ROLE OF LOSS OF THE SHORT ARM OF CHROMOSOME 3 IN HUMAN ORAL SQUAMOUS CELL CARCINIGENESIS

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Cytogenetic and restriction fragment length polymorphism (RFLP) analyses have suggested that a putative tumor suppressor gene(s), which may play an important role in the development of human oral squamous cell carcinoma (SCC), is located on the short arm of chromosome 3 (3p). We previously reported that introducing an intact human chromosome 3 into three different oral SCC tumorigenic cell lines completely suppresses the tumorigenicity of each cell line with significant decrease in the in vitro growth rate and morphological changes. To map the tumor suppressor gene(s) on 3p, we have now examined the tumorigenicity of microcell hybrid clones which contain various fragments derived from 3p that were introduced via microcell-mediated chromosome transfer. Sixteen hybrid clones were obtained from four successful experiments and these clones were classified into two groups four fully tumorigenic clones and 12 suppressed phenotype clones. Analyses of the 3p segments in the series of hybrid clones using RFLP or microsatellite markers revealed that the 3p21.2-p2l.3 and/or 3p25 regions were consistently retained in the 12 clones with suppressed phenotype, but not in the four tumorigenic clones. The more proximal 3pl3 regions was also retained in three non-tumorigenic clones. The overall results are fairly compatible with the recent data that there are three discrete regions on 3p showing frequent allelic losses in oral SCC, and directly provide functional evidence for the presence of tumor suppressor genes for oral SCC in these regions. The possibility that three genes, FHIT, VHL, and TbetaR-II recently identified on 3p may be significantly involved in oral SCC development is also discussed.