Molecular Analyses of h-Warts/Latsl Alterations in Human neoplasms

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h-Warts/LATS1 is a human homologue of the Drosophila warts tumor suppressor gene, that functions as a component of the mitotic apparatus, and LATS1-deficient (Lats1^+) mice have been reported to develop ovarian stromal tumors and soft tissue sarcomas. We investigated the status of the h-Warts/LATS1 in 50 human soft tissue sarcomas to address its potential function as a tumor suppressor in human sarcoma development. In our reverse transcription-polymerase chain reaction (PCR) assay, 7 (14%) (3 of 4 myxoid liposarcomas, 3 of 7 leiomyosarcomas, 1 of 9 malignant fibrous histiocytomas) of 50 sarcomas examined had no or a reduced expression of the h-Warts/LATS1, indicating down-regulated gene expression. We further analyzed alterations of the h-Warts/LATS1 in these 7 sarcomas. Using microsatellite markers for chromosome 6q23-25.1 to which the h-Warts/LATS1 is localized, an allelic loss of this locus was detected in one leiomyosarcoma, in which a misssense point mutation of the h-Warts/LATS1 was detected by PCR-single-strand conformation polymorphism. Clusters of CpG dinucleotides in a 5' putative promoter region were hypermethylated in the other 6 sarcomas. Our data suggest that the molecular alterations of the h-Warts/LATS1 could be of pathological importance in human sarcomagenesis, and provide potential clues for further clinical treatments of human soft tissue sarcomas.