Carcinogenesis, Vol 18, 633-639, Copyright © 1997 by Oxford University Press
C Kaplanski, FV Chisari and CP Wild
Transgenic mice carrying an integrated subgenomic human hepatitis B virus
(HBV) DNA fragment coding for the viral envelope polypeptides, represent a
model for the study of the mechanisms involved in hepatocarcinogenesis. The
mice develop a progressive liver injury characterized by inflammation,
regenerative hyperplasia and dysplasia terminating in hepatocellular
carcinoma (HCC) at around 18-21 months of age. No alterations in specific
oncogenes and tumour suppressor genes in the HCC arising in this transgenic
model have been observed. However, onset of liver tumours is significantly
earlier in mice treated with aflatoxin B1 (AFB1). In order to examine more
generally for genetic rearrangements during the natural history of the
disease, DNA multilocus fingerprinting was performed using probes
recognizing mouse minisatellites. Liver tumour samples from HBV transgenic
mice either untreated or treated with AFB1 transplacentally were included
in the study. In a total of 28 tumour samples from HBV transgenic mice
receiving no carcinogen treatment, using three minisatellite probes, no
alterations were detected. The frequency of rearrangements using any one of
the three probes is calculated to be below 0.2%. This result demonstrates
that genetic instability in minisatellite sequences is not a common event
associated with HBV gene expression and liver injury in this model. In 11
liver tumours from mice exposed to AFB1 transplacentally six had
minisatellite alterations (band gains and losses) revealed by at least one
of the three probes used. The frequency of rearrangements was between 1.1%
and 2% depending on the minisatellite probe. These data show that genetic
alterations can be induced by transplacental exposure to AFB1 and suggest
that genetic instability could be important in hepatocarcinogenesis with
combined exposures to AFB1 and HBV.
ARTICLES
Minisatellite rearrangements are increased in liver tumours induced by transplacental aflatoxin B1 treatment of hepatitis B virus transgenic mice, but not in spontaneously arising tumours
Unit of Environmental Carcinogenesis, International Agency for Research on Cancer, Lyon, France.
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