This Article Full Text Full Text (PDF) Alert me when this article is cited Alert me if a correction is posted Services Similar articles in this journal Similar articles in PubMed Alert me to new issues of the journal Download to citation manager Google Scholar Articles by Kreizenbeck, G. M. Articles by Gould Rothberg, B. E. PubMed PubMed Citation Articles by Kreizenbeck, G. M. Articles by Gould Rothberg, B. E.

Prognostic Significance of Cadherin-Based Adhesion Molecules in Cutaneous Malignant Melanoma

Departments of ¹ Pathology, ² Dermatology, and ³ Epidemiology and Public Health, Yale University School of Medicine, New Haven, Connecticut

Requests for reprints: Bonnie E. Gould Rothberg, Department of Epidemiology and Public Health, Yale University School of Medicine, 60 College Street, New Haven, CT 06520-8034. Phone: 203-737-4205; Fax: 203-737-5089. E-mail: bonnie.gouldrothberg{at}yale.edu

Background: The need for novel molecular prognostic markers that can supplement validated clinicopathologic correlates for cutaneous malignant melanoma is well recognized. Proteins that mediate the epithelial-mesenchymal transition, the process by which a cancer cell disengages from its parent tumor, are important candidates.

Methods: The prognostic relevance of E-cadherin, N-cadherin, and P-cadherin, calcium-dependent transmembrane glycoproteins that regulate cell-cell adhesion, and their adaptors, -catenin, β-catenin, and p120-catenin, was evaluated on a cohort of 201 primary and 274 metastatic melanoma tumors using fluorescence-based immunohistochemical methods and Automated Quantitative Analysis of protein expression on digitally captured photomicrographs.

Results: Increasing levels of N-cadherin expression improved overall survival (log-rank = 7.31; P = 0.03) but did not retain significance following adjustment for established clinicopathologic correlates (P = 0.50). Higher levels of E-cadherin approached significance for favorable prognosis on both univariate (P = 0.13) and multivariable (P = 0.10) analyses. Hierarchical clustering of the composite profiles for all six markers identified four unique clusters that yielded differential overall survival (log-rank = 10.54; P = 0.01). Cluster 4, expressing high E-cadherin and N-cadherin levels, possessed the most favorable outcome and cluster 2, featuring low E-cadherin and -catenin but modest N-cadherin, showed least favorable outcomes. Cluster 2 remained significant on multivariable analysis (hazard ratio, 3.29; 95% confidence interval, 1.50-7.19; P = 0.003).

Conclusions: Although none of the cadherin-based adhesion molecules were independently prognostic, multimarker profiles were significant. Similar to epithelial-derived tumors, loss of E-cadherin correlates with poor outcome. In contrast, for neural crest–derived cutaneous malignant melanoma, N-cadherin overexpression can be associated with either a successful epithelial-mesenchymal transition or a favorably differentiated tumor. Additional cadherin profiles are needed to discriminate these distinctive phenotypes. (Cancer Epidemiol Biomarkers Prev 2008;17(4):949–58)