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 - 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 -