Abstract 4336: Integrative genomic and transcriptomic analysis of leiomyosarcoma

Abstract

Abstract Leiomyosarcomas (LMS) are malignant tumors of smooth-muscle origin that occur across age groups. The mechanisms underlying LMS development, including clinically actionable genetic vulnerabilities, are largely unknown, and few therapeutic options exist for LMS patients. To detect somatic mutations, copy number alterations, and structural rearrangements, we performed whole-exome and transcriptome sequencing of 49 and 37 LMS tumors, respectively, and performed integrative analysis. Recurrence analysis identified TP53, RB1, and ATRX as significantly mutated genes and various other cancer-associated genes mutated at low frequency, indicating substantial mutational heterogeneity. Copy number analysis revealed widespread chromosomal gains and losses and highly rearranged genomes in all tumors. Additionally, chromothripsis and whole-genome duplication were detected in 35% and 51% of cases, respectively. Principle component analysis and unsupervised hierarchical clustering of transcriptome data revealed three distinct subgroups of patients. Furthermore, we detected multiple non-recurrent fusion transcripts resulting from chromosomal rearrangements, many of which were predicted to result in loss of TP53 and RB1 function. In-depth analysis of these loci revealed protein-damaging microdeletions, intragenic or distal inversions, and exon skipping events as additional, previously unrecognized mechanisms of TP53 and RB1 disruption. Integration of whole-exome and transcriptome data demonstrated biallelic disruption of TP53 and RB1 in 92% and 94% of cases, respectively, and tumors with wildtype RB1 displayed loss of CDKN2A expression, overexpression of CCND1, or mutation of MAX resulting in CDK4 and CCND2 overexpression as alternative mechanisms of RB1 suppression. We also detected alternative lengthening of telomeres (ALT) in 78% of cases, and identified recurrent alterations in telomere maintenance genes such as ATRX, RBL2, and SP100, providing novel insight into the genetic basis of this mechanism. Finally, most tumors displayed hallmarks of “BRCAness”, including alterations in homologous recombination DNA repair genes and enrichment of specific mutational signatures, and cultured LMS cells were sensitive towards olaparib and cisplatin. This comprehensive genomic and transcriptomic analysis has unveiled that LMS is characterized by mutational heterogeneity, genomic instability, near-universal inactivation of TP53 and RB1, and frequent whole-genome duplication. Furthermore, we have established that most LMS tumors rely on ALT to escape replicative senescence, and identified recurrent alterations in a broad spectrum of telomere maintenance genes. Finally, our findings uncover “BRCAness” as potentially actionable feature of LMS tumors, and provide a rich resource for guiding future investigations into the mechanisms underlying LMS development and the design of novel therapeutic strategies. Citation Format: Priya Chudasama, Sadaf Mughal, Mathijs Sanders, Daniel Hübschmann, Inn Chung, Aurélie Ernst, Bernd Kasper, Hans-Georg Kopp, Sebastian Bauer, Karsten Rippe, Benedikt Brors, Marcus Renner, Peter Hohenberger, Claudia Scholl, Stefan Fröhling. Integrative genomic and transcriptomic analysis of leiomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 4336.