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in the Liver
From the Laboratory of Experimental Carcinogenesis, Division of Basic Sciences, National Cancer Institute, Bethesda, Maryland
Identification of specific and primary chromosomal alterations
during the course of neoplastic development is an essential part of
defining the genetic basis of cancer. We have developed a transgenic
mouse model for liver neoplasia in which chromosomal lesions associated
with both the initial stages of the neoplastic process and the
acquisition of malignancy can be analyzed. Here we analyze chromosomal
alterations in 11 hepatocellular carcinomas from the c-myc/TGF-
double-transgenic mice by fluorescent in situ
hybridization with whole chromosome probes, single-copy
genes, and 4'-6-diamidino-2-phenylindole (DAPI-) and
G-banded chromosomes and report nonrandom cytogenetic alterations
associated with the tumor development. All tumors were aneuploid and
exhibited nonrandom structural and numerical alterations. A balanced
translocation t(5:6)(G1;F2) was identified by two-color fluorescent
in situ hybridization in all tumors,
and, using a genomic probe, the c-myc transgene was
localized near the breakpoint on derivative chromosome der 6. Partial
or complete loss of chromosome 4 was observed in all tumors with
nonrandom breakage in band C2. Deletions of chromosome 1 were observed
in 80% of the tumors, with the most frequent deletion at the
border of bands C4 and C5. An entire copy of chromosome 7 was lost in
80% of the tumors cells. Eighty-five percent of the tumor cells had
lost one copy of chromosome 12, and the most common breakpoint
on chromosome 12 occurred at band D3 (28%). A copy of chromosome 14
was lost in 72%, and band 14E1 was deleted in 32% of the
tumor cells. The X chromosome was lost in the majority of the tumor
cells. The most frequent deletion on the X chromosome involved band F1.
We have previously shown that breakages of chromosomes 1,
6, 7, and 12 were observed before the appearance of
morphologically distinct neoplastic liver lesions in this transgenic
mouse model. Thus breakpoints on chromosome 4, 9,
14, and X appear to be later events in this model of liver
neoplasia. This is the first study to demonstrate that specific sites
of chromosomal breakage observed during a period of chromosomal
instability in early stages of carcinogenesis are later involved in
stable rearrangements in solid tumors. The identification of the 5;6
translocation in all of the tumors has a special significance,
being the first balanced translocation reported in human and mouse
hepatocellular carcinoma and having the breakpoint near a tumor
susceptibility gene and myc transgene site of integration.
Moreover, its early occurrence indicates that this is a primary
and relevant alteration to the initiation of the neoplastic process. In
addition, the concordance between the breakpoints observed
during the early dysplastic stage of hepatocarcinogenesis and the
stable deletions of chromosomes 1, 4, 6,
7, 9, and 12 in the tumors provides evidence for
preferential site of genetic changes in
hepatocarcinogenesis.
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