title: Supervised clustering of immunohistochemical markers to distinguish atypical endometrial hyperplasia from grade 1 endometrial cancer.
abstract: OBJECTIVE
  Differentiation between grade-1 endometrial cancer (EC) and atypical endometrial hyperplasia (AEH) is crucial to determine optimal surgical management. However, discrepancies exist between preoperative diagnosis of AEH and final histology. Our aim was to establish clusters of immunohistochemical markers to distinguish AEH from grade-1 EC.
  
  
  METHODS
  We studied 13 immunohistochemical markers (steroid receptors, pro/anti apoptotic proteins, metalloproteinases (MMP) and tissue inhibitor of metalloproteinase (TIMP), and CD44 isoforms) known for their role in endometrial pathology. Using supervised clustering, we determined clusters of co-expressed proteins which contributed the most in differentiating grade-1 EC from AEH.
  
  
  RESULTS
  From 42 tissue samples (20 ECs and 22 AEHs), we found 3 clusters of co-expressed proteins: Cluster 1 included 3 proteins (over-expression of MMP-9 and under-expression of estrogen receptor (ER) and progesterone receptor (PR) A in grade-1 EC compared to AEH); cluster 2 showed an MMP-9 over-expression and ER under-expression; cluster 3 showed over-expression of MMP-9 and bcl-2 and under-expression of ER, PR A and CD44-v6 variant. These three clusters together predicted grade-1 EC with a misclassification rate of 8%.
  
  
  CONCLUSIONS
  Supervised clustering of immunohistochemical markers in grade-1 EC and AEH tissue identified proteins acting together and resulted in accurate differentiation between these two histological entities.
authors.affiliation: Service de Gynécologie-Obstétrique, Hôpital Tenon, AP-HP, 4 rue de la Chine, 75020 Paris, France; Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, Paris 6, France. Electronic address: enora.laas@tnn.aphp.fr.
authors.forename: Enora
authors.initials: E
authors.lastname: Laas
authors.affiliation: Service de Gynécologie-Obstétrique, Hôpital Tenon, AP-HP, 4 rue de la Chine, 75020 Paris, France; Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, Paris 6, France; ER2 UPMC, Université Pierre et Marie Curie, Paris 6, France.
authors.forename: Marcos
authors.initials: M
authors.lastname: Ballester
authors.affiliation: Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, Paris 6, France; Service d'Anatomie Pathologie, Hôpital Tenon, AP-HP, 4 rue de la Chine, 75020 Paris, France.
authors.forename: Annie
authors.initials: A
authors.lastname: Cortez
authors.affiliation: Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, Paris 6, France; Service d'Anatomie Pathologie, Hôpital Tenon, AP-HP, 4 rue de la Chine, 75020 Paris, France.
authors.forename: Julie
authors.initials: J
authors.lastname: Gonin
authors.affiliation: Service de Gynécologie-Obstétrique, Hôpital Tenon, AP-HP, 4 rue de la Chine, 75020 Paris, France; Institut Universitaire de Cancérologie, Université Pierre et Marie Curie, Paris 6, France; UMRS 938, Université Pierre et Marie Curie, Paris 6, France.
authors.forename: Emile
authors.initials: E
authors.lastname: Daraï
authors.affiliation: Service de Gynécologie-Obstétrique, Hôpital Alix de Champagne, CHU de Reims, 45 rue Cognacq-Jay, 51100 Reims, France.
authors.forename: Olivier
authors.initials: O
authors.lastname: Graesslin
mesh_terms: D000368:Aged; D017209:Apoptosis; D014408:Biomarkers, Tumor / Q000032:analysis*; D018269:Carcinoma, Endometrioid / Q000737:chemistry* / Q000473:pathology; D003937:Diagnosis, Differential; D004714:Endometrial Hyperplasia / Q000378:metabolism* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000737:chemistry* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000032:analysis; D005260:Female; D006801:Humans; D018960:Hyaluronan Receptors / Q000032:analysis; D007150:Immunohistochemistry; D019394:Ki-67 Antigen / Q000032:analysis; D020782:Matrix Metalloproteinases / Q000032:analysis*; D008875:Middle Aged; D060787:Neoplasm Grading; D019253:Proto-Oncogene Proteins c-bcl-2 / Q000032:analysis; D011980:Receptors, Progesterone / Q000032:analysis; D011987:Receptors, Steroid / Q000032:analysis*; D019714:Tissue Inhibitor of Metalloproteinases / Q000032:analysis*; D016159:Tumor Suppressor Protein p53 / Q000032:analysis
chemical_list: D014408:Biomarkers, Tumor; C497483:CD44 protein, human; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D018960:Hyaluronan Receptors; D019394:Ki-67 Antigen; D019253:Proto-Oncogene Proteins c-bcl-2; D011980:Receptors, Progesterone; D011987:Receptors, Steroid; D019714:Tissue Inhibitor of Metalloproteinases; D016159:Tumor Suppressor Protein p53; C101118:progesterone receptor A; C097314:progesterone receptor B; D020782:Matrix Metalloproteinases
keywords: Atypical endometrial hyperplasia; Grade-1 endometrial cancer; Immunohistochemistry; Predictive model; Supervised clustering