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 have 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 on 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 neoplastic loci that have been mapped to specific chromosomal positions. The human gene map contains about 74 loci whose products have been related to cancer cause and progression, and of these, 45 are proto-oncogenes. We have genetically mapped 13 (29%) of these proto-oncogenes and 20 of the 74 (27%) neoplasia-related genes. This year we have concentrated on several new oncogenes (trk, tpr, ets, erg, gli), growth factors and receptors (endothelial cell growth factor, interleukin-3), and viral integration sites (HEPBI, MLVI1 and -2). Truncation of these cellular genes in a variety of human neoplasias, as well as in certain nonneoplastic pathologies (e.g., ets-2 in Down's syndrome or met in cystic fibrosis), which were suggested by their chromosomal positions, are under investigation. A previously unknown cluster of nine structural loci related to hematological development was discovered on human chromosome 5q and was found to be related to the 5q-anemia, a syndrome characterized by several abnormalities in blood cell production. The collaborative gene mapping studies have served as the basis for several ongoing projects which relate to the genetic events involved in neoplastic transformation.