Abstract 968: Molecular and clinical correlates of PTEN expression in melanoma
Authors: Davies Michael A. , Chen Guo , Liu Diane D. , Malke Jared , Gershenwald Jeffrey E. , Lazar Alexander J. 
Published: August 2012

The management of melanoma is being revolutionized due to an improved understanding of oncogenic events in this disease. Many prevalent genetic alterations in this disease implicate activation of the RAS-RAF-MEK-ERK and PI3K-AKT pathways in melanoma. While the detection of activating BRAF, NRAS, and KIT mutations is relatively standardized, evaluation of PTEN, a tumor suppressor that inhibits the PI3K-AKT pathway, is challenging due to its regulation by epigenetic mechanisms. In order to understand the molecular correlates of PTEN expression in clinical specimens, we performed immunohistochemistry (IHC) for PTEN in a CLIA-certified laboratory at the MD Anderson Cancer Center on a cohort of FFPE melanomas with mutational and proteomic data from frozen tissue from the same tumors. The expression of PTEN in the tumor tissue was compared to staining intensity in internal positive controls (i.e. endothelial cells), and was scored as Absent, Markedly Reduced, Mildly Reduced, or Normal/Increased. In a cohort of 93 tumors, Absent PTEN expression was observed in 21%, Markedly Reduced in 23%, Mildly Reduced in 36%, and Normal/Increased in 18%. PTEN expression was not evaluable in 1 tumor, and 2% of tumors showed clonality of PTEN expression in the tumors with distinct areas of Normal/Increased and Absent PTEN expression. Absent PTEN expression was detected in 38% of BRAF mutant, 0% of NRAS mutant, and 11% of Wild-type tumors. Quantitative proteomic data generated by reverse phase protein array (RPPA) analysis of the frozen tissue demonstrated that tumors with Absent PTEN by IHC had significantly lower PTEN (p&lt;0.001), and higher levels of P-AKT Thr308 (p=0.004), P-AKT Ser473 (p=0.008) and P-P70S6K (p=0.01) than tumors with Reduced/Normal/Increased PTEN expression, consistent with increased activation of the downstream signaling by the PI3K-AKT pathway. In contrast, tumors with Markedly Reduced PTEN had lower levels of PTEN expression by RPPA than the Mildly Reduced and Normal/Increased PTEN tumors (p=0.046) but they did not exhibit significant differences in P-AKT or P-P70S6K. In light of these results, PTEN expression in subsequent samples was scored as Absent, Present, or Clonal. PTEN IHC of 323 distant metastases identified Absent PTEN expression in 18%, Clonal expression in 2%, and PTEN Present in 79% of resected stage IV melanomas. Among tumor sites with at least 15 samples available for analysis, the rate of Absent PTEN expression was relatively high in CNS (n=39; 28%) and intestinal metastases (n=76; 30%), but was lower in lung (n=147; 10%) and liver (n=18; 6%). Twenty six patients had tissue available from both CNS and extracranial metastases; the concordance rate of PTEN Absence in the paired specimens was 77%. These integrated analyses provide molecularly-defined parameters for the evaluation of PTEN expression in melanoma, and add to our understanding of its expression in this disease.

Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 968. doi:1538-7445.AM2012-968