Genetic approaches to the study of the molecular basis of human cancer.

During the past few years molecular genetics has been providing answers concerning the mechanisms that are involved in the pathogenesis of human malignancies. Essentially two different mechanisms are involved. One results in the activation of cellular protooncogenes. This activation can occur by activation of transcription, mutation, or gene fusion. Chromosomal translocations and inversions in malignant cells have provided very powerful tools to identify and characterize genes involved in malignant transformation and to probes specific for breakpoint cluster regions are being used extensively for the diagnosis, prognosis, and clinical monitoring of hematopoietic malignancies. The other mechanism results in loss of function of cancer suppressor genes or antioncogenes. Loss of heterozygosity at specific sites of the human genome has provided the means to identify, by the molecular genetic approach, genes the function of which is eliminated or suppressed in human cancers. During the last few years a number of such genes, such as Rb and p53, have been identified and characterized. By this approach a potential candidate involved in the 3p deletion characteristic of lung cancer has been identified. Interestingly, this gene codes for a protein tyrosine phosphatase (14). If this gene should turn out to be involved in the pathogenesis of lung and kidney tumors, it will indicate that transmembrane protein tyrosine phosphatase may represent a class of tumor suppressors.