title: Prognostic significance of cadherin-based adhesion molecules in cutaneous malignant melanoma.
abstract: 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, alpha-catenin, beta-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 alpha-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.
authors.affiliation: Department of Pathology and Public Health, Yale University School of Medicine, New Haven, CT 06520-8034, USA.
authors.forename: Gretchen M
authors.initials: GM
authors.lastname: Kreizenbeck
authors.forename: Aaron J
authors.initials: AJ
authors.lastname: Berger
authors.forename: Antonio
authors.initials: A
authors.lastname: Subtil
authors.forename: David L
authors.initials: DL
authors.lastname: Rimm
authors.forename: Bonnie E
authors.initials: BE
authors.lastname: Gould Rothberg
mesh_terms: D015820:Cadherins / Q000145:classification / Q000378:metabolism*; D015815:Cell Adhesion Molecules / Q000145:classification / Q000378:metabolism*; D005260:Female; D006801:Humans; D016015:Logistic Models; D008297:Male; D008545:Melanoma / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D008875:Middle Aged; D009362:Neoplasm Metastasis; D011379:Prognosis; D012189:Retrospective Studies; D012878:Skin Neoplasms / Q000378:metabolism* / Q000401:mortality / Q000473:pathology; D016019:Survival Analysis
chemical_list: D015820:Cadherins; D015815:Cell Adhesion Molecules