GENETIC ANALYSIS OF HUMAN CELLULAR GENES IN NEOPLASTIC TRANSFORMATION

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The cumulative techniques of cell genetics, molecular biology, linkage analysis and in situ hybridization has resulted in the identification and characterization of over 1500 human loci, a value which now exceeds the number of genes mapped in Drosophila. We have concentrated our efforts on somatic cell hybrid panels and in situ hybridizations to genes related to neoplastic processes including (1) cellular proto-oncogenes, (2) growth factors, (3) growth factors and receptors, (4) endogenous retroviral families, (5) integration sites for retrovirus, and (6) restriction genes that delimit retrovirus replication in mammals. Within the last few years, the human gene map has experienced a large increase in the number of neoplasia loci that have been mapped to specific chromosomal positions. Of the 35 specific human loci that have been chromosomally mapped to date, 13 (40%) have been assigned by the Genetics Section scientists and their collaborators. This year we have concentrated on understanding the genomic organization of several genes: rel, ets, trk, tpr, fms, met and endogenous retroviral families. Three of these genes, ets, met-tpr and trk, were found to be composite genes derived from the fusion of chromosomally disparate functional loci. Truncation of these cellular genes in a variety of human neoplasias, as well as in certain non-neoplastic pathologies (e.g., ets-2 in Down's syndrome or met in cystic fibrosis) which were suggested by their chromosomal position, are under investigation. The emerging gene map neoplasia-associated loci continues to provide an unprecedented opportunity for molecular genetic analysis of the initiation and progression of neoplastic processes.