IN-VITRO LOSS OF HETEROZYGOSITY TARGETS THE PTEN MMAC1 GENE IN MELANOMA/

Gross genetic lesions of chromosome 10 occur in 30-50% of sporadic hum an melanomas. To test the functional significance of this observation, we have developed an in vitro loss of heterozygosity approach in whic h a wild-type chromosome 10 was transferred into melanoma cells, where there was selection for its breakage and regional deletion to relieve its growth suppressive effects. The overlap of these events was at ha nd 10q23, the site of the recently isolated PTEN/MMAC1 tumor suppresso r gene, suggesting it as a potential target. Although the gene was exp ressed in the parental cells, both of its chromosomal alleles containe d truncating mutations. In vitro loss of heterozygosity resulted in lo ss of the chromosomally introduced wild-type PTEN/MMAC1, and ectopic e xpression of the gene caused cell growth suppression. Thus, this appro ach identified PTEN/MMAC1 as a target in malignant melanoma and may pr ovide an alter native means to localizing tumor suppressor genes.