POU2AF3‐rearranged sarcomas: A novel tumor defined by fusions of EWSR1 or FUS to a gene formerly designated COLCA2

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Abstract

Gene fusions involving EWSR1 or FUS as the 5′ partner have been reported in a diverse array of sarcomas. Here, we characterize the histopathology and genomics of six tumors harboring a gene fusion between EWSR1 or FUS and POU2AF3, an understudied, putative colorectal cancer predisposition gene. Striking morphologic features reminiscent of synovial sarcoma were observed including a biphasic appearance with variable fusiform to epithelioid cytomorphology and staghorn‐type vasculature. RNA sequencing demonstrated variable breakpoints in EWSR1/ FUS along with similar breakpoints in POU2AF3 that encompassed a 3′ portion of this gene. For cases in which additional information was available, the behavior of these neoplasms was aggressive with local spread and/or distant metastases. Although further studies are needed to confirm the functional significance of our findings, POU2AF3 fusions to EWSR1 or FUS may define a novel type of POU2AF3‐rearranged sarcomas with aggressive, malignant behavior.

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Analysis of 100,000 human cancer genomes reveals the landscape of tumor mutational burden

Zachary Chalmers, Caitlin Connelly, David Fabrizio … (2017)

Background High tumor mutational burden (TMB) is an emerging biomarker of sensitivity to immune checkpoint inhibitors and has been shown to be more significantly associated with response to PD-1 and PD-L1 blockade immunotherapy than PD-1 or PD-L1 expression, as measured by immunohistochemistry (IHC). The distribution of TMB and the subset of patients with high TMB has not been well characterized in the majority of cancer types. Methods In this study, we compare TMB measured by a targeted comprehensive genomic profiling (CGP) assay to TMB measured by exome sequencing and simulate the expected variance in TMB when sequencing less than the whole exome. We then describe the distribution of TMB across a diverse cohort of 100,000 cancer cases and test for association between somatic alterations and TMB in over 100 tumor types. Results We demonstrate that measurements of TMB from comprehensive genomic profiling are strongly reflective of measurements from whole exome sequencing and model that below 0.5 Mb the variance in measurement increases significantly. We find that a subset of patients exhibits high TMB across almost all types of cancer, including many rare tumor types, and characterize the relationship between high TMB and microsatellite instability status. We find that TMB increases significantly with age, showing a 2.4-fold difference between age 10 and age 90 years. Finally, we investigate the molecular basis of TMB and identify genes and mutations associated with TMB level. We identify a cluster of somatic mutations in the promoter of the gene PMS2, which occur in 10% of skin cancers and are highly associated with increased TMB. Conclusions These results show that a CGP assay targeting ~1.1 Mb of coding genome can accurately assess TMB compared with sequencing the whole exome. Using this method, we find that many disease types have a substantial portion of patients with high TMB who might benefit from immunotherapy. Finally, we identify novel, recurrent promoter mutations in PMS2, which may be another example of regulatory mutations contributing to tumorigenesis. Electronic supplementary material The online version of this article (doi:10.1186/s13073-017-0424-2) contains supplementary material, which is available to authorized users.

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Rucaparib in relapsed, platinum-sensitive high-grade ovarian carcinoma (ARIEL2 Part 1): an international, multicentre, open-label, phase 2 trial

Elizabeth M Swisher, Kevin K Lin, Amit M Oza … (2017)

Poly(ADP-ribose) polymerase (PARP) inhibitors have activity in ovarian carcinomas with homologous recombination deficiency. Along with BRCA1 and BRCA2 (BRCA) mutations genomic loss of heterozygosity (LOH) might also represent homologous recombination deficiency. In ARIEL2, we assessed the ability of tumour genomic LOH, quantified with a next-generation sequencing assay, to predict response to rucaparib, an oral PARP inhibitor.

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Ewing sarcoma

Uta Dirksen, Enrique de Álava, Didier Surdez … (2018)

Ewing sarcoma is the second most frequent bone tumour of childhood and adolescence that can also arise in soft tissue. Ewing sarcoma is a highly aggressive cancer, with a survival of 70-80% for patients with standard-risk and localized disease and ~30% for those with metastatic disease. Treatment comprises local surgery, radiotherapy and polychemotherapy, which are associated with acute and chronic adverse effects that may compromise quality of life in survivors. Histologically, Ewing sarcomas are composed of small round cells expressing high levels of CD99. Genetically, they are characterized by balanced chromosomal translocations in which a member of the FET gene family is fused with an ETS transcription factor, with the most common fusion being EWSR1-FLI1 (85% of cases). Ewing sarcoma breakpoint region 1 protein (EWSR1)-Friend leukaemia integration 1 transcription factor (FLI1) is a tumour-specific chimeric transcription factor (EWSR1-FLI1) with neomorphic effects that massively rewires the transcriptome. Additionally, EWSR1-FLI1 reprogrammes the epigenome by inducing de novo enhancers at GGAA microsatellites and by altering the state of gene regulatory elements, creating a unique epigenetic signature. Additional mutations at diagnosis are rare and mainly involve STAG2, TP53 and CDKN2A deletions. Emerging studies on the molecular mechanisms of Ewing sarcoma hold promise for improvements in early detection, disease monitoring, lower treatment-related toxicity, overall survival and quality of life.

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Author and article information

Contributors

Zheng Kuang: (View ORCID Profile)

Douglas A. Mata: (View ORCID Profile)

O. Hans Iwenofu: (View ORCID Profile)

Steven C. Smith: (View ORCID Profile)

Journal

Title: Genes, Chromosomes and Cancer

Abbreviated Title: Genes Chromosomes & Cancer

Publisher: Wiley

ISSN (Print): 1045-2257

ISSN (Electronic): 1098-2264

Publication date Created: August 2023

Publication date (Electronic): March 31 2023

Publication date (Print): August 2023

Volume: 62

Issue: 8

Pages: 460-470

Affiliations

[1 ] Foundation Medicine Cambridge Massachusetts USA

[2 ] Department of Pathology University of Arkansas for Medical Sciences Little Rock Arkansas USA

[3 ] Department of Pathology and Laboratory Medicine University of Kentucky Lexington Kentucky USA

[4 ] Department of Pathology and Laboratory Medicine The Ohio State University Wexner Medical Center Columbus Ohio USA

[5 ] Department of Pathology and Laboratory Medicine University of Wisconsin School of Medicine and Public Health Madison Wisconsin USA

[6 ] Wisconsin State Laboratory of Hygiene University of Wisconsin‐Madison Madison Wisconsin USA

[7 ] Department of Hematology and Oncology Georgetown Lombardi Comprehensive Cancer Center Washington DC USA

[8 ] Department of Pathology Wake Forest School of Medicine and Wake Forest Comprehensive Cancer Center Winston‐Salem North Carolina USA

[9 ] Departments of Pathology and Surgery and Massey Cancer Center Virginia Commonwealth University School of Medicine Richmond Virginia USA

Article

DOI: 10.1002/gcc.23136

PubMed ID: 36862145

SO-VID: 66921734-750c-4f3d-9c31-4d0656e57eb2

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http://onlinelibrary.wiley.com/termsAndConditions#vor

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