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<p>Desmoplastic small round cell tumor (DSRCT) is an ultra-rare sarcoma with limited treatment options. Here, we show that comprehensive molecular profiling informs diagnosis and individualized therapy in this disease. We report the results of whole-genome/exome, transcriptome, and DNA methylome analyses performed in 30 refractory DSRCT patients, complemented by (phospho)proteomic profiling in nine, within a nationwide precision oncology program. In eight patients (27%), DSRCT was diagnosed only after molecular profiling. Although DSRCTs have “quiet” genomes, 28 patients (93%) received 107 molecular-based management recommendations, including assessment of clinical trial eligibility in 17 (57%). Most recommendations are informed by overexpression of tyrosine kinases, SSTR3/5, and CLDN6, detected in 45%, 33%, and 20% of cases, respectively. Thirteen patients (46%) received recommended therapies, yielding disease control in eight (62%), including three long-lasting responses to pazopanib and trastuzumab deruxtecan, the latter administered based on ERBB2 overexpression in the absence of aberrant ERBB2 kinase activation. These findings demonstrate that multi-omics profiling provides clinically actionable insights for DSRCT management.</p>

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Multi-layered molecular profiling informs the diagnosis and targeted therapy of desmoplastic small round cell tumor

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年4月9日

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  • Marcus Renner,
  • Małgorzata Oleś,
  • Nagarajan Paramasivam,
  • Christoph E. Heilig,
  • Annika Schneider,
  • Caroline Modugno,
  • Catherine Herremans,
  • Jennifer Hüllein,
  • Barbara Hutter,
  • Cihan Erkut,
  • Andreas Mock,
  • Eva Krieghoff-Henning,
  • Cecilia B. Jensen,
  • Amirhossein Sakhteman,
  • Matthew The,
  • Tony Prinz,
  • Panna Lajer,
  • Annika Baude-Müller,
  • Katja Beck,
  • Bettina Beuthien-Baumann,
  • Leonidas Apostolidis,
  • Sebastian Bauer,
  • Melanie Boerries,
  • Christian H. Brandts,
  • Damian T. Rieke,
  • Thomas Kindler,
  • Frederick Klauschen,
  • Klaus Schulze-Osthoff,
  • Richard F. Schlenk,
  • Guy Berchem,
  • Michael Allgäuer,
  • Gunhild Mechtersheimer,
  • Albrecht Stenzinger,
  • Daniel B. Lipka,
  • Matthias Schlesner,
  • Bernhard Kuster,
  • Arne Jahn,
  • Evelin Schröck,
  • Christoph Heining,
  • Maria-Veronica Teleanu,
  • Peter Horak,
  • Simon Kreutzfeldt,
  • Daniel Hübschmann,
  • Wolfgang Hartmann,
  • Hanno Glimm,
  • Stefan Fröhling

摘要

Desmoplastic small round cell tumor (DSRCT) is an ultra-rare sarcoma with limited treatment options. Here, we show that comprehensive molecular profiling informs diagnosis and individualized therapy in this disease. We report the results of whole-genome/exome, transcriptome, and DNA methylome analyses performed in 30 refractory DSRCT patients, complemented by (phospho)proteomic profiling in nine, within a nationwide precision oncology program. In eight patients (27%), DSRCT was diagnosed only after molecular profiling. Although DSRCTs have “quiet” genomes, 28 patients (93%) received 107 molecular-based management recommendations, including assessment of clinical trial eligibility in 17 (57%). Most recommendations are informed by overexpression of tyrosine kinases, SSTR3/5, and CLDN6, detected in 45%, 33%, and 20% of cases, respectively. Thirteen patients (46%) received recommended therapies, yielding disease control in eight (62%), including three long-lasting responses to pazopanib and trastuzumab deruxtecan, the latter administered based on ERBB2 overexpression in the absence of aberrant ERBB2 kinase activation. These findings demonstrate that multi-omics profiling provides clinically actionable insights for DSRCT management.