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

作者：Marcus Renner, Małgorzata Oleś, Nagarajan Paramasivam, Christoph E. Heilig, Annika Schneider, Caroline Modugno, Catherine Herremans, Jennifer Hüllein, Barbara Hutter, Cihan Erkut, Andreas Möck, Eva Krieghoff-Henning, Cecilia Bang Jensen, Amirhossein Sakhteman, Matthew The, Tony Prinz, Panna Lajer, Annika Baude-Müller, Katja Beck, Bettina Beuthien-Baumann, Leonidas Apostolidis, Sebastian Bauer, Melanie Boerries, Christian Brandts, Damian Rieke, Thomas Kindler, Frederick Klauschen, Klaus Schulze-Osthoff, R. Schlenk, Guy Berchem, Michael Allgäeuer, Gunhild Mechtersheimer, Albrecht Stenzinger, Daniel B. Lipka, Matthias Schlesner, Bernhard Küster, Arne Jahn, Evelin Schröck, Christoph Heining, Maria‐Veronica Teleanu, Peter Horak, Simon Kreutzfeldt, Daniel Hübschmann, Wolfgang Hartmann, Hanno Glimm, S. Fröhling · 发表于：Nature Communications · 年份：2026 · DOI：10.1038/s41467-026-71636-0 · 被引用次数：2 · 研究领域：Sarcoma Diagnosis and Treatment、Protein Degradation and Inhibitors、Chromatin Remodeling and Cancer

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.