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

The majority of ocular melanomas occur in the uveal tract. Chemotherapy is generally ineffective and large tumours requiring enucleation have a greater than 50% mortality at 5 years. Monosomy for chromosome 3 is common in uveal melanoma and it is known that there is loss of responsiveness to transforming growth factor beta (TGFβ) in melanoma cell lines. Since the gene for TGFβ receptor II (TGFβR2) is located on chromosome 3p22, this study investigates the possibility that the TGFβ pathway, and TGFβR2 in particular, might be involved in the pathogenesis of this rare eye tumour. To this end, the expression of molecules in the pathway has been examined by immunocytochemistry (TGFβ, TGFβR2, SMAD2, SMAD3, SMAD4, and p27), backed up by a cell culture assay of TGFβ-mediated growth suppression, RT-PCR for SMAD4, and loss of heterozygosity (LOH) on 3p22. There was LOH at 3p22 in 6/19 tumours and loss of TGFβR2 expression in 10/27 tumours. Immunohistochemistry for SMADs 2, 3, and 4 showed potential loss of signal transduction in 14/27 tumours. The results indicate abnormality of the TGFβ pathway in 61% of tumours for which unequivocal results were obtained and suggest that abrogation of control of melanocyte growth by the TGFβ pathway may be important in the formation of uveal melanoma. Copyright © 2000 John Wiley & Sons, Ltd.