Revisiting the Clinical and Biologic Relevance of Partial PTEN Loss in Melanoma

Keith M. Giles, Brooke E. Rosenbaum, Marlies Berger, Allison Izsak, Yang Li, Irineu Illa Bochaca, Eleazar Vega-Saenz de Miera, Jinhua Wang, Farbod Darvishian, Hua Zhong, Iman Osman

Research output: Contribution to journalArticlepeer-review

8 Scopus citations

Abstract

The extent of PTEN loss that confers clinical and biological impact in melanoma is unclear. We evaluated the clinical and biologic relevance of PTEN dosage in melanoma and tested the postulate that partial PTEN loss is due to epigenetic mechanisms. PTEN expression was assessed by immunohistochemistry in a stage III melanoma cohort (n = 190) with prospective follow up. Overall, 21 of 190 (11%) tumors had strong PTEN expression, 51 of 190 (27%) had intermediate PTEN, 44 of 190 (23%) had weak PTEN, and 74 of 190 (39%) had absent PTEN. Both weak and absent PTEN expression predicted shorter survival in multivariate analyses (hazard ratio = 2.13, P < 0.01). We show a continuous negative correlation between PTEN and activated Akt in melanoma cells with titrated PTEN expression and in two additional independent tumor datasets. PTEN genomic alterations (deletion, mutation), promoter methylation, and protein destabilization did not fully explain PTEN loss in melanoma, whereas PTEN levels increased with treatment of melanoma cells with the histone deacetylase inhibitor LBH589. Our data indicate that partial PTEN loss is due to modifiable epigenetic mechanisms and drives Akt activation and worse prognosis, suggesting a potential approach to improve the clinical outcome for a subset of patients with advanced melanoma.

Original languageEnglish (US)
Pages (from-to)430-438
Number of pages9
JournalJournal of Investigative Dermatology
Volume139
Issue number2
DOIs
StatePublished - Feb 2019

Bibliographical note

Funding Information:
We acknowledge the patients from this study. Funding was provided by the NYU Cancer Center and National Institutes of Health / National Cancer Institute Cancer Center Support Grant P30CA016087 , Marc Jacobs campaign to support melanoma research, Goldberg Charitable Trust, Wings For Things Foundation, and Clayman Family Foundation (to IO) and Melanoma Research Foundation Student Research Award, American Skin Association Medical Student Grant Targeting Melanoma and Skin Cancer, and the American Dermatological Association Medical Student Fellowship (to BR).

Funding Information:
We acknowledge the patients from this study. Funding was provided by the NYU Cancer Center and National Institutes of Health/National Cancer Institute Cancer Center Support Grant P30CA016087, Marc Jacobs campaign to support melanoma research, Goldberg Charitable Trust, Wings For Things Foundation, and Clayman Family Foundation (to IO) and Melanoma Research Foundation Student Research Award, American Skin Association Medical Student Grant Targeting Melanoma and Skin Cancer, and the American Dermatological Association Medical Student Fellowship (to BR).

Publisher Copyright:
© 2018 The Authors

Copyright:
Copyright 2019 Elsevier B.V., All rights reserved.

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