Chromosome aberrations and oncogenes in human cancer

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).