Retained Expression of P- and E-Cadherin Does Not Predict an Epithelial Molecular Phenotype in Melanoma
AJ Finn, PA Groben, A Lachiewicz, H Hao, C Boyd, K Pedone, H Welch, B Ozanne, J Shields, CJ Der, N Sharpless, NE Thomas. University of North Carolina, Chapel Hill, NC; Babraham Research Campus, Cambridge, United Kingdom; Beatson Institute for Cancer Research, Glasgow, United Kingdom
Background: Gain-of-function mutations in the small guanine triphosphatase N-Ras and the serine-threonine kinase B-Raf activate the mitogen-activated protein kinase (MAPK) cascade in the majority of melanomas. Development of anti-tumor pharmacotherapy has focused on MAPKs and their effectors for this reason. Yet a recent large-scale RNA expression analysis of 21 human melanoma cell lines identified several with neither Ras nor Raf mutations and no alternate mechanism of MAPK activation (Shields, JM et al. Cancer Res. 67; 4. Feb 15 2007: 1502-12). A unique aspect of these lineages was persistent expression of epithelial markers, including P- and E-cadherin.
Design: To assess both the prevalence of the proposed "epithelial-like" subtype in human melanomas and the potential for P- and E-cadherins to serve as markers thereof, we used immunohistochemistry to determine the level and subcellular locale of P- and E-cadherin, activated (phosphorylated) MAPK, and P-Rex1, a MAPK-dependent regulator of cell migration, in a "progression" series comprising 11 benign nevi, 17 dysplastic nevi with varying degrees of atypia, and 30 melanomas in situ, invasive, and metastatic.
Results: 25 percent of invasive and 22 percent of metastatic melanomas in our series demonstrated an "epithelial-like" phenotype of strong P- and E-cadherin expression paired with minimal MAPK activation, but the former was an unreliable predictor of the latter.
Conclusions: Retained expression of P- and E-cadherin in a significant proportion of the invasive and metastatic melanomas examined is in keeping with recent reports that cadherin expression levels do not always track neatly with melanoma progression. Absence of a correlation between this retained expression and the level of MAPK activity argues for direct assessment of the latter in predicting sensitivity to targeted therapy.
Monday, March 22, 2010 9:30 AM
Poster Session I Stowell-Orbison/Surgical Pathology/Autopsy Awards Poster Session # 62, Monday Morning