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Integrated molecular analysis of undifferentiated uterine sarcomas reveals clinically relevant molecular subtypes

Binzer-Panchal, Amrei ; Hardell, Elin ; Viklund, Björn ; Ghaderi, Mehran ; Bosse, Tjalling ; Nucci, Marisa R. ; Lee, Cheng Han ; Hollfelder, Nina ; Corcoran, Pádraic and Gonzalez-Molina, Jordi , et al. (2019) In Clinical Cancer Research 25(7). p.2155-2165
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. Experimental Design: Fifty cases of UUS with full clinicopathologic annotation were analyzed for gene expression (n ¼ 50), copy-number variation (CNV, n ¼ 40), cell morphometry (n ¼ 39), and protein expression (n ¼ 22). Gene ontology and network enrichment analysis were used to relate over- and underexpressed genes to pathways and further to clinicopathologic and phenotypic... (More)


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 ¼ 50), copy-number variation (CNV, n ¼ 40), cell morphometry (n ¼ 39), and protein expression (n ¼ 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 multi-variable, 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.

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published
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Clinical Cancer Research
volume
25
issue
7
pages
11 pages
publisher
American Association for Cancer Research
external identifiers
  • scopus:85064171570
  • pmid:30617134
ISSN
1078-0432
DOI
10.1158/1078-0432.CCR-18-2792
language
English
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no
id
03c38bf7-f797-4c67-b23d-66ec05fd8573
date added to LUP
2019-04-26 10:07:36
date last changed
2020-08-05 05:16:29
@article{03c38bf7-f797-4c67-b23d-66ec05fd8573,
  abstract     = {<p><br>
                                                         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 ¼ 50), copy-number variation (CNV, n ¼ 40), cell morphometry (n ¼ 39), and protein expression (n ¼ 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 multi-variable, 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                             <br>
                            <sup>2</sup><br>
                                                          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.                         <br>
                        </p>},
  author       = {Binzer-Panchal, Amrei and Hardell, Elin and Viklund, Björn and Ghaderi, Mehran and Bosse, Tjalling and Nucci, Marisa R. and Lee, Cheng Han and Hollfelder, Nina and Corcoran, Pádraic and Gonzalez-Molina, Jordi and Moyano-Galceran, Lidia and Bell, Debra A. and Schoolmeester, John K. and Måsbäck, Anna and Kristensen, Gunnar B. and Davidson, Ben and Lehti, Kaisa and Isaksson, Anders and Carlson, Joseph W.},
  issn         = {1078-0432},
  language     = {eng},
  number       = {7},
  pages        = {2155--2165},
  publisher    = {American Association for Cancer Research},
  series       = {Clinical Cancer Research},
  title        = {Integrated molecular analysis of undifferentiated uterine sarcomas reveals clinically relevant molecular subtypes},
  url          = {http://dx.doi.org/10.1158/1078-0432.CCR-18-2792},
  doi          = {10.1158/1078-0432.CCR-18-2792},
  volume       = {25},
  year         = {2019},
}