The emerging genetics of cancer

The rapid progress in molecular biology has allowed investigators to define some of the basic mechanisms of carcinogenesis. At the molecular level, cellular transformation results from the occurrence of two or three distinct genetic events that uncouple the cell from its normal regulatory mechanisms. One family of genes, the oncogenes, may be particularly important in the process. The aberrant expression of oncogenes, either by mutation or simply by increased transcription, may result in cellular transformation. The genes usually code for growth factors, growth factor receptors or for proteins involved in the transduction of growth signals into the nucleus. Genetic activation causes the cell to continuously sense a message to undergo mitosis, and the cell no longer responds to its normal regulatory signals. The concepts are rapidly moving into the clinical realm as the genetic mechanisms of particular neoplasms have been investigated. The neuroblastoma is the first tumor system in which the biologic characteristics of the tumor were found to be related to a known oncogene; the amplification of the myc gene is an independent marker of the aggressiveness of the tumor. In addition, much progress has been made in defining the specific genetic lesions responsible for retinoblastomas, Wilms' tumors and carcinomas of the colon that arise in patients with familial polyposis coli. As more knowledge accumulates regarding the exact mechanisms through which the proteins encoded by oncogenes affect these carcinomas and others, it may become possible to design pharmacologic agents rationally to hinder their growth selectively.