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Cancers (Basel). 2019 Jul 9;11(7). pii: E964. doi: 10.3390/cancers11070964.

Molecular Basis of Tumor Heterogeneity in Endometrial Carcinosarcoma.

Author information

1
Department of Pathology, Institute Ramón y Cajal for Health Research, 28034 Madrid, Spain. susanna.leskela@gmail.com.
2
CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain. susanna.leskela@gmail.com.
3
CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain.
4
Department of Pathology, Hospital Ramón y Cajal, 28034 Madrid, Spain.
5
Department of Pathology, Institute Ramón y Cajal for Health Research, 28034 Madrid, Spain.
6
Department of Pathology, Instituto de Biomedicina de Sevilla (IBiS), 41013 Seville, Spain.
7
Hospital Universitario Virgen del Rocío/CSIC/Universidad de Sevilla, 41013 Seville, Spain.
8
Department of Hematology and Hemotherapy, Clínica Universidad de Navarra, 31008 Pamplona, Spain.
9
NanoString Technologies, Inc, Seattle, WA 98109, USA.
10
Department of Pathology, Hospital U Arnau de Vilanova, 25198 Lleida, Spain.
11
Department of Pathology, Hospital U de Bellvitge, L'Hospitalet de Llobregat, 08907 Barcelona, Spain.
12
IRBLLEIDA, IDIBELL, University of Lleida, 25003 Lleida, Spain.
13
Department of Pathology, Institute Ramón y Cajal for Health Research, 28034 Madrid, Spain. jose.palacios@salud.madrid.org.
14
CIBER-ONC, Instituto de Salud Carlos III, 28029 Madrid, Spain. jose.palacios@salud.madrid.org.
15
Faculty of Medicine, University of Alcalá de Henares, Alcalá de Henares, 28801 Madrid, Spain. jose.palacios@salud.madrid.org.

Abstract

Endometrial carcinosarcoma (ECS) represents one of the most extreme examples of tumor heterogeneity among human cancers. ECS is a clinically aggressive, high-grade, metaplastic carcinoma. At the morphological level, intratumor heterogeneity in ECS is due to an admixture of epithelial (carcinoma) and mesenchymal (sarcoma) components that can include heterologous tissues, such as skeletal muscle, cartilage, or bone. Most ECSs belong to the copy-number high serous-like molecular subtype of endometrial carcinoma, characterized by the TP53 mutation and the frequently accompanied by a large number of gene copy-number alterations, including the amplification of important oncogenes, such as CCNE1 and c-MYC. However, a proportion of cases (20%) probably represent the progression of tumors initially belonging to the copy-number low endometrioid-like molecular subtype (characterized by mutations in genes such as PTEN, PI3KCA, or ARID1A), after the acquisition of the TP53 mutations. Only a few ECS belong to the microsatellite-unstable hypermutated molecular type and the POLE-mutated, ultramutated molecular type. A common characteristic of all ECSs is the modulation of genes involved in the epithelial to mesenchymal process. Thus, the acquisition of a mesenchymal phenotype is associated with a switch from E- to N-cadherin, the up-regulation of transcriptional repressors of E-cadherin, such as Snail Family Transcriptional Repressor 1 and 2 (SNAI1 and SNAI2), Zinc Finger E-Box Binding Homeobox 1 and 2 (ZEB1 and ZEB2), and the down-regulation, among others, of members of the miR-200 family involved in the maintenance of an epithelial phenotype. Subsequent differentiation to different types of mesenchymal tissues increases tumor heterogeneity and probably modulates clinical behavior and therapy response.

KEYWORDS:

PI3K/AKT pathway; TP53; clonality; endometrial carcinoma; epithelial-to-mesenchymal transition; gene expression; metaplastic carcinoma; miRNA expression; mutation; uterine carcinosarcoma

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