Journal Article

DKFZ-2018-00072

http://join2-wiki.gsi.de/foswiki/pub/Main/Artwork/join2_logo100x88.png Integrative genomic and transcriptomic analysis of leiomyosarcoma.

Chudasama, P. (First author)DKFZ* ; Mughal, S. S. (First author)DKFZ* ; Sanders, M. A. ; Hübschmann, D. (First author)DKFZ* ; Chung, I.DKFZ* ; Deeg, K.DKFZ* ; Wong, S.-H.DKFZ* ; Rabe, S.DKFZ* ; Hlevnjak, M.DKFZ* ; Zapatka, M. ; Ernst, A.DKFZ* ; Kleinheinz, K. ; Schlesner, M. ; Sieverling, L.DKFZ* ; Klink, B. ; Schröck, E.DKFZ* ; Hoogenboezem, R. M. ; Kasper, B. ; Heilig, C. E. ; Egerer, G. ; Wolf, S.DKFZ* ; von Kalle, C.DKFZ* ; Eils, R.DKFZ* ; Stenzinger, A.DKFZ* ; Weichert, W.DKFZ* ; Glimm, H.DKFZ* ; Gröschel, S.DKFZ* ; Kopp, H.-G. ; Omlor, G. ; Lehner, B. ; Bauer, S.DKFZ* ; Schimmack, S. ; Ulrich, A. ; Mechtersheimer, G. ; Rippe, K. ; Brors, B. ; Hutter, B. ; Renner, M. ; Hohenberger, P. ; Scholl, C.DKFZ* ; Fröhling, S. (Last author)DKFZ*

2018
Nature Publishing Group London

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Please use a persistent id in citations: doi:10.1038/s41467-017-02602-0

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.

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Contributing Institute(s):

1. Translationale Onkologie (G100)
2. Angewandte Bioinformatik (G200)
3. Theoretische Bioinformatik (B080)
4. Bioinformatik und Omics Data Analytics (B240)
5. B060 Molekulare Genetik (B060)
6. DKTK Heidelberg (L101)
7. DKTK Dresden (L301)
8. Hochdurchsatz-Sequenzierung (W190)
9. Molekulare Leukämogenese (G240)
10. DKTK München (L701)
11. Molekulare Therapie in der Hämatologie und Onkologie (G250)
12. DKTK Tübingen (L801)
13. DKTK Essen (L401)
14. Angewandte Funktionelle Genomik (G102)

Research Program(s):

1. 317 - Translational cancer research (POF3-317) (POF3-317)

Appears in the scientific report 2018

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Database coverage:
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