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Macrophage infiltration and genetic landscape of undifferentiated uterine sarcomas
Joanna Przybyl, … , Matt van de Rijn, Maria Debiec-Rychter
Joanna Przybyl, … , Matt van de Rijn, Maria Debiec-Rychter
Published June 2, 2017
Citation Information: JCI Insight. 2017;2(11):e94033. https://doi.org/10.1172/jci.insight.94033.
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Research Article Immunology Oncology

Macrophage infiltration and genetic landscape of undifferentiated uterine sarcomas

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Abstract

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.

Authors

Joanna Przybyl, Magdalena Kowalewska, Anna Quattrone, Barbara Dewaele, Vanessa Vanspauwen, Sushama Varma, Sujay Vennam, Aaron M. Newman, Michal Swierniak, Elwira Bakuła-Zalewska, Janusz A. Siedlecki, Mariusz Bidzinski, Jan Cools, Matt van de Rijn, Maria Debiec-Rychter

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Figure 2

Identification of M2 macrophage infiltration in UUS.

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Identification of M2 macrophage infiltration in UUS.
(A) Top 3 gene fami...
(A) Top 3 gene families overrepresented in UUS include numerous macrophage-associated differentiation markers and chemokines (gene family classification based on Molecular Signatures Database, MSigDB). (B) CIBERSORT analysis of microarray data indicates significantly higher fractions of M2 macrophages in UUS (n = 8) compared with ESS specimens (n = 13). (C) Forty of 216 genes overexpressed in UUS in both microarray and RNA-seq data belong to the M2 macrophage–related CSF1 response signature. (D) Heatmap of loge (TPM+1) expression values of the 40 CSF1-response genes that distinguish UUS and ESS specimens. TPM, transcript per million.

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