Nature Communications

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

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

Abstract

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.

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Article Details

Volume / Issue Vol. 17, Issue 1
Published April 09, 2026
ISSN 2041-1723
Publisher Nature Portfolio

Journal Info

Nature Communications

Nature Portfolio
ISSN: 2041-1723 Open Access Life Sciences

Authors (46)

M

Marcus Renner

M

Małgorzata Oleś

N

Nagarajan Paramasivam

C

Christoph E. Heilig

A

Annika Schneider

C

Caroline Modugno

C

Catherine Herremans

J

Jennifer Hüllein

B

Barbara Hutter

C

Cihan Erkut

A

Andreas Mock

E

Eva Krieghoff-Henning

C

Cecilia B. Jensen

A

Amirhossein Sakhteman

M

Matthew The

T

Tony Prinz

P

Panna Lajer

A

Annika Baude-Müller

K

Katja Beck

B

Bettina Beuthien-Baumann

L

Leonidas Apostolidis

S

Sebastian Bauer

M

Melanie Boerries

C

Christian H. Brandts

D

Damian T. Rieke

Charité–Universitätsmedizin Berlin, Freie Universität Berlin and Humboldt-Universität zu Berlin, Berlin

T

Thomas Kindler

F

Frederick Klauschen

K

Klaus Schulze-Osthoff

R

Richard F. Schlenk

G

Guy Berchem

M

Michael Allgäuer

G

Gunhild Mechtersheimer

A

Albrecht Stenzinger

D

Daniel B. Lipka

M

Matthias Schlesner

B

Bernhard Kuster

A

Arne Jahn

E

Evelin Schröck

C

Christoph Heining

M

Maria-Veronica Teleanu

P

Peter Horak

S

Simon Kreutzfeldt

D

Daniel Hübschmann

W

Wolfgang Hartmann

H

Hanno Glimm

S

Stefan Fröhling

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