Publications by authors named "Benjamin B Ozenberger"

3 Publications

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The clear cell sarcoma functional genomic landscape.

J Clin Invest 2021 Jun 22. Epub 2021 Jun 22.

Department of Orthopedics and Oncological Sciences, University of Utah, Salt Lake City, United States of America.

Clear Cell Sarcoma (CCS) is a deadly malignancy affecting adolescents and young adults. It is characterized by reciprocal translocations resulting in the expression of the chimeric EWSR1-ATF1 or EWSR1-CREB1 fusion proteins, driving sarcomagenesis. Besides these characteristics, CCS has remained genomically uncharacterized. Copy number analysis of human CCSs showed frequent amplifications of the MITF locus and chromosomes 7 and 8. Few alterations were shared with Ewing sarcoma or desmoplastic small round cell tumors, other EWSR1-rearranged tumors. Exome sequencing in mouse tumors generated by expressing EWSR1-ATF1 from the Rosa26 locus demonstrated no other repeated pathogenic variants. Additionally, we generated a new CCS mouse by Cre-loxP-induced chromosomal translocation between Ewsr1 and Atf1, resulting in copy number loss of chromosome 6 and chromosome 15 instability, including amplification of a portion syntenic with human chromosome 8, surrounding Myc. Additional experiments in the Rosa26 conditional model demonstrated that Mitf or Myc can contribute to sarcomagenesis. Copy number observations in human tumors and genetic experiments in mice render, for the first time, a functional landscape of the CCS genome. These data advance efforts to understand the biology of CCS with innovative models, in which we can eventually validate preclinical therapies, necessary to move toward longer and better survival of the young victims of this disease.
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http://dx.doi.org/10.1172/JCI146301DOI Listing
June 2021

A role for SMARCB1 in synovial sarcomagenesis reveals that SS18-SSX induces canonical BAF destruction.

Cancer Discov 2021 Jun 2. Epub 2021 Jun 2.

Departments of Orthopaedics and Oncological Sciences, University of Utah, Huntsman Cancer Institute

Reduced protein levels of SMARCB1 (a.k.a. BAF47, INI1, SNF5) have long been observed in synovial sarcoma (SS). Here, we show that combined Smarcb1 genetic loss with SS18-SSX expression in mice synergized to produce aggressive tumors with histomorphology, transcriptomes, and genome-wide BAF-family complex distributions distinct from SS18-SSX alone, indicating a defining role for SMARCB1 in SS. Smarcb1 silencing alone in mesenchyme modeled epithelioid sarcomagenesis. In mouse and human SS cells, SMARCB1 was identified within PBAF and canonical BAF (CBAF) complexes, co-incorporated with SS18-SSX in the latter. Recombinant expression of CBAF components in human cells reconstituted CBAF sub-complexes that contained equal levels of SMARCB1, regardless of SS18 or SS18-SSX inclusion. In vivo, SS18-SSX expression led to whole-complex CBAF degradation, rendering increases in the relative prevalence of other BAF-family subtypes, PBAF and GBAF complexes, over time. Thus, SS18-SSX alters BAF subtypes levels/balance and genome distribution, driving synovial sarcomagenesis.
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http://dx.doi.org/10.1158/2159-8290.CD-20-1219DOI Listing
June 2021

Genetic drivers and cells of origin in sarcomagenesis.

J Pathol 2021 Jul 18;254(4):474-493. Epub 2021 Mar 18.

Departments of Orthopaedics and Oncological Sciences, Huntsman Cancer Institute, University of Utah School of Medicine, Salt Lake City, UT, USA.

Sarcoma comprises a group of malignancies that includes over 100 individual disease entities. Type-specific genetic events initiate each tumor, occurring within a specific cellular context or circumstance. All sarcomas share a relationship with mesenchymal tissues of origin. Conceptual models for each specific route towards sarcomagenesis have developed over the years as clinical, cellular, and increasingly molecular observations have advanced hypotheses to be tested in the forward or reverse direction in experimental systems, often genetically engineered model organisms. This review considers the history of these discoveries in the context of technologies available at the time each was made and provides a comprehensive summary of the current knowledge of sarcoma genetics, including characteristic translocations, oncogene activation and loss of tumor suppressor gene events, and their putative cells of origin. Also considered are the interrelatedness of molecular clinical observations and genetic experiments in model systems to move this field of knowledge forward, as well as their implications for diagnostic and therapeutic paradigms for sarcoma. © 2021 The Pathological Society of Great Britain and Ireland. Published by John Wiley & Sons, Ltd.
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http://dx.doi.org/10.1002/path.5617DOI Listing
July 2021