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Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes.
- Source :
-
Clinical cancer research : an official journal of the American Association for Cancer Research [Clin Cancer Res] 2019 Apr 01; Vol. 25 (7), pp. 2155-2165. Date of Electronic Publication: 2019 Jan 07. - Publication Year :
- 2019
-
Abstract
- 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.<br />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.<br />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 <superscript>2</superscript> 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.<br />Conclusions: Molecular evaluation of UUS provides novel insights into the biology, prognosis, phenotype, and possible treatment of these tumors.<br /> (©2019 American Association for Cancer Research.)
- Subjects :
- Chromosome Aberrations
Computational Biology methods
DNA Copy Number Variations
Female
Gene Expression Profiling
Gene Ontology
Humans
Image Processing, Computer-Assisted
Immunohistochemistry
Kaplan-Meier Estimate
Molecular Diagnostic Techniques
Neoplasm Grading
Prognosis
Proportional Hazards Models
Proteomics methods
Sarcoma mortality
Uterine Neoplasms mortality
Biomarkers, Tumor
Sarcoma diagnosis
Sarcoma etiology
Uterine Neoplasms diagnosis
Uterine Neoplasms etiology
Subjects
Details
- Language :
- English
- ISSN :
- 1557-3265
- Volume :
- 25
- Issue :
- 7
- Database :
- MEDLINE
- Journal :
- Clinical cancer research : an official journal of the American Association for Cancer Research
- Publication Type :
- Academic Journal
- Accession number :
- 30617134
- Full Text :
- https://doi.org/10.1158/1078-0432.CCR-18-2792