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Mutational analysis of selected genes in the TGFbeta, Wnt, pRb, and p53 pathways in primary uveal melanoma

Mutational analysis of selected genes in the TGFbeta, Wnt, pRb, and p53 pathways in primary uveal melanoma

Investigative Ophthalmology & Visual Science 43(9): 2845-2851

Purpose. It is known that the pRb pathway cell-cycle inhibitor p16INK4A plays a significant role in cutaneous melanoma and that alteration of p16INK4A, which resides within the 9p21-22 locus that also contains p15INK4B and p14ARF, may occur in up to one third of uveal melanomas. The absence of TGFbeta responsiveness noted in cultured uveal melanoma cells also suggests that the TGFbeta pathway plays a role in the formation of this tumor. Therefore, mutational screening was performed in several key genes in tumor-suppressor pathways that are known to be altered in some uveal melanomas. Methods. Using denaturing high-performance liquid chromatography (DHPLC) analysis and DNA sequencing, a series of 67 uveal melanomas were screened for inactivating mutations in the TGFbeta pathway members Smad4 and TGFbeta receptor type 2 (TGFbetaR2), the downstream cell-cycle inhibitor p15INK4B, and the cell-cycle inhibitors p14ARF and p16INK4A was also investigated for promoter hypermethylation. Mutational analysis was also performed on the Wnt pathway gene beta-catenin, known to be mutated in approximately one quarter of cutaneous melanoma cell lines. Results. Polymorphisms in p16INK4A were detected in 3 of 50 samples, but no inactivating mutations were detected in any of the genes screened. Promoter hypermethylation of p16INK4A was detected in 5 of 55 tumors, and loss of heterozygosity of the p16INK4A locus was detected in 5 of 16 tumors. Conclusions. Most primary uveal melanomas do not appear to contain somatic mutations in Smad4, TGFbetaR2, p14ARF, p15INK4B, p16INK4A, or beta-catenin. However, methylation of the p16INK4A promoter and loss of heterozygosity of the p14ARF p16INK4A locus occurs in some tumors.

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Accession: 011029799

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PMID: 12202501

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