Multi-layered molecular profiling informs the diagnosis and targeted therapy of desmoplastic small round cell tumor.
Renner M, Oleś M, Paramasivam N, Heilig CE, Schneider A, Modugno C, Herremans C, Hüllein J, Hutter B, Erkut C, Mock A, Krieghoff-Henning E, Jensen CB, Sakhteman A, The M, Prinz T, Lajer P, Baude-Müller A, Beck K, Beuthien-Baumann B, Apostolidis L, Bauer S, Boerries M, Brandts CH, Rieke DT, Kindler T, Klauschen F, Schulze-Osthoff K, Schlenk RF, Berchem G, Allgäuer M, Mechtersheimer G, Stenzinger A, Lipka DB, Schlesner M, Kuster B, Jahn A, Schröck E, Heining C, Teleanu MV, Horak P, Kreutzfeldt S, Hübschmann D, Hartmann W, Glimm H, Fröhling S
Abstract
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.