Carcinogenesis, Vol 18, 905-910, Copyright © 1997 by Oxford University Press
J Riley, HG Mandel, S Sinha, DJ Judah and GE Neal
Activation of ras proto-oncogenes occurs frequently in vivo in chemically
induced rodent tumours, including rat hepatomas induced by aflatoxin B1.
This study examines the in vitro activation of a human ras gene by this
mycotoxin. A plasmid containing the human Ha-ras proto- oncogene, together
with a neomycin resistance gene (pECneo), was incubated in vitro with a
microsomal system generating aflatoxin B1 8,9- epoxide. Subsequent
transfection of the plasmid into mouse NIH 3T3 fibroblasts, followed by
G418 selection and s.c. injection of surviving cells into immunodeficient
mice demonstrated that the proto-oncogene had acquired transforming
capacity. Although a single tumour resulted from similar treatment of
incubated unconjugated plasmid, no tumours were produced by a secondary
round of transfections using DNA from this tumour. Selective PCR
amplification of the human Ha-ras gene in extracted tumour DNA followed by
sequencing demonstrated the presence of G-->T transversions either at
the first or middle base of codon 12 in tumours resulting from transfection
with the aflatoxin-B1-modified pECneo plasmid, but this was not detected in
the single tumour resulting from transfection with the unmodified plasmid.
Thus, although a mutation in the Ha-ras gene has not been reported for
human primary hepatomas occurring in aflatoxin-exposed populations,
metabolically activated aflatoxin B1 is capable of mutating this
proto-oncogene to its oncogenic form in vitro. No mutations were observed
in codon 61. It appears that, in contrast to the frequently reported
G-->T transversions in codon 249 of the p53 gene in primary hepatomas in
aflatoxin-exposed humans, the failure to detect Ha-ras mutations in these
tumours is not due to an inability of aflatoxin B1 to activate this
proto-oncogene. The G-->T transversions observed in this study contrast
with the most frequent aflatoxin B1 in vivo induced mutations, G-->A
transitions in the rat Ki-ras gene. Possible mechanisms for these
differences are discussed.
ARTICLES
In vitro activation of the human Harvey-ras proto-oncogene by aflatoxin B1
Medical Research Council Toxicology Unit, University of Leicester, UK.
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