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Molecular Cancer Research
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Cancer “-omics”

Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor

Emily K. Slotkin, Anita S. Bowman, Max F. Levine, Filemon Dela Cruz, Diego F. Coutinho, Glorymar I. Sanchez, Nestor Rosales, Shakeel Modak, William D. Tap, Mrinal M. Gounder, Katherine A. Thornton, Nancy Bouvier, Daoqi You, Gunes Gundem, Justin T. Gerstle, Todd E. Heaton, Michael P. LaQuaglia, Leonard H. Wexler, Paul A. Meyers, Andrew L. Kung, Elli Papaemmanuil, Ahmet Zehir, Marc Ladanyi and Neerav Shukla
Emily K. Slotkin
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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  • ORCID record for Emily K. Slotkin
  • For correspondence: slotkine@mskcc.org
Anita S. Bowman
2Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Max F. Levine
3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Filemon Dela Cruz
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Diego F. Coutinho
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Glorymar I. Sanchez
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Nestor Rosales
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Shakeel Modak
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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William D. Tap
4Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Mrinal M. Gounder
4Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Katherine A. Thornton
4Department of Medicine, Memorial Sloan Kettering Cancer Center, New York, New York.
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Nancy Bouvier
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Daoqi You
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Gunes Gundem
3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Justin T. Gerstle
5Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Todd E. Heaton
5Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Michael P. LaQuaglia
5Department of Surgery, Memorial Sloan Kettering Cancer Center, New York, New York.
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Leonard H. Wexler
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Paul A. Meyers
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Andrew L. Kung
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Elli Papaemmanuil
3Department of Epidemiology and Biostatistics, Memorial Sloan Kettering Cancer Center, New York, New York.
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Ahmet Zehir
2Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Marc Ladanyi
2Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, New York.
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Neerav Shukla
1Department of Pediatrics, Memorial Sloan Kettering Cancer Center, New York, New York.
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DOI: 10.1158/1541-7786.MCR-20-0722
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Abstract

Desmoplastic small round cell tumor (DSRCT) is characterized by the EWSR1–WT1 t(11;22) (p13:q12) translocation. Few additional putative drivers have been identified, and research has suffered from a lack of model systems. Next-generation sequencing (NGS) data from 68 matched tumor-normal samples, whole-genome sequencing data from 10 samples, transcriptomic and affymetrix array data, and a bank of DSRCT patient-derived xenograft (PDX) are presented. EWSR1–WT1 fusions were noted to be simple, balanced events. Recurrent mutations were uncommon, but were noted in TERT (3%), ARID1A (6%), HRAS (5%), and TP53 (3%), and recurrent loss of heterozygosity (LOH) at 11p, 11q, and 16q was identified in 18%, 22%, and 34% of samples, respectively. Comparison of tumor-normal matched versus unmatched analysis suggests overcalling of somatic mutations in prior publications of DSRCT NGS data. Alterations in fibroblast growth factor receptor 4 (FGFR4) were identified in 5 of 68 (7%) of tumor samples, whereas differential overexpression of FGFR4 was confirmed orthogonally using 2 platforms. PDX models harbored the pathognomic EWSR1–WT1 fusion and were highly representative of corresponding tumors. Our analyses confirm DSRCT as a genomically quiet cancer defined by the balanced translocation, t(11;22)(p13:q12), characterized by a paucity of secondary mutations but a significant number of copy number alterations. Against this genomically quiet background, recurrent activating alterations of FGFR4 stood out, and suggest that this receptor tyrosine kinase, also noted to be highly expressed in DSRCT, should be further investigated. Future studies of DSRCT biology and preclinical therapeutic strategies should benefit from the PDX models characterized in this study.

Implications: These data describe the general quiescence of the desmoplastic small round cell tumor (DSRCT) genome, present the first available bank of DSRCT model systems, and nominate FGFR4 as a key receptor tyrosine kinase in DSRCT, based on high expression, recurrent amplification, and recurrent activating mutations.

Footnotes

  • Note: Supplementary data for this article are available at Molecular Cancer Research Online (http://mcr.aacrjournals.org/).

  • Mol Cancer Res 2021;XX:XX–XX

  • Received August 19, 2020.
  • Revision received January 27, 2021.
  • Accepted March 16, 2021.
  • Published first March 22, 2021.
  • ©2021 American Association for Cancer Research.
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doi: 10.1158/1541-7786.MCR-20-0722

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Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
Emily K. Slotkin, Anita S. Bowman, Max F. Levine, Filemon Dela Cruz, Diego F. Coutinho, Glorymar I. Sanchez, Nestor Rosales, Shakeel Modak, William D. Tap, Mrinal M. Gounder, Katherine A. Thornton, Nancy Bouvier, Daoqi You, Gunes Gundem, Justin T. Gerstle, Todd E. Heaton, Michael P. LaQuaglia, Leonard H. Wexler, Paul A. Meyers, Andrew L. Kung, Elli Papaemmanuil, Ahmet Zehir, Marc Ladanyi and Neerav Shukla
Mol Cancer Res April 9 2021 DOI: 10.1158/1541-7786.MCR-20-0722

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Comprehensive Molecular Profiling of Desmoplastic Small Round Cell Tumor
Emily K. Slotkin, Anita S. Bowman, Max F. Levine, Filemon Dela Cruz, Diego F. Coutinho, Glorymar I. Sanchez, Nestor Rosales, Shakeel Modak, William D. Tap, Mrinal M. Gounder, Katherine A. Thornton, Nancy Bouvier, Daoqi You, Gunes Gundem, Justin T. Gerstle, Todd E. Heaton, Michael P. LaQuaglia, Leonard H. Wexler, Paul A. Meyers, Andrew L. Kung, Elli Papaemmanuil, Ahmet Zehir, Marc Ladanyi and Neerav Shukla
Mol Cancer Res April 9 2021 DOI: 10.1158/1541-7786.MCR-20-0722
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