GENETIC ANALYSIS OF HUMAN CELLULAR GENES IN NEOPLASTIC TRANSFORMATION

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The combined application of principles and techniques of molecular biology and cell genetics has resulted in the identification and characterization of over 1000 human loci, a value that approaches the gene maps of 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 factor receptors, (4) endogenous retroviral families, (5) integration sites for retroviruses, 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 27 specific human loci that have been chromosomally mapped to date, 11 (40%) have been assigned by the Genetics Section scientists and their collaborators. This year, we have specifically concentrated on understanding the genomic organization of several genes: ets, rel, raf, onc-D, fms, DHFR and a Y chromosome gene family in man. The mammalian homologue to the v-ets oncogene of the avian E26 transforming virus has been shown to be encoded by two transcriptionally active, nonoverlapping structural genes (ets-1 and ets-2) located on human chromosomes 11 and 21, respectively. Over 30 endogenous retroviral loci have been chromosomally assigned using the hybrid panels. A hematological disorder, the 5q- syndrome, has been shown to be hemizygous for the fms oncogene by genetic analysis. This proto-onc-gene was shown to be transcriptionally active in hematopoetic cells and has been shown by our collaborator (C. Sherr) to encode to specific receptor for macrophage colony-stimulating factor. The emerging human gene map continues to provide an unprecedented opportunity for molecular genetic analyses of the initiation and progression of neoplastic processes.