Dataset Information

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

ABSTRACT: 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.

PROVIDER: EGAS00001002437 | EGA |

REPOSITORIES: EGA

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Publications

Integrative genomic and transcriptomic analysis of leiomyosarcoma.

Chudasama Priya P Mughal Sadaf S SS Sanders Mathijs A MA Hübschmann Daniel D Chung Inn I Deeg Katharina I KI Wong Siao-Han SH Rabe Sophie S Hlevnjak Mario M Zapatka Marc M Ernst Aurélie A Kleinheinz Kortine K Schlesner Matthias M Sieverling Lina L Klink Barbara B Schröck Evelin E Hoogenboezem Remco M RM Kasper Bernd B Heilig Christoph E CE Egerer Gerlinde G Wolf Stephan S von Kalle Christof C Eils Roland R Stenzinger Albrecht A Weichert Wilko W Glimm Hanno H Gröschel Stefan S Kopp Hans-Georg HG Omlor Georg G Lehner Burkhard B Bauer Sebastian S Schimmack Simon S Ulrich Alexis A Mechtersheimer Gunhild G Rippe Karsten K Brors Benedikt B Hutter Barbara B Renner Marcus M Hohenberger Peter P Scholl Claudia C Fröhling Stefan S

Nature communications 20180110 1

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. Fu ...[more]

PMID: 29321523

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Project description:Leiomyosarcoma (LMS) is a soft tissue tumor with a significant degree of morphologic and molecular heterogeneity. We employed integrative molecular profiling to discover and characterize molecular subtypes of LMS. Gene expression profiling was performed on 51 LMS samples. Unsupervised clustering demonstrated 3 reproducible LMS clusters. Array comparative genomic hybridization (aCGH) was performed on 20 LMS samples and demonstrated that the molecular subtypes defined by gene-expression showed distinct genomic changes. Tumors from the "muscle-enriched" cluster showed significantly increased copy number changes (p=0.04). Most muscle-enriched cases showed loss at 16q24 which contains FANCA, known to play an important role in DNA repair, and loss at 1p36 which contains PRDM16, whose loss promotes muscle differentiation. Immunohistochemistry was performed on LMS tissue microarrays (n= 377) for five markers with high levels of mRNA in the muscle-enriched cluster (ACTG2, CASQ2, SLMAP,CFL2, MYLK) and demonstrated significantly correlated expression of the 5 proteins (all pairwise p < 0.005). Expression of the 5 markers was associated with improved disease-specific survival (DSS) in a multivariate Cox regression analysis (p < 0.04). In this analysis that combined gene expression profiling, aCGH and immunohistochemistry, we characterized distinct molecular LMS subtypes, provided insight into their pathogenesis, and identified prognostic biomarkers. This set contains microarray slides from expression studies. VARIABLES: Phenotype: Tumour morphology Age: age at the time of the primary lesion diagnosis (*:Age of diagnosis at the time of tumor resection) Individual Compound Based Treatment: Patient received treatment (CT: exposure to chemotherapy, RT: exposure to radiation therapy) Organism Part: Primary tumour site (UT: uterine origin, ST: soft tissue origin; **:clinically most likely anatomic origin of the tumor) Disease State: Tumour status (P: primary tumor, M: metastatic tumor, LR: local recurrence, N/A: information not available.) Sex/Mating type: M(ale)/F(emale) Experiment type: aCGH or Expression type II

Dataset Information

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

Publications

Integrative genomic and transcriptomic analysis of leiomyosarcoma.

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