Carcinogenesis, Vol 19, 1045-1052, Copyright © 1998 by Oxford University Press
KM Gressani, LA Rollins, S Leone-Kabler, JM Cline and MS Miller
An understanding of the basic mechanisms responsible for the pathogenesis
of liver neoplasms is needed in order to develop better therapeutic
strategies. The present study utilized a pharmacogenetic mouse model to
assess the role of cytochrome P4501A1 (Cyp1a1) in modulating genetic damage
to oncogenic and tumor suppressor loci following in utero exposure to the
polycyclic aromatic hydrocarbon, 3- methylcholanthrene (MC). Analysis of
the Ha-ras, Ki-ras, INK4a and p53 genes was carried out with lysates from
paraffin-embedded liver tissue from transplacentally-treated mice. The
lysates were subjected to DNA amplification by the PCR technique followed
by allele-specific oligonucleotide hybridization screening and SSCP
analysis. All of the 26 neoplasms screened (23 hepatocellular carcinomas,
two hepatocellular adenomas and one sarcoma) exhibited a GGC-->CGC
(GLY13-->ARG13) transversion at the Ki-ras gene locus. None of the
tumors had Ki-ras mutations at codon 12 of exon 1. Approximately 12% (3/26)
of the liver tumors exhibited point mutations in exon 1 of the INK4a gene,
with each of the three tumors exhibiting two point mutations. Analysis of
exon 2 of the INK4a gene showed the presence of a CCG-->CTG
(PRO73-->LEU73) transition in two of the 26 neoplasms. No mutations were
found in exons 1 or 2 of the Ha-ras gene, or in exons 5-8 of the p53 gene.
Analysis of tumor RNAs showed overexpression of Ha-ras, cip1 and c-jun in
approximately 38% of the liver tumor samples. The results of this study
suggest that mutagenic damage to oncogenes and tumor suppressor genes may
be critical factors in mediating transplacentally-induced liver
tumorigenesis. The fact that Ki-ras mutations were found in all of the
tumors suggests that mutation at this gene locus may be an early event in
liver tumor pathogenesis, while mutation in tumor suppressor genes may
occur later during tumor progression. These combined results are consistent
with the pathogenesis of cancer in humans.
ARTICLES
Induction of mutations in Ki-ras and INK4a in liver tumors of mice exposed in utero to 3-methylcholanthrene
Department of Physiology and Pharmacology, Comprehensive Cancer Center, Wake Forest University School of Medicine, Winston-Salem, NC 27157, USA.
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