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

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.

PTEN as a Prognostic/Predictive Biomarker in Cancer: An Unfulfilled Promise?

“…The clinical evaluation of PTEN protein in patients is often carried out by IHC; however, IHC is not the only detection method to identify a correlation between PTEN loss status and patient prognosis. Indeed, Giles et al demonstrated that an analysis of PTEN epigenetic modifications could also identify patients with an inactive PTEN and a worse prognosis [111]. More specifically, methylation of the PTEN gene, which is associated with gene silencing, is significantly correlated with excess deaths when analyzed in the context of specific prognostic characteristics (e.g., mitotic index, tumor surface diameter and age) [112].…”

Molecular Mechanisms Underlying Autophagy-Mediated Treatment Resistance in Cancer

“…The phosphatase and tensin homolog (PTEN) protein is a key negative regulator of PI3K/AKT signaling, and functions as a phosphatase that inhibits AKT activity via dephosphorylation of PtdIns (4,5) P3. Loss of PTEN function is a frequent observation in many cases of melanoma and has been associated with poor clinical outcomes [350,351]. Concurrently, most patients also present with activating BRAF mutations, but a subset of such patients possess tumors that are insensitive to BRAF inhibitors [350,351].…”

“…Loss of PTEN function is a frequent observation in many cases of melanoma and has been associated with poor clinical outcomes [350,351]. Concurrently, most patients also present with activating BRAF mutations, but a subset of such patients possess tumors that are insensitive to BRAF inhibitors [350,351]. It was previously demonstrated that PTEN is required for the upregulation of the pro-apoptotic protein, BIM, following inhibition of BRAF.…”

Genome‐wide characterization of 5‐hydoxymethylcytosine in melanoma reveals major differences with nevus

“…In the genetically engineered mouse models studied deregulated expression of CDKN2A was observed. Even partial PTEN loss due to epigenetic mechanisms has biological relevance in melanoma 36 . Of note, the CpG sites showing hypermethylation in the study by Giles et al 36 are located within the DhMR we identified.…”

“…Here, we demonstrate the presence of hydroxymethylation in the promoter region of the PTEN gene (chr10:89621419‐89622084) in nevi and its absence in melanomas. It has been reported that PTEN expression is uniformly high in nevus and markedly lower in melanoma samples 10,35,36 . In melanomas, PTEN is functionally inactivated through genetic and epigenetic mechanisms, including promoter hypermethylation 25,37 .…”