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M.H. Abdel–Rahman, K. Wallace, I. Qureshi, F.H. Davidorf, C. Eng; Molecular Genetic Profiling Identify the Involvement of Different Molecular Pathways in the Pathogenesis of Aggressive Uveal and Cutaneous Melanomas . Invest. Ophthalmol. Vis. Sci. 2005;46(13):4617.
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© ARVO (1962-2015); The Authors (2016-present)
Purpose: Uveal melanoma (UM) and cutaneous melanomas (CM) have similar embryological origin from the neural crest, but the two tumors differ in their biological behavior and associated chromosomal abnormalities. UM metastasize through a hematogenous route, mostly to the liver, while CM metastasize to regional lymph nodes. The aim of our study was to identify molecular genetic changes associated with aggressive UM and CM. Methods: We studied 3 metastatic CMs and 10 primary UMs, four of which developed liver metastasis during the follow up period. We used comparative genomic hybridization (CGH) and/or genotyping utilizing markers on chromosome 1, 3, 6 and 8 to identify genetic alteration in the tumors. We used the Affymetrix U133 Genechips to detect gene expression profiling alteration. Results: Molecular genetic alterations were successfully assessed in 8/10 UMs and in the 3 CMs. Genetic alterations involving chromosome 3 were detected in all 8 UMs tested, while only 1/3 CM showed any alteration of chromosome 3. Other common genetic changes in UMs, seen in ≥ 3/8 samples, included loss of 1p, 16p, 19q and gain of 4p, 4q, 5p, 5q, 6p, 6q, 8q. Common genetic changes in CMs, seen in ≥ 2/3 samples, included loss of 1p, 9p, 9q, 10q and gain of 4p, 5p, 6p, 6q and 7q. Unsupervised cluster analysis of the expression profiling data identified 2 major clusters, one containing the 3 metastatic CMs in addition to 4 UMs. The other major cluster contained 6 UMs, 4 of which had documented metastases. The expression pattern of a subset of UM showed partial similarity to that of metastatic CMs. The expression of genes coding for major histocompatibility cluster (MHC) and extra–cellular matrix was significantly higher in CMs relative to UMs. This may explain some of the biological differences between UMs and CMs. Further, metastatic UMs and CMs showed a significant (p=0.02) under–expression of PTEN mRNA relative to non–metastatic tumors. The expression of PTEN was validated using quantitative RT–PCR and immunohistochemistry. Conclusions: Our data suggest the involvement of different molecular genetic pathways in the progression of CM and UM. However, these results also indicate the contribution of some common genetic pathways in the tumorgenesis of CM and a subset of UM. Our results hint to an important role of extracellular matrix and MHC expression in the pathogenesis of metastatic CMs. Finally, our data suggest a role for PTEN down–regulation in the tumorgenesis and/or progression of both CM and UM.
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