Originally published as JCO Early Release 10.1200/JCO.2005.02.2418 on December 12 2005

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High Frequency of Submicroscopic Hemizygous Deletion Is a Major Mechanism of Loss of Expression of PTEN in Uveal Melanoma

From the Department of Ophthalmology, the Ohio State University, Columbus; Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute and Department of Genetics, Case Western Reserve University School of Medicine, Cleveland, OH; and Cancer Research UK Human Cancer Genetics Research Group, University of Cambridge, Cambridge, United Kingdom

Address reprint requests to Charis En, MD, PhD, Genomic Medicine Institute, Cleveland Clinic Lerner Research Institute, 9500 Euclid Ave, NE-50, Cleveland, OH 44195; e-mail: engc{at}ccf.org or spsmce{at}netscape.net

PURPOSE: Although cytogenetic aberrations at 10q have been reported in up to 27% of uveal melanomas, the role of PTEN in the pathogenesis of uveal melanoma is largely unknown. Our aim was to determine the frequency and clinical significance of PTEN alterations in uveal melanomas.

PATIENTS AND METHODS: We examined PTEN expression using immunohistochemistry in 75 sporadic uveal melanomas, with an average follow-up of 89 months. Molecular cytogenetic alterations were studied using comparative genomic hybridization (CGH). Genotyping was carried out using an intragenic PTEN marker and two flanking markers. Mutational analysis of PTEN was also carried out.

RESULTS: Of the 75 tumors, 12 (16%) showed no PTEN immunostaining, 32 (42.7%) showed weak to moderate staining and the remaining 31 (38.2%) showed staining similar to the normal internal controls. Using CGH, only two (15.4%) of 13 samples showed any loss of 10q. However, in the 38 tumors with informative genotyping, we found that 29 (76.3%) had loss of heterozygosity (LOH) of at least one PTEN marker, and 15 (39.5%) showed LOH of at least two markers. Mutations in the coding region of PTEN were identified in four (11.4%) of 35 tumors. Further, loss of cytoplasmic PTEN expression by immunohistochemistry was associated with shortened disease-free survival (P = .029).

CONCLUSION: This is the first demonstration that PTEN is a tumor suppressor involved in uveal melanoma pathogenesis and may be associated with clinical outcome. Our data also suggest that submicroscopic deletion, but not large deletions, is the major mechanism of loss of PTEN expression in uveal melanomas.

Supported by a clinical cancer genetics fellowship funded by the Department of Internal Medicine, The Ohio State University (M.A.-R.) and a Doris Duke Distinguished Clinical Scientist Award (C.E.), and partially funded by the Patti Blow Research fund in Ophthalmology.

Presented in part at the 96th Annual Meeting of the American Association for Cancer Research, Anaheim, CA, April 16-20, 2005.

Terms in blue are defined in the glossary, found at the end of this article and online at www.jco.org.

Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.

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