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

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Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes Author Manuscript Published OnlineFirst on January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2792 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Integrated Molecular Analysis of Undifferentiated Uterine Sarcomas Reveals Clinically Relevant Molecular Subtypes Amrei Binzer-Panchal*1, Elin Hardell*2, Björn Viklund1, Mehran Ghaderi2, Tjalling Bosse3, Marisa R. Nucci4, Cheng-Han Lee5, Nina Hollfelder1, Pádraic Corcoran1, Jordi Gonzalez-Molina2,6, Lidia Moyano-Galceran6, Debra A. Bell8, John K. Schoolmeester8, Anna Måsbäck9, Gunnar B. Kristensen10, Ben Davidson11, Kaisa Lehti6,7, Anders Isaksson†1, Joseph W. Carlson†2 *Contributed equally to this work †Contributed equally to this work 1 Science for Life Laboratory, Department of Medical Sciences, Uppsala University, 751 85 Uppsala, Sweden 2 Department of Oncology-Pathology, Karolinska Institutet, and Department of Pathology and Cytology, Karolinska University Hospital, SE-171 76 Stockholm, Sweden. 3 Department of Pathology, Leiden University Medical Center, 2300 RC Leiden, The Netherlands 4 Department of Pathology, Brigham and Women’s Hospital, Boston, MA, 02138 USA 5 Department of Pathology and Laboratory Medicine, BC Cancer, Vancouver, BC. Canada 6 Department of Microbiology, Tumor and Cell Biology, Biomedicum, Karolinska Institutet, SE-171 65, Stockholm, Sweden 7 Genome-Scale Biology, Research Programs Unit, University of Helsinki, Helsinki, Finland 8 Department of Laboratory Medicine and Pathology, Mayo Clinic, Rochester, MN, 55905, USA 9 Department of Pathology, Skånes University Hospital, 222 41 Lund, Sweden 10 Department Gynecologic Oncology and Institute for Cancer Genetics and Informatics, Norwegian Radium Hospital, Oslo University Hospital, N-0424 Oslo, Norway 11 Department of Pathology, Norwegian Radium Hospital, Oslo University Hospital, N-0424 Oslo, Norway; Institute for Clinical Medicine, The Medical Faculty, University of Oslo, N-0316 Oslo, Norway Address for Correspondence Joseph W. Carlson [email protected] Radiumhemmet P1:02 Karolinska University Hospital 17176 Stockholm 1 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2792 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. 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 clinicopathological 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 mm2 could separate ECM tumors from the remaining cases with a sensitivity of 83% and a specificity of 94%. Immunohistochemical 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. 2 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2792 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Translational Relevance: Undifferentiated uterine sarcomas are among the rarest and deadliest of the uterine sarcomas. This has hindered the molecular understanding of their biology, and thus limited the introduction of new therapies. This study uses a well-annotated, large cohort of UUS, combined with RNA expression, chromosomal copy number, computer assisted histological analyses and immunohistochemistry, to identify and describe four intrinsic subtypes of these tumors. These subtypes vary in their biology, clinicopathological parameters, and survival. The most aggressive, ECM, subtype was characterized by a tumor cell phenotype with distinct morphology and protein expression, which will provide means to identify these cases using current laboratory techniques. Unique chromosomal changes were significantly associated with each group. Finally, gene ontology and network enrichment analysis identified target candidates for therapy. These results, from our hypothesis-generating comprehensive approach, will open new avenues to study and stratify these tumors, with the long- term goal of developing clinical interventions that will help improve patient survival. 3 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2792 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Introduction Undifferentiated uterine sarcomas are high-grade malignant mesenchymal tumors (1). These tumors are extremely rare, so knowledge of their biology, prognosis, and therapy has been limited to small case series with often patchy or limited follow up. They are diagnosed after exclusion of other, more common, mesenchymal tumors of the uterus and soft tissue, particularly leiomyosarcoma, low-grade and high-grade endometrial stromal sarcoma and carcinosarcoma (2). Recent large scale genomic studies of sarcomas have revealed several important conclusions (3–5) First, they can be generally divided into translocation sarcomas, which show a diploid or near-diploid genome, and karyotypically complex sarcomas, which often show large and complex chromosomal gains and losses of genetic material (6). Second, within traditionally defined sarcoma subtypes are subtype- specific molecular characteristics that can govern biology, therapy and prognosis (3,4). Thus, although general conclusions regarding sarcoma biology can be made with these studies, further work is required to understand the subtype and location specific changes that might govern biology, prognosis and, ultimately, therapy. Uterine sarcomas have a distinct biology from other soft tissue sarcomas. They demonstrate unique translocations, such as JJAZ-JAZF1 and YWHAE-FAM22, that are not seen at other tissue sites (7–9). Benign tissues of the female genital tract express hormone receptors, and this is retained in a subset of sarcomas (10,11). This expression has been demonstrated to confer a better prognosis in leiomyosarcomas (10). Indeed, smooth muscle tumors have a distinct biology depending upon whether they arise in the gynecologic tract or not (3,5). Previously, our group has demonstrated that division into mitotic index groups has prognostic significance for overall survival (12,13). Other studies have attempted to use atypia to subdivide UUS into “uniform” and “pleomorphic” types (14,15). To date, no large scale molecular characterization has been performed on undifferentiated uterine sarcomas. Research into therapies for gynecologic sarcomas has been limited by the difficulty of assembling a sufficient number of cases for clinical trials. Despite limited evidence, primary therapy is complete surgical resection, if possible. There is no conclusive data regarding the use of adjuvant therapy in UUS, and the current suggestion is to use therapies indicated for soft tissue sarcomas at other sites (16). One study evaluated the use of pazopanib, a multi-targeted receptor tyrosine kinase inhibitor, in pretreated, metastatic uterine sarcomas (17). This study demonstrated clinically relevant efficacy and tolerability. The goal of this study was to comprehensively examine the biology of a large, well- annotated cohort of UUS, in order to identify tumor intrinsic molecular subgroups with biological, clinical and potential therapeutic significance. 4 Downloaded from clincancerres.aacrjournals.org on September 25, 2021. © 2019 American Association for Cancer Research. Author Manuscript Published OnlineFirst on January 7, 2019; DOI: 10.1158/1078-0432.CCR-18-2792 Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Materials and Methods Patient cohort and central review This retrospective patient cohort was assembled via international collaboration from seven collaborating centers. Ethical approval was obtained
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