Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes

被引:15
|
作者
Binzer-Panchal, Amrei [1 ]
Hardell, Elin [2 ,3 ]
Viklund, Bjorn [1 ]
Ghaderi, Mehran [2 ,3 ]
Bosse, Tjalling [4 ]
Nucci, Marisa R. [5 ]
Lee, Cheng-Han [6 ]
Hollfelder, Nina [1 ]
Corcoran, Padraic [1 ]
Gonzalez-Molina, Jordi [2 ,3 ,7 ]
Moyano-Galceran, Lidia [7 ]
Bell, Debra A. [8 ]
Schoolmeester, John K. [8 ]
Masback, Anna [9 ]
Kristensen, Gunnar B. [10 ,11 ]
Davidson, Ben [12 ,13 ]
Lehti, Kaisa [7 ,14 ]
Isaksson, Anders [1 ]
Carlson, Joseph W. [2 ,3 ]
机构
[1] Uppsala Univ, Dept Med Sci, Sci Life Lab, Uppsala, Sweden
[2] Karolinska Univ Hosp, Karolinska Inst, Dept Oncol Pathol, Stockholm, Sweden
[3] Karolinska Univ Hosp, Dept Pathol & Cytol, Stockholm, Sweden
[4] Leiden Univ, Med Ctr, Dept Pathol, Leiden, Netherlands
[5] Brigham & Womens Hosp, Dept Pathol, 75 Francis St, Boston, MA 02115 USA
[6] BC Canc, Dept Pathol & Lab Med, Vancouver, BC, Canada
[7] Karolinska Inst, Dept Microbiol Tumor & Cell Biol, Biomed, Stockholm, Sweden
[8] Mayo Clin, Dept Pathol & Lab Med, Rochester, MN USA
[9] Skanes Univ Hosp, Dept Pathol, Lund, Sweden
[10] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Gynecol Oncol, Oslo, Norway
[11] Oslo Univ Hosp, Norwegian Radium Hosp, Inst Canc Genet & Informat, Oslo, Norway
[12] Oslo Univ Hosp, Norwegian Radium Hosp, Dept Pathol, Oslo, Norway
[13] Univ Oslo, Med Fac, Oslo, Norway
[14] Univ Helsinki, Res Programs Unit, Genome Scale Biol, Helsinki, Finland
关键词
ENDOMETRIAL STROMAL SARCOMAS; GENOMIC HYBRIDIZATION; MITOTIC INDEX; CLASSIFICATION; EXPRESSION; FUSION; TOOL;
D O I
10.1158/1078-0432.CCR-18-2792
中图分类号
R73 [肿瘤学];
学科分类号
100214 ;
摘要
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.
引用
收藏
页码:2155 / 2165
页数:11
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