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Mutational Analysis of Selected Genes in the TGFß, Wnt, pRb, and p53 Pathways in Primary Uveal Melanoma

¹ From the Centre for Cutaneous Research, St Bartholomew’s and the London School of Medicine and Dentistry, Queen Mary College, University of London, London, United Kingdom; the ² Department of Pathology, Institute of Ophthalmology, London, United Kingdom; the ³ Ocular Oncology Service, St. Bartholomew’s and Moorfields Eye Hospital, London, United Kingdom; and the ⁴ Translational Oncology Research Centre, Queen Alexandra Hospital, Portsmouth, United Kingdom.

PURPOSE. It is known that the pRb pathway cell-cycle inhibitor p16^INK4A plays a significant role in cutaneous melanoma and that alteration of p16^INK4A, which resides within the 9p21-22 locus that also contains p15^INK4B and p14^ARF, may occur in up to one third of uveal melanomas. The absence of TGFß responsiveness noted in cultured uveal melanoma cells also suggests that the TGFß 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 TGFß pathway members Smad4 and TGFß receptor type 2 (TGFßR2), the downstream cell-cycle inhibitor p15^INK4B, and the cell-cycle inhibitors p14^ARF and p16^INK4A. p16^INK4A was also investigated for promoter hypermethylation. Mutational analysis was also performed on the Wnt pathway gene ß-catenin, known to be mutated in approximately one quarter of cutaneous melanoma cell lines.

RESULTS. Polymorphisms in p16^INK4A were detected in 3 of 50 samples, but no inactivating mutations were detected in any of the genes screened. Promoter hypermethylation of p16^INK4A was detected in 5 of 55 tumors, and loss of heterozygosity of the p16^INK4A locus was detected in 5 of 16 tumors.

CONCLUSIONS. Most primary uveal melanomas do not appear to contain somatic mutations in Smad4, TGFßR2, p14^ARF, p15^INK4B, p16^INK4A, or ß-catenin. However, methylation of the p16^INK4A promoter and loss of heterozygosity of the p14^ARF-p16^INK4A locus occurs in some tumors.

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