Original ArticlesMolecular Profiles of Mixed Endometrial CarcinomaMatrai, Cathleen MD*; Motanagh, Samaneh MD*,†; Mirabelli, Susanna BSc*; Ma, Lucy MD*; He, Bing MSc*; Chapman-Davis, Eloise MD‡; Kurtis, Boaz MD§; Elemento, Olivier PhD†,∥,¶; Mosquera, Juan Miguel MD*,†; Ellenson, Lora H. MD*Author Information Departments of *Pathology and Laboratory Medicine ∥Physiology and Biophysics ‡Obstetrics and Gynecology, Division of Gynecologic Oncology ¶Institute for Computational Biomedicine, Weill Cornell Medicine †Caryl and Israel Englander Institute for Precision Medicine, Weill Cornell Medicine and New York–Presbyterian, New York, NY §Cancer Genetics Incorporated, Rutherford, NJ J.M.M. and L.H.E. share senior authorship. Present address: Lora H. Ellenson, MD, Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY. Presented in part at the 107th Annual Meeting of the United States and Canadian Academy of Pathology in March 2018, Vancouver, BC, Canada. Conflicts of Interest and Source of Funding: Supported in part by the Translational Research Program at WCM Pathology and Laboratory Medicine. The authors have disclosed that they have no significant relationships with, or financial interest in, any commercial companies pertaining to this article. Correspondence: Cathleen Matrai, MD, Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 525 East 68th Street, Starr 10, New York, NY 10065 (e-mail: [email protected]). The American Journal of Surgical Pathology: August 2020 - Volume 44 - Issue 8 - p 1104-1111 doi: 10.1097/PAS.0000000000001519 Buy SDC Metrics Abstract Mixed endometrial carcinomas are defined as a combination of 2 or more distinct histologic subtypes, one of which must be a type II tumor comprising at least 5% of the tumor volume. The oncogenesis of these tumors remains unclear, particularly in light of the increasingly appreciated morphologic overlap among subtypes, as well as evolving molecular data. We evaluated 8 cases of mixed endometrial carcinoma, including 4 endometrioid (EC)/serous (SC), 1 SC/clear cell (CC), and 3 EC/CC cases, to study the underlying molecular features and oncogenic mechanisms at play. Each component was analyzed by a targeted next-generation sequencing assay. All tumors shared mutations in both components. In 6 cases, one component showed additional mutations. Two EC/SC cases showed shared mutations and mutations unique to each component. When present, unique mutations were typically seen in the SC component, including variants in POLE and TP53, as well as potentially targetable genes DDR2, MAP2K1, and CCNE1. In EC/SC tumors, ERBB2 abnormalities were seen in 2 cases. EC/CC cases showed FGFR2 activating mutations in the EC component only. No fusion drivers were identified. Our data suggest that the majority of these tumors begin as a single clone and diverge along 2 pathways: (1) tumor progression, with one component showing additional mutations, and (2) tumor divergence, in which tumor components have both shared mutations and mutations unique to each component. In addition, the findings suggest a component of morphologic mimicry in these tumors. Our findings are clinically relevant since targetable mutations may be present in only one component of mixed tumors. Copyright © 2020 Wolters Kluwer Health, Inc. All rights reserved.