCC in North America,
Europe and Japan that HBV alone does not induce the 249 ser mutation, the high prevalence
of HBV infection in aflatoxin-endemic areas has made it hard to establish
whether both risk factors are required for the mutation to occur.
Lasky and Madger (1997) summarized thirteen studies that both ascertained HBV
status and analysed TP53 mutations. Data were available on 449 patients, of whom 201
were positive and 248 negative for HBV markers. The association between aflatoxin
exposure and the 249 ser mutation was still observed when the analysis was restricted to
HBV-positive patients in the groups with high and low aflatoxin exposure. However, the
number of HBV-negative patients with high aflatoxin exposure was too small to allow a
similar comparison in HBV-negative cases. Overall, it appears that the 249 ser mutation
related to aflatoxin exposure is not explained by any confounding introduced by possible
associations between aflatoxin and HBV.
It remains unclear at what stage in the natural history of HCC the TP53 mutation
occurs. Some information is available from the analysis of histologically normal liver
samples from patients resident in areas reportedly differing in aflatoxin exposure level.
Aguilar et al. (1993, 1994) examined non-tumorous liver tissue from small numbers of
HCC patients from Qidong (China), Thailand and the USA and demonstrated the
presence of TP53 AGG to AGT mutations (in codon 249) at a higher frequency in
samples from China than in those from Thailand or the USA. By use of an allele-specific
polymerase chain reaction (PCR) assay, Kirby et al. (1996b) detected the TP53 249 ser