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Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways

Steele, CD; Tarabichi, M; Oukrif, D; Webster, AP; Ye, H; Fittall, M; Lombard, P; ... Pillay, N; + view all (2019) Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways. Cancer Cell , 35 (3) 441-456.e8. 10.1016/j.ccell.2019.02.002. Green open access

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Abstract

Undifferentiated sarcomas (USARCs) of adults are diverse, rare, and aggressive soft tissue cancers. Recent sequencing efforts have confirmed that USARCs exhibit one of the highest burdens of structural aberrations across human cancer. Here, we sought to unravel the molecular basis of the structural complexity in USARCs by integrating DNA sequencing, ploidy analysis, gene expression, and methylation profiling. We identified whole genome duplication as a prevalent and pernicious force in USARC tumorigenesis. Using mathematical deconvolution strategies to unravel the complex copy-number profiles and mutational timing models we infer distinct evolutionary pathways of these rare cancers. In addition, 15% of tumors exhibited raised mutational burdens that correlated with gene expression signatures of immune infiltration, and good prognosis. Steele et al. determine the molecular landscape of undifferentiated sarcomas. They identify tumors with high mutation burdens, which are enriched for activation of immune pathways and have good prognoses, and deduce four tumorigenic routes, all of which begin with driver mutations before whole genome duplication.

Type: Article
Title: Undifferentiated Sarcomas Develop through Distinct Evolutionary Pathways
Open access status: An open access version is available from UCL Discovery
DOI: 10.1016/j.ccell.2019.02.002
Publisher version: https://doi.org/10.1016/j.ccell.2019.02.002
Language: English
Additional information: This is an open access article under the CC BY license (http://creativecommons.org/licenses/by/4.0/).
Keywords: sarcoma, cancer evolution, genomics, mutational signatures, copy-number signatures, tumor mutational burden, immuno-oncology
UCL classification: UCL > Provost and Vice Provost Offices
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Cancer Bio
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Oncology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Cancer Institute > Research Department of Pathology
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci
UCL > Provost and Vice Provost Offices > School of Life and Medical Sciences > Faculty of Medical Sciences > Div of Surgery and Interventional Sci > Department of Targeted Intervention
URI: https://discovery.ucl.ac.uk/id/eprint/10070483
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