IARC MONOGRAPHS ON THE EVALUATION OF CARCINOGENIC ...

mutation in non-tumorous liver DNA from five of six HCC patients in Mozambique;
none of seven samples from North American patients had a positive signal in the assay.
These observations suggest that this type of mutation is found in histologically normal
cells of patients with HCC.
The TP53 249 ser mutation has also been detected in blood samples from HCC
patients, patients with cirrhosis and individuals without clinically diagnosed liver
disease. Kirk et al. (2000) compared 53 HCC patients, 13 patients with cirrhosis and 53
control subjects in The Gambia with 60 non-African French patients, 50 of whom had
HCC and 10 had cirrhosis. The 249 ser mutation was detected by restriction fragment
length polymorphism (RFLP)-PCR in circulating DNA in plasma from 19 (36%) of the
HCC patients, two (15%) cirrhosis patients and three (6%) of the African control
subjects. The prevalence of the 249 ser mutation did not differ between HBsAg-positive
and -negative individuals. The mutation was not detected in any of the French plasma
samples. No tumour tissue was available from the Gambian patients and so the presence
of the same mutations in the corresponding HCC could not be confirmed. The detection
of the 249 ser mutation in circulating DNA in the plasma of non-cancer patients again
could reflect either an early neoplastic event or exposure to aflatoxin.
Jackson et al. (2001) examined 20 paired plasma and HCC samples from patients
from Qidong County, China, for the presence of the TP53 249 ser mutation analysed by
short oligonucleotide mass spectrometry. Eleven tumours were positive for the mutation
and the same mutation was detected in six of the paired plasma samples. An additional
four plasma samples were positive for the mutation in the absence of a detectable mutation
in the corresponding tumour. The authors suggested that this might be due to other
non-sampled HCCs in those patients. In contrast to the findings of Aguilar et al. (1993),
no 249 ser mutations were detected in DNA from normal tissue adjacent to the HCC.
(c) Other genetic alterations in human HCC
AFLATOXINS 233
It would be unexpected if aflatoxin carcinogenesis were exclusively associated with
a specific TP53 mutation, given the multiple genetic alterations observed in human
HCC. Consequently, several studies have tested the hypothesis that aflatoxin exposure is
associated with other specific genetic alterations.
In the study by Fujimoto et al. (1994) described above, while the 249 ser mutation was
more frequent in samples from Qidong than in those from Beijing, additional differences
were found in the pattern of loss of heterozygosity (LOH). Specifically, in tumours from
Qidong, four of 14 informative cases (28%) showed LOH on chromosome 4 (4p11-q21)
and nine of 10 (90%) and 11 of 19 (58%) showed LOH on chromosome 16q22.1 and
16q22-24, respectively. In contrast, none of six informative cases from Beijing showed
LOH at 16q22-24 and none of five at 4p11-q21.
Wong et al. (2000) studied 83 HCC samples from patients undergoing curative
resection. Of these, 50 were from China (30 from Hong Kong, 20 from Shanghai), 16
from Japan and 17 from the USA. The Chinese subjects were all HBV-positive, the
Japanese patients were HCV-positive and the patients from the USA were HBV-negative.