Chromosomes, Genes, and Cancer

THE "MODERN" ERA of tumor cytogenetics began in the 1950s and accelerated rapidly with the development of so-called banding techniques in the 1970s. During this period, chromosome studies of neoplasms added significantly to our understanding of various aspects of tumor biology. The recognition that most neoplasms have visible cytogenetic alterations contributed to general acceptance of the view that somatic genetic changes are important in tumorigenesis. In addition, the demonstration that in a given tumor all the neoplastic cells often have the same karyotypic change, or related changes, helped to indicate the derivation of most tumors from a single altered cell. Presumably, the specific somatic genetic change, often recognizable at the chromosome level, confers on the progenitor cell a selective growth advantage, allowing its progeny to expand as a neoplastic "clone" of unicellular origin. The further demonstration that, in general, karyotypic abnormalities are more extensive in advanced tumors has also added importantly to our understanding of the phenomenon of tumor progression. It led to the hypothesis that neoplasms become more aggressive with time because of the sequential appearance in the neoplastic clone of subpopulations of cells with additional alterations in genetic makeup. Neoplastic cells show increased genetic instability and are thus more likely than normal cells to generate such genetic variants. In this concept of "clonal evolution," most of these genetic variants that arise in a tumor cell population do not survive, but those few mutants that have an additional selective growth advantage expand to become predominant subpopulations within the neoplasm, and demonstrate the characteristics of more aggressive growth and increased "malignancy" that we recognize as tumor progression. The continued presence of multiple subpopulations in the neoplasm provides the basis for the heterogeneity that is also typically observed in malignant tumors. Cytogenetic data contributing to these evolving concepts have been incorporated into several recent reviews of the mechanisms of tumor progression.1I2 Most current developments in tumor cytogenetics, however, have related to another aspect that has been increasingly recognized as techniques have improved: specific alterations in particular chromosomes are associated, with different degrees of consistency, with specific types of tumors, or with neoplasia in general.3'4 It has been suggested that these nonrandom karyotypic changes might indicate sites in the genome where particular genes important in carcinogenesis are located, and provide clues as to how the function of such "oncogenes" might be significantly altered. Much of the initial support for this hypothesis has come from the study of specific reciprocal chromosome translocations in various hematopoietic tumors such as Burkitt's lymphoma and chronic myelogenous leukemia (CML), in which alteration in structure and/or function of proto-oncogenes, the human homolog of retroviral oncogenes, has been demonstrated. At the same time, chromosomal changes in other tumors, reflecting gain or loss of genetic material, have suggested a critical role for oncogene dosage in some instances of carcinogenesis. This brief review of recent findings will focus on this aspect of the cytogenetics and related molecular genetics of neoplasia, with emphasis primarily on our own recent studies in leukemia and lymphoma.