Rate of generation of major karyotypic abnormalities in relationship to the metastatic potential of B16 murine melanoma.

To test the hypothesis that genetic instability correlates with malignant potential, we compared the rate of generation of marker chromosomal abnormalities in clones of B16 F1 and B16 F10 murine melanoma. These rates were estimated through an adaptation of fluctuation analysis of Luria and Delbruck (S. E. Luria and M. Delbruck, Genetics, 28: 491-511, 1943). The highly metastatic F10 line showed the same degree of marker chromosomal instability as the poorly metastatic F1 line (0.01 variants/cell/generation). When subclones of a karyotypically unstable F10 clone were compared with those of a more stable F10 clone, both groups caused the same number of pulmonary metastases, thus demonstrating a further lack of correlation of malignant potential with the level of genomic instability. Since measurements based on marker chromosomes may not truly reflect all of the changes detectable by G-banding, we also analyzed the G-banded karyotypes of the cell lines and their clones (chromatid or chromosomal breaks were not considered in this study). The F10 clones possessed an additional copy of chromosome 1 and also a significantly higher prevalence of the translocation t(9,12) when compared with the F1 clones. Rather than general rates of major karyotypic change determining tumor progression, we suggest the importance of other genetic or epigenetic mechanisms, particularly subtle nonrandom genetic or molecular changes, as the determining factors for malignant potential.