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Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes
Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences. Uppsala University, Science for Life Laboratory, SciLifeLab.
Karolinska Univ Hosp, Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Pathol & Cytol, Stockholm, Sweden.
Uppsala University, Science for Life Laboratory, SciLifeLab. Uppsala University, Disciplinary Domain of Medicine and Pharmacy, Faculty of Medicine, Department of Medical Sciences.
Karolinska Univ Hosp, Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden;Karolinska Univ Hosp, Dept Pathol & Cytol, Stockholm, Sweden.
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2019 (English)In: Clinical Cancer Research, ISSN 1078-0432, E-ISSN 1557-3265, Vol. 25, no 7, p. 2155-2165Article in journal (Refereed) Published
Abstract [en]

Purpose: Undifferentiated uterine sarcomas (UUS) are rare, extremely deadly, sarcomas with no effective treatment. The goal of this study was to identify novel intrinsic molecular UUS subtypes using integrated clinical, histopathologic, and molecular evaluation of a large, fully annotated, patient cohort.

Experimental Design: Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n = 50), copy-number variation (CNV, n = 40), cell morphometry (n = 39), and protein expression (n = 22). Gene ontology and network enrichment analysis were used to relate over-and underexpressed genes to pathways and further to clinicopathologic and phenotypic findings.

Results: Gene expression identified four distinct groups of tumors, which varied in their clinicopathologic parameters. Gene ontology analysis revealed differential activation of pathways related to genital tract development, extracellular matrix (ECM), muscle function, and proliferation. A multivariable, adjusted Cox proportional hazard model demonstrated that RNA group, mitotic index, and hormone receptor expression influence patient overall survival (OS). CNV arrays revealed characteristic chromosomal changes for each group. Morphometry demonstrated that the ECM group, the most aggressive, exhibited a decreased cell density and increased nuclear area. A cell density cutoff of 4,300 tumor cells per mm(2) could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. IHC staining of MMP-14, Collagens 1 and 6, and Fibronectin proteins revealed differential expression of these ECM-related proteins, identifying potential new biomarkers for this aggressive sarcoma subgroup. Conclusions: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.

Place, publisher, year, edition, pages
AMER ASSOC CANCER RESEARCH , 2019. Vol. 25, no 7, p. 2155-2165
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Cancer and Oncology
Identifiers
URN: urn:nbn:se:uu:diva-382512DOI: 10.1158/1078-0432.CCR-18-2792ISI: 000462991900019PubMedID: 30617134OAI: oai:DiVA.org:uu-382512DiVA, id: diva2:1308043
Funder
The Cancer Research Funds of RadiumhemmetSwedish Cancer SocietyMagnus Bergvall FoundationStockholm County CouncilAvailable from: 2019-04-30 Created: 2019-04-30 Last updated: 2019-04-30Bibliographically approved

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Binzer-Panchal, AmreiViklund, BjörnHollfelder, NinaCorcoran, PádraicIsaksson, Anders

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Binzer-Panchal, AmreiViklund, BjörnHollfelder, NinaCorcoran, PádraicGonzalez-Molina, JordiLehti, KaisaIsaksson, Anders
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