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Nat Commun. 2018 Jan 10;9(1):144. doi: 10.1038/s41467-017-02602-0.

Integrative genomic and transcriptomic analysis of leiomyosarcoma.

Author information

1
Division of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany.
2
Division of Applied Bioinformatics, DKFZ and NCT Heidelberg, 69120, Heidelberg, Germany.
3
Faculty of Biosciences, Heidelberg University, 69120, Heidelberg, Germany.
4
Department of Hematology, Erasmus Medical Center, 3015 CN, Rotterdam, The Netherlands.
5
Wellcome Trust Sanger Institute, Hinxton, UK.
6
Division of Theoretical Bioinformatics, DKFZ, 69120, Heidelberg, Germany.
7
Department of Bioinformatics and Functional Genomics, Institute of Pharmacy and Molecular Biotechnology, Heidelberg University and BioQuant Center, 69120, Heidelberg, Germany.
8
Department of Pediatric Immunology, Hematology and Oncology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
9
Research Group Genome Organization and Function, DKFZ and BioQuant Center, 69120, Heidelberg, Germany.
10
Division of Molecular Genetics, DKFZ, 69120, Heidelberg, Germany.
11
German Cancer Consortium (DKTK), 69120, Heidelberg, Germany.
12
Institute for Clinical Genetics, Faculty of Medicine Carl Gustav Carus, Technical University Dresden, 01307, Dresden, Germany.
13
NCT Dresden, 01307, Dresden, Germany.
14
DKTK, 01307, Dresden, Germany.
15
Sarcoma Unit, Interdisciplinary Tumor Center Mannheim, Mannheim University Medical Center, Heidelberg University, 68167, Mannheim, Germany.
16
Department of Internal Medicine V, Heidelberg University Hospital, 69120, Heidelberg, Germany.
17
Genomics and Proteomics Core Facility, DKFZ, 69120, Heidelberg, Germany.
18
Section for Personalized Oncology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
19
DKFZ-Heidelberg Center for Personalized Oncology (HIPO), 69120, Heidelberg, Germany.
20
Institute of Pathology, Heidelberg University Hospital, 69120, Heidelberg, Germany.
21
Institute of Pathology, Technical University Munich, 81675, Munich, Germany.
22
DKTK, 81675, Munich, Germany.
23
Research Group Molecular Leukemogenesis, DKFZ, 69120, Heidelberg, Germany.
24
Department of Hematology and Oncology, Eberhard Karls University, 72076, Tübingen, Germany.
25
DKTK, 72076, Tübingen, Germany.
26
Department of Orthopedics, Heidelberg University Hospital, 69118, Heidelberg, Germany.
27
Sarcoma Center, Western German Cancer Center, 45147, Essen, Germany.
28
DKTK, 45147, Essen, Germany.
29
Department of General, Visceral and Transplantation Surgery, Heidelberg University Hospital, 69120, Heidelberg, Germany.
30
Department of Surgery, Mannheim University Medical Center, Heidelberg University, 68167, Mannheim, Germany.
31
Division of Applied Functional Genomics, DKFZ, 69120, Heidelberg, Germany.
32
Division of Translational Oncology, National Center for Tumor Diseases (NCT) Heidelberg and German Cancer Research Center (DKFZ), 69120, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
33
German Cancer Consortium (DKTK), 69120, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.
34
Section for Personalized Oncology, Heidelberg University Hospital, 69120, Heidelberg, Germany. stefan.froehling@nct-heidelberg.de.

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.

PMID:
29321523
PMCID:
PMC5762758
DOI:
10.1038/s41467-017-02602-0
[Indexed for MEDLINE]
Free PMC Article

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