Integrative genomic and transcriptomic analysis of adult leiomyosarcoma (HIPO-028, HIPO-018, HIPO-021)

Leiomyosarcoma (LMS) is an aggressive mesenchmyal malignancy with few therapeutic options. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown. We performed genomic and transcriptomic profiling of a large cohort of LMS tumors and identified substantial mutational heterogeneity, near-universal inactivation of TP53 and RB1, widespread DNA copy number alterations, chromothripsis, and frequent whole-genome duplication. Furthermore, we discovered recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and RPA1, resulting in alternative lengthening of telomeres in 78% of cases. Finally, most tumors displayed hallmarks of “BRCAness”, including alterations in various homologous recombination DNA repair genes, multiple structural rearrangements, and enrichment of specific mutational signatures, and cultured LMS cells were sensitive towards olaparib and cisplatin treatment. This first comprehensive study of genetic alterations in LMS has uncovered key biological features that may inform future experimental research and enable the design of novel therapeutic strategies for this disease.

Type: Other
Archiver: European Genome-Phenome Archive (EGA)

3 Datasets 3 Publications

Click on a Dataset ID in the table below to learn more, and to find out who to contact about access to these data

Dataset ID	Description	Technology	Samples
EGAD00001003827	The data set contains bam files aligned using bwa-0.7.8 mem -t 8 -R.	HiSeq X Ten	4
EGAD00001003828	This dataset contains paired fastq files for LMS tumor samples	Illumina HiSeq 2000 Illumina HiSeq 2500	37
EGAD00001003829	The data set contains paired end fastq files for whole exome sequencing data for Leiomyosarcoma tumor and control samples	Illumina HiSeq 2000 Illumina HiSeq 2500	96

Publications	Citations
Integrative genomic and transcriptomic analysis of leiomyosarcoma. Chudasama P, Mughal SS, Sanders MA, Hübschmann D, Chung I, Deeg KI, Wong SH, Rabe S, Hlevnjak M, Zapatka M, Ernst A, Kleinheinz K, Schlesner M, Sieverling L, Klink B, Schröck E, Hoogenboezem RM, Kasper B, Heilig CE, Egerer G, Wolf S, von Kalle C, Eils R, Stenzinger A, Weichert W, Glimm H, Gröschel S, Kopp HG, Omlor G, Lehner B, Bauer S, Schimmack S, Ulrich A, Mechtersheimer G, Rippe K, Brors B, Hutter B, Renner M, Hohenberger P, Scholl C, Fröhling S. Nat Commun 9: 2018 144	134
TelomereHunter - in silico estimation of telomere content and composition from cancer genomes. Feuerbach L, Sieverling L, Deeg KI, Ginsbach P, Hutter B, Buchhalter I, Northcott PA, Mughal SS, Chudasama P, Glimm H, Scholl C, Lichter P, Fröhling S, Pfister SM, Jones DTW, Rippe K, Brors B. BMC Bioinformatics 20: 2019 272	49
Deconvolution of sarcoma methylomes reveals varying degrees of immune cell infiltrates with association to genomic aberrations. Simon M, Mughal SS, Horak P, Uhrig S, Buchloh J, Aybey B, Stenzinger A, Glimm H, Fröhling S, Brors B, Imbusch CD. J Transl Med 19: 2021 204	6