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JCI Insight. 2017 Jun 2;2(11). pii: 94033. doi: 10.1172/jci.insight.94033. [Epub ahead of print]

Macrophage infiltration and genetic landscape of undifferentiated uterine sarcomas.

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Department of Pathology, Stanford University School of Medicine, Stanford, California, USA.
Department of Molecular and Translational Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute - Oncology Center, Warsaw, Poland.
Department of Human Genetics, KU Leuven and University Hospitals Leuven, Leuven, Belgium.
Department of Immunology, Biochemistry and Nutrition, Medical University of Warsaw, Warsaw, Poland.
Institute for Stem Cell Biology and Regenerative Medicine.
Department of Medicine, Division of Oncology, Stanford Cancer Institute, Stanford University, Stanford, California, USA.
Human Cancer Genetics, Center of New Technologies, CENT, University of Warsaw, Warsaw, Poland.
Department of Pathology.
Department of Gynecologic Oncology, Maria Sklodowska-Curie Memorial Cancer Center and Institute - Oncology Center, Warsaw, Poland.
The Faculty of Medicine and Health Sciences, Jan Kochanowski University, Kielce, Poland.
KU Leuven and Flanders Interuniversity Institute for Biotechnology (VIB), Leuven, Belgium.


Endometrial stromal tumors include translocation-associated low- and high-grade endometrial stromal sarcomas (ESS) and highly malignant undifferentiated uterine sarcomas (UUS). UUS is considered a poorly defined group of aggressive tumors and is often seen as a diagnosis of exclusion after ESS and leiomyosarcoma (LMS) have been ruled out. We performed a comprehensive analysis of gene expression, copy number variation, point mutations, and immune cell infiltrates in the largest series to date of all major types of uterine sarcomas to shed light on the biology of UUS and to identify potential novel therapeutic targets. We show that UUS tumors have a distinct molecular profile from LMS and ESS. Gene expression and immunohistochemical analyses revealed the presence of high numbers of tumor-associated macrophages (TAMs) in UUS, which makes UUS patients suitable candidates for therapies targeting TAMs. Our results show a high genomic instability of UUS and downregulation of several TP53-mediated tumor suppressor genes, such as NDN, CDH11, and NDRG4. Moreover, we demonstrate that UUS carry somatic mutations in several oncogenes and tumor suppressor genes implicated in RAS/PI3K/AKT/mTOR, ERBB3, and Hedgehog signaling.

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