Role of heterochromatin variation in the instability of a marker chromosome during tumor progression.

Karyotypic evolution of the poorly metastasizing tumorigenic RSV-transformed B77-3T3 fibroblast line was investigated both in highly metastasizing clones (selected by growth in hard agar) and in spontaneous metastases. Analysis of structural chromosome aberrations associated with the transition from the nonmetastatic to the metastatic phenotype was focused on a readily identifiable marker chromosome (A), displaying an extracentromeric heterochromatic region as a main feature promoting genetic instability. Well-defined changes in the structure of this marker were observed, both in vitro and in vivo, and invariably involved C-heterochromatic variation. In the metastatic clones, a specific rearrangement of the A chromosome was selected. This structural variant (B) showed two extracentromeric C-positive regions and probably originated from duplication of the segment of A included between the centromere and the internal C-band. On the other hand, selection of a modified form of chromosome A, not displaying the interpolated C-heterochromatin, had occurred in the extremely rare B77-3T3 spontaneous metastases. The connection among heterochromatin variants, genetic instability, and chromosome aberrations is discussed.