Alterations of the Neurofibromatosis Type 1 Tumor Suppressor Locus in Uveal Melanoma

Abstract

Abstract: : Purpose: Although uveal melanoma is the most common primary ocular malignancy, the genetic abnormalities that lead to this cancer remain poorly understood. Tumor suppressor genes such as p53, Rb, and p16 are not mutated in the majority of uveal melanomas, and few cases have familial clustering to allow genetic linkage analysis. Since neurofibromatosis type 1 (NF1) has been associated with uveal melanoma, and NF1 mutations have been reported in cutaneous melanoma, we examined whether the NF1 locus may be altered in uveal melanoma. Methods: The NF1 locus was examined in thirty-eight paraffin-embedded primary uveal melanomas from patients without neurofibromatosis type 1 using dual-color fluorescence in-situ hybridization and immunohistochemistry. Three of these melanomas, along with matching normal uveal melanocytes, were available for western blot analysis of the NF1 protein, neurofibromin. Results: One of the melanomas, the thickest tumor in our series, contained a deletion of the NF1 locus and lacked neurofibromin expression. Two tumors demonstrated polyploidy of the NF1 chromosomal region. Neurofibromin expression was weak, compared to normal uveal melanocytes, in 47% of the tumors. No statistical correlations were detected between neurofibromin expression levels and clinical or pathologic features. Conclusion: Genetic alterations of the NF1 tumor suppressor locus may play a role in tumor progression in some uveal melanomas in patients without neurofibromatosis. A search for bi-allelic loss of the NF1 locus in uveal melanomas from neurofibromatosis patients will be of interest to determine whether germline NF1 mutations may predispose to uveal melanoma.

Keywords: 464 melanoma • 610 tumors • 496 oncology