TY - JOUR
T1 - Integrative genomic and transcriptomic analysis of leiomyosarcoma
AU - Chudasama, Priya
AU - Mughal, Sadaf S.
AU - Sanders, Mathijs A.
AU - Hübschmann, Daniel
AU - Chung, Inn
AU - Deeg, Katharina I.
AU - Wong, Siao Han
AU - Rabe, Sophie
AU - Hlevnjak, Mario
AU - Zapatka, Marc
AU - Ernst, Aurélie
AU - Kleinheinz, Kortine
AU - Schlesner, Matthias
AU - Sieverling, Lina
AU - Klink, Barbara
AU - Schröck, Evelin
AU - Hoogenboezem, Remco M.
AU - Kasper, Bernd
AU - Heilig, Christoph E.
AU - Egerer, Gerlinde
AU - Wolf, Stephan
AU - Von Kalle, Christof
AU - Eils, Roland
AU - Stenzinger, Albrecht
AU - Weichert, Wilko
AU - Glimm, Hanno
AU - Gröschel, Stefan
AU - Kopp, Hans Georg
AU - Omlor, Georg
AU - Lehner, Burkhard
AU - Bauer, Sebastian
AU - Schimmack, Simon
AU - Ulrich, Alexis
AU - Mechtersheimer, Gunhild
AU - Rippe, Karsten
AU - Brors, Benedikt
AU - Hutter, Barbara
AU - Renner, Marcus
AU - Hohenberger, Peter
AU - Scholl, Claudia
AU - Fröhling, Stefan
N1 - Funding Information:
The authors thank N. Paramasivam, J. Park, the DKFZ-HIPO and NCT Precision Oncology Program (POP) Sample Processing Laboratory, the DKFZ Genomics and Proteomics Core Facility, and the DKFZ-HIPO Data Management Group for technical support. We also thank K. Beck, D. Richter, and P. Lichter for infrastructure and program development within DKFZ-HIPO and NCT POP and D. Braun for providing the TelNet gene list. Tissue samples were provided by the NCT Heidelberg Tissue Bank in accordance with its regulations and after approval by the Ethics Committee of Heidelberg University. This work was supported by grants H018, H021, and H028 from DKFZ-HIPO and NCT POP, as well as by the e:Med Systems Medicine Program of the German Federal Ministry of Education and Research within the CancerTelSys Consortium (grant 01ZX1302). M.A.S. is the recipient of a Rubicon Fellowship from Nederlandse Organi-satie voor Wetenschappelijk Onderzoek (grant 019.153LW.038). D.H. is a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology and of the MD/PhD Program of Heidelberg University. C.S. was supported by an Emmy Noether Fellowship from the German Research Foundation.
Funding Information:
The authors thank N. Paramasivam, J. Park, the DKFZ-HIPO and NCT Precision Oncology Program (POP) Sample Processing Laboratory, the DKFZ Genomics and Proteomics Core Facility, and the DKFZ-HIPO Data Management Group for technical support. We also thank K. Beck, D. Richter, and P. Lichter for infrastructure and program development within DKFZ-HIPO and NCT POP and D. Braun for providing the TelNet gene list. Tissue samples were provided by the NCT Heidelberg Tissue Bank in accordance with its regulations and after approval by the Ethics Committee of Heidelberg University. This work was supported by grants H018, H021, and H028 from DKFZHIPO and NCT POP, as well as by the e:Med Systems Medicine Program of the German Federal Ministry of Education and Research within the CancerTelSys Consortium (grant 01ZX1302). M.A.S. is the recipient of a Rubicon Fellowship from Nederlandse Organisatie voor Wetenschappelijk Onderzoek (grant 019.153LW.038). D.H. is a member of the Hartmut Hoffmann-Berling International Graduate School of Molecular and Cellular Biology and of the MD/PhD Program of Heidelberg University. C.S. was supported by an Emmy Noether Fellowship from the German Research Foundation.
Publisher Copyright:
© 2018 The Author(s).
PY - 2018/12/1
Y1 - 2018/12/1
N2 - 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.
AB - 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.
UR - http://www.scopus.com/inward/record.url?scp=85040523492&partnerID=8YFLogxK
U2 - 10.1038/s41467-017-02602-0
DO - 10.1038/s41467-017-02602-0
M3 - Article
C2 - 29321523
AN - SCOPUS:85040523492
SN - 2041-1723
VL - 9
JO - Nature Communications
JF - Nature Communications
IS - 1
M1 - 144
ER -