Recurring sites of chromosome change represent the byproducts of molecular events that participate in the generation or progression of human cancers. Chromosome abnormalities in patients with hematopoietic cancers have proven to be of diagnostic and prognostic value, and the molecular defects for many have been described (see Chap. 19). Despite solid tumors being exceedingly more common than the blood-borne cancers of man, and their significantly greater contribution to morbidity and mortality relative to hematologic neoplasms, less is known about chromosome changes and their clinical and biologic importance in solid tumors. Nevertheless, significant information is accumulating on recurring chromosome alterations in solid tumors including the molecular dissection of recurring breakpoints in many malignancies.
The pattern of chromosome alterations in human solid tumors is decidedly nonrandom. Solid tumors tend to demonstrate multiple clonal structural and numeric chromosome rearrangements and databases are being developed to describe new karyotypic abnormalities in the context of tumor histopathology.
General categories of structural chromosome rearrangements in human solid tumors include chromosome translocations, deletions, inversions and changes associated with increases in DNA sequence copy number (double minutes [dmin]; and homogeneously staining regions [HSRs]).
Tumor-specific chromosome rearrangements have been identified in human solid tumors. Chromosome alterations in many common cancers are described.
Human sarcomas represent a paradigm for molecular dissection of human solid tumors. Tumor-specific chromosome translocations have been described and characterized at the molecular level for several sarcomas including Ewing's sarcoma, alveolar rhabdomyosarcoma, synovial sarcoma, myxoid liposarcoma, and soft tissue clear-cell sarcoma. In general, these translocations juxtapose segments of two genes, which can give rise to a chimeric fusion transcript. Two closely related genes EWS (on chromosome 22q12) and FUS (on chromosome 16p11) have been demonstrated to participate in tumor-specific translocations in several sarcomas. In each case, EWS or FUS acquires a DNA-binding domain from the translocation partner chromosome. These tumor-specific chimeric oncoproteins have transcription factor activity, and it appears that they contribute to malignant transformation by leading to dysregulated gene expression.
Numerous benign neoplasms, such as lipoma and leiomyoma, exhibit translocations involving members of the HMGI family of DNA-binding proteins. Multiple-partner genes are involved with one of the two HMGI genes in various tumors. The disturbance of HMGI protein function appears to have a profound effect on the proliferation of mesenchymal cells in multiple lineages, yet these tumors do not become malignant.
The clinical value of chromosome rearrangements in the common solid tumors of adults is largely indeterminate. Recent advances and the development of new technical approaches for analysis of complex changes in solid tumors suggest that further insights into chromosome rearrangements (and the genes dysregulated by them) may increase clinical utility.