title: Supervised clustering of immunohistochemical markers to distinguish atypical and non-atypical endometrial hyperplasia.
abstract: The risk of endometrial hyperplasia (EH) progressing into endometrioid endometrial cancer ranges from 1% for simple EH without atypia (EHWA) to 46.2% for atypical EH (AEH). Differentiation between both entities is crucial to determine optimal management. As preoperative diagnosis of AEH can be difficult, we aimed to establish clusters of immunohistochemical markers to distinguish EHWA from AEH. We studied 13 immunohistochemical markers (steroid receptors, pro/anti-apoptotic proteins, metalloproteinases (MMP), tissue inhibitor of metalloproteinase (TIMP), 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 EHWA from AEH. From 39 tissue samples (17 EHWA and 22 AEH), we found three clusters of co-expressed proteins: Cluster 1 included two proteins (over-expression of estrogen receptor (ER) and under-expression of progesterone receptor (PR) B in AEH compared to EHWA); Cluster 2: an ER, PR A, MMP-2 and TIMP-1 over-expression and a PR B and TIMP-2 under-expression; Cluster 3: over-expression of ER and MMP-7 and under-expression of PR B and TIMP-2. AEH can be accurately distinguished from EHWA using a supervised clustering of immunohistochemical markers. This promising approach could be useful to improve the preoperative diagnosis of EH.
authors.affiliation: Service de Gynécologie-Obstétrique, Hôpital Tenon , AP-HP, Paris , France .
authors.forename: Enora
authors.initials: E
authors.lastname: Laas
authors.forename: Marcos
authors.initials: M
authors.lastname: Ballester
authors.forename: Annie
authors.initials: A
authors.lastname: Cortez
authors.forename: Julie
authors.initials: J
authors.lastname: Gonin
authors.forename: Geoffroy
authors.initials: G
authors.lastname: Canlorbe
authors.forename: Emile
authors.initials: E
authors.lastname: Daraï
authors.forename: Olivier
authors.initials: O
authors.lastname: Graesslin
mesh_terms: D015415:Biomarkers / Q000378:metabolism; D016000:Cluster Analysis; D003937:Diagnosis, Differential; D015536:Down-Regulation; D004714:Endometrial Hyperplasia / Q000175:diagnosis* / Q000378:metabolism / Q000473:pathology; D004717:Endometrium / Q000201:enzymology / Q000378:metabolism* / Q000473:pathology; D047628:Estrogen Receptor alpha / Q000378:metabolism; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D020778:Matrix Metalloproteinase 2 / Q000378:metabolism; D020783:Matrix Metalloproteinase 7 / Q000378:metabolism; D008875:Middle Aged; D011237:Predictive Value of Tests; D011980:Receptors, Progesterone / Q000378:metabolism; D000069553:Supervised Machine Learning; D019715:Tissue Inhibitor of Metalloproteinase-1 / Q000378:metabolism; D019716:Tissue Inhibitor of Metalloproteinase-2 / Q000378:metabolism; D015854:Up-Regulation
chemical_list: D015415:Biomarkers; C506487:ESR1 protein, human; D047628:Estrogen Receptor alpha; D011980:Receptors, Progesterone; C560822:TIMP1 protein, human; C560823:TIMP2 protein, human; D019715:Tissue Inhibitor of Metalloproteinase-1; C101118:progesterone receptor A; C097314:progesterone receptor B; D019716:Tissue Inhibitor of Metalloproteinase-2; C060932:MMP7 protein, human; D020783:Matrix Metalloproteinase 7; C522361:MMP2 protein, human; D020778:Matrix Metalloproteinase 2
keywords: Atypical endometrial hyperplasia; endometrial hyperplasia without atypia; immunohistochemistry; predictive model; supervised clustering