title: A 9-protein biomarker molecular signature for predicting histologic type in endometrial carcinoma by immunohistochemistry.
abstract: Histologic typing may be difficult in a subset of endometrial carcinoma (EC) cases. In these cases, interobserver agreement improves when immunohistochemistry (IHC) is used. A series of endometrioid type (EEC) grades 1, 2, and 3 and serous type (SC) were immunostained for p53, p16, estrogen receptor, PTEN, IMP2, IMP3, HER2, cyclin B2 and E1, HMGA2, FolR1, MSLN, Claudins 3 and 4, and NRF2. Nine biomarkers showed significant differences with thresholds in IHC value scale between both types (p53 ≥ 20, IMP2 ≥ 115, IMP3 ≥ 2, cyclin E1 ≥ 220, HMGA2 ≥ 30, FolR1 ≥ 50, p16 ≥ 170, nuclear PTEN ≥ 2 and estrogen receptor ≤ 50; P < .005). This combination led to increased discrimination when considering cases satisfying 0 to 5 conditions predicted as EEC and those satisfying 6 to 9 conditions predicted as SC. This signature correctly predicted all 48 EEC grade 1-2 cases and 18 SC cases, but 3 SC cases were wrongly predicted as EEC. Sensitivity was 86% (95% confidence interval [CI], 64%-97%), and specificity was 100% (95% CI, 89%-100%). The classifier correctly predicted all 28 EEC grade 3 cases but only identified the EEC and SC components in 4 of 9 mixed EEC-SC. An independent validation series (29 EEC grades 1-2, 28 EEC grade 3, and 31 SC) showed 100% sensitivity (95% CI, 84%-100%) and 83% specificity (95% CI, 64%-94%). We propose an internally and externally validated 9-protein biomarker signature to predict the histologic type of EC (EEC or SC) by IHC. The results also suggest that mixed EEC-SC is molecularly ambiguous.
authors.affiliation: Hospital Universitari Arnau de Vilanova. Universitat de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Maria
authors.initials: M
authors.lastname: Santacana
authors.affiliation: Hospital Universitari Arnau de Vilanova. Universitat de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Oscar
authors.initials: O
authors.lastname: Maiques
authors.affiliation: Hospital Universitari Arnau de Vilanova. Universitat de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Joan
authors.initials: J
authors.lastname: Valls
authors.affiliation: Hospital Universitari Arnau de Vilanova. Universitat de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Sònia
authors.initials: S
authors.lastname: Gatius
authors.affiliation: Hospital Universitari Arnau de Vilanova. Universitat de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Ana Isabel
authors.initials: AI
authors.lastname: Abó
authors.affiliation: Hospital Virgen del Rocío de Sevilla, Sevilla, Spain.
authors.forename: María Ángeles
authors.initials: MÁ
authors.lastname: López-García
authors.affiliation: Foundation MD Anderson Cancer Centre Madrid and Departament of Biochemistry, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: Alba
authors.initials: A
authors.lastname: Mota
authors.affiliation: Vall d'Hebron Research Institute, Barcelona, Spain.
authors.forename: Jaume
authors.initials: J
authors.lastname: Reventós
authors.affiliation: Foundation MD Anderson Cancer Centre Madrid and Departament of Biochemistry, Universidad Autonoma de Madrid (UAM), Instituto de Investigaciones Biomédicas "Alberto Sols" (CSIC-UAM), IdiPAZ, Madrid, Spain.
authors.forename: Gema
authors.initials: G
authors.lastname: Moreno-Bueno
authors.affiliation: Hospital Virgen del Rocío de Sevilla, Sevilla, Spain; Hospital Ramon y Cajal, Madrid, Spain.
authors.forename: Jose
authors.initials: J
authors.lastname: Palacios
authors.affiliation: Portuguese Oncology Institute-Porto, Research Center of Portuguese Oncology Institute-Porto, Centro Hospitalar São João, Porto, Portugal.
authors.forename: Carla
authors.initials: C
authors.lastname: Bartosch
authors.affiliation: Hospital Universitari Arnau de Vilanova. Universitat de Lleida, IRBLleida, Lleida, Spain.
authors.forename: Xavier
authors.initials: X
authors.lastname: Dolcet
authors.affiliation: Hospital Universitari Arnau de Vilanova. Universitat de Lleida, IRBLleida, Lleida, Spain. Electronic address: fjmatiasguiu.lleida.ics@gencat.cat.
authors.forename: Xavier
authors.initials: X
authors.lastname: Matias-Guiu
mesh_terms: D014408:Biomarkers, Tumor / Q000378:metabolism*; D002277:Carcinoma / Q000378:metabolism* / Q000473:pathology; D018269:Carcinoma, Endometrioid / Q000378:metabolism* / Q000473:pathology; D016889:Endometrial Neoplasms / Q000378:metabolism* / Q000473:pathology; D005260:Female; D006801:Humans; D007150:Immunohistochemistry; D000090204:Mesothelin; D012680:Sensitivity and Specificity
chemical_list: D014408:Biomarkers, Tumor; C000715527:MSLN protein, human; D000090204:Mesothelin
keywords: Biomarker; Endometrial carcinoma; Endometrioid/serous; Histologic type; Immunohistochemistry