Prospects for the Development of Antineoplastic Therapy Based on Molecular Pathology

Abstract

It is only in recent years that it has become apparent that neoplasia is frequently, and perhaps invariably, a consequence of somatic genetic aberrations [1–3]. The earliest evidence for this was provided by the demonstration of chromosomal abnormalities in hemopoietic neoplasms, which are more readily subjected to karyotypic analysis than other neoplasms [4]. With improvements in the methodology of cytogenetics, neoplasms of all kinds have been shown to be associated with non-random chromosomal abnormalities. Cytogenetic analysis can detect, however, only gross structual changes in chromosomes, and the presence of multiple karyotypic abnormalities can sometimes obscure the primary genetic abnormality. In such circumstances, if the molecular consequences of the karyotypic abnormalities have been identified (e.g., in 14;18 translocations [5]), molecular analysis may increase the likelihood of detecting genetic changes. Knowledge of the molecular changes associated with specific cytogenetic abnormalities is, of course, essential to the elucidation of the functional results of the genetic rearrangements. Moreover, many relevant genetic changes may be sufficiently subtle not to be detectable by cytogenetic analysis (e.g., mutation in a gene such as may occur in Wilms’ tumor or retinoblastoma). This new discipline, molecular pathology, is likely to become of increasing value in establishing a diagnosis. In fact, it seems entirely appropriate that definitions of individual tumors should ultimately be based upon structural genetic changes or their functional consequences. This is fast becoming a reality for chronic myeloid leukemia and Burkitt’s lymphoma, both of which are associated with chromosomal translocations which have been analyzed in detail, and which can be further subdivided according to the position of the chromosomal breakpoints, ascertained by molecular biological techniques [6, 7].