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

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 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.

Uterine mesenchymal tumours: recent advances

“…UUS is morphologically and genetically diverse in publications and practice due probably to contamination by misdiagnosed morphological variants of common sarcoma entities and recently described sarcoma subtypes . Four molecular groups – extracellular matrix, LMS‐like, developmental and low proliferation – were detected by RNA expression analysis of UUS after exclusion of tumours harbouring YWHAE–NUTM2 and JAZF1–SUZ12 fusions . Copy number variation analysis also showed a wide spectrum of chromosomal changes, with approximately half being diploid or near diploid associated with low copy number variation and the other half exhibiting extensive gains and losses .…”

“…14,31 Four molecular groupsextracellular matrix, LMS-like, developmental and low proliferation were detected by RNA expression analysis of UUS after exclusion of tumours harbouring YWHAE-NUTM2 and JAZF1-SUZ12 fusions. 32 Copy number variation analysis also showed a wide spectrum of chromosomal changes, with approximately half being diploid or near diploid associated with low copy number variation and the other half exhibiting extensive gains and losses. 32 These findings suggest that LMS variants, recently described fusion-driven sarcomas and other possibly distinctive clinicopathological entities with as-yet undiscovered translocations probably contribute to the perceived morphological and genetic diversity of UUS.…”

“…32 Copy number variation analysis also showed a wide spectrum of chromosomal changes, with approximately half being diploid or near diploid associated with low copy number variation and the other half exhibiting extensive gains and losses. 32 These findings suggest that LMS variants, recently described fusion-driven sarcomas and other possibly distinctive clinicopathological entities with as-yet undiscovered translocations probably contribute to the perceived morphological and genetic diversity of UUS. Similar observations were made in our separate study, which showed that 70% of UUS were in fact misdiagnosed HGESS harbouring YWHAE-NUTM2, ZC3H7B-BCOR and BRD8-PHF1 fusions as well as BCOR ITD by FISH and targeted RNA sequencing.…”

Regulatory FOXP3+ T cells in uterine sarcomas are associated with favorable prognosis, low extracellular matrix expression and reduced YAP activation

“…All cases were reviewed centrally, and the cases of endometrial stromal sarcoma and UUS were analyzed with RT-PCR for detection of the YWHAE-FAM22 translocation. Details of the histopathological review have been described previously at Binzer-Panchal et al (15).…”

MMP14 in Sarcoma: A Regulator of Tumor Microenvironment Communication in Connective Tissues

“…Moreover, no significant differences have been observed in the expression of MMP14 between non-metastatic and metastatic undifferentiated pleomorphic sarcoma (UPS) groups [67]. On the other hand, we reported that an aggressive subgroup of undifferentiated uterine sarcoma cases, presenting the poorest survival rates of all subgroups, is characterized by high MMP14 gene and protein expression [68].…”