The combined application of cytogenetic and molecular
genetic techniques has elucidated the involvement of cellular
oncogenes in tumor specific chromosomal abnormalities. Although
these studies further underline the fundamental role of chromosomal
abnormalities in tumor-development, as yet virtually
nothing is known of the generation of these aberrations. DNA
sequence analysis of BL and CML specific chromosomal breakpoint
regions revealed no clue to a possible translocation mechanism.
However, a report by Fialkow et al. (1981) indicates that in
CML, the acquisition of the Ph1 chromosome is preceded by an
initial phase of marked genetic instability. A similar phase of
genetic instability of Ig or TCR loci may occur during the
process of somatic rearrangements of these genes. During these
phases, presumably various translocations occur and those with
a selective growth advantage will eventually result in a clinically
apparent leukemia.
It has been suggested that fragile sites may act as predisposing factors for certain specific chromosomal rearrangements
(Yunis and Soreng, 1984~ LeBeau and Rowley, 1984). The chromosomal
location of a number of these fragile sites coincides
with specific chromosomal breakpoint regions. Furthermore,
leukemic patients were identified as carriers of a fragile site
at the observed chromosomal breakpoint (Yunis, 1983~ LeBeau,
1986). Although several genes, among which some oncogenes, have
been mapped to an identical chromosomal region as a fragile
site, at present the exact nature and function of the genes
located at these sites remains an enigma.
Molecular techniques as Southern blotting and chromosomal
walking have demonstrated in a few tumor specific aberrations
the localization of (putative) oncogenes in the direct vicinity
of the chromosomal breakpoint region. However, in other tumor
specific aberrations the exact nature of the association between
cytogenetic changes and alterations at the DNA or gene
level remains obscure. The application of new techniques as
Pulsed Field Gradient (PFG) gel electrophoresis (Schwartz and
Cantor, 1984~ Carle and Olson, 1984), which allows the separation
of large (50-2000 kb) DNA fragments could help to corroborate
a possible involvement of oncogenes in these cases.
Furthermore, the use of PFG gels could lead to the detection of
deletions which are not visible at the cytogenetic level. An
example concerning deletions of part of chromosome lp32, which
resulted in the activation of the trk oncogene in a human colon
carcinoma has recently been reported (Martin-Zanca et al.,
1986)