Integrative genomic and transcriptomic analysis of leiomyosarcoma

Priya Chudasama, Sadaf S. Mughal, Mathijs A. Sanders, Daniel Hübschmann, Inn Chung, Katharina I. Deeg, Siao-Han Wong, Sophie Rabe, Mario Hlevnjak, Marc Zapatka, Aurélie Ernst, Kortine Kleinheinz, Matthias Schlesner, Lina Sieverling, Barbara Klink, Evelin Schröck, Remco M. Hoogenboezem, Bernd Kasper, Christoph E. Heilig, Gerlinde Egerer, Stephan Wolf, Christof Kalle, Roland Eils, Albrecht Stenzinger, Wilko Weichert, Hanno Glimm, Stefan Gröschel, Hans-Georg Kopp, Georg Omlor, Burkhard Lehner, Sebastian Bauer, Simon Schimmack, Alexis Ulrich, Gunhild Mechtersheimer, Karsten Rippe, Benedikt Brors, Barbara Hutter, Marcus Renner, Peter Hohenberger, Claudia Scholl and Stefan Fröhling ()
Additional contact information
Priya Chudasama: National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)
Sadaf S. Mughal: DKFZ and NCT Heidelberg
Mathijs A. Sanders: Erasmus Medical Center
Daniel Hübschmann: DKFZ
Inn Chung: DKFZ and BioQuant Center
Katharina I. Deeg: DKFZ and BioQuant Center
Siao-Han Wong: DKFZ and NCT Heidelberg
Sophie Rabe: National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)
Mario Hlevnjak: DKFZ
Marc Zapatka: DKFZ
Aurélie Ernst: DKFZ
Kortine Kleinheinz: DKFZ
Matthias Schlesner: DKFZ
Lina Sieverling: DKFZ and NCT Heidelberg
Barbara Klink: Technical University Dresden
Evelin Schröck: Technical University Dresden
Remco M. Hoogenboezem: Erasmus Medical Center
Bernd Kasper: Heidelberg University
Christoph E. Heilig: Heidelberg University Hospital
Gerlinde Egerer: Heidelberg University Hospital
Stephan Wolf: DKFZ
Christof Kalle: National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)
Roland Eils: DKFZ
Albrecht Stenzinger: German Cancer Consortium (DKTK)
Wilko Weichert: Technical University Munich
Hanno Glimm: National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)
Stefan Gröschel: National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)
Hans-Georg Kopp: Eberhard Karls University
Georg Omlor: Heidelberg University Hospital
Burkhard Lehner: Heidelberg University Hospital
Sebastian Bauer: Western German Cancer Center
Simon Schimmack: Heidelberg University Hospital
Alexis Ulrich: Heidelberg University Hospital
Gunhild Mechtersheimer: Heidelberg University Hospital
Karsten Rippe: DKFZ and BioQuant Center
Benedikt Brors: DKFZ and NCT Heidelberg
Barbara Hutter: DKFZ and NCT Heidelberg
Marcus Renner: Heidelberg University Hospital
Peter Hohenberger: Heidelberg University
Claudia Scholl: National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)
Stefan Fröhling: National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ)

Nature Communications, 2018, vol. 9, issue 1, 1-15

Abstract: Abstract Leiomyosarcoma (LMS) is an aggressive mesenchymal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. Here we show, using whole-exome and transcriptome sequencing, that LMS tumors are characterized by substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations including chromothripsis, and frequent whole-genome duplication. Furthermore, we detect alternative telomere lengthening in 78% of cases and identify recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing insight into the genetic basis of this mechanism. Finally, most tumors display hallmarks of “BRCAness”, including alterations in homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells are sensitive towards olaparib and cisplatin. This comprehensive study of LMS genomics has uncovered key biological features that may inform future experimental research and enable the design of novel therapies.

Date: 2018
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DOI: 10.1038/s41467-017-02602-0

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