Abnormalities of the transforming growth factor-beta pathway in ocular melanoma

The majority of ocular melanomas occur in the meal tract. Chemotherapy is g enerally ineffective and large tumours requiring enucleation have a greater than 50% mortality at 5 years. Monosomy for chromosome 3 is common in uvea l melanoma and it is known that there is loss of responsiveness to transfor ming growth factor beta (TGF beta) in melanoma cell lines. Since the gene f or TGF beta receptor II (TGF beta R2) is located on chromosome 3p22, this s tudy investigates the possibility that the TGF beta pathway, and TGF beta R 2 in particular, might be involved in the pathogenesis of this rare eye tum our. To this end, the expression of molecules in the pathway has been exami ned by immunocytochemistry (TGF beta, TGF beta R2, SMAD2, SMAD3, SMAD4 and p27), backed up by a cell culture assay of TGF beta -mediated growth suppre ssion, RT-PCR for SMAD4, and loss of heterozygosity (LOH) on 3p22. There wa s LOH at 3p22 in 6/19 tumours and loss of TGF beta R2 expression in 10/27 t umours. Immunohistochemistry for SMADs 2, 3, and 4 showed potential loss of signal transduction in 14/27 tumours. The results indicate abnormality of the TGF beta pathway in 61% of rumours for which unequivocal results were o btained and suggest that abrogation of control of melanocyte growth by the TGF beta pathway may be important in the formation of meal melanoma. Copyri ght (C) 2000 John Wiley & Sons, Ltd.