Abstract 2286: Profiling the complex rearrangement landscape of sarcoma
Authors: Waise Sara , Lesluyes Tom , Demeulemeester Jonas , Tarabichi Maxime ,   Sarcoma Genomics England Clinical Interpretation Partnership, Pillay Nischalan , Flanagan Adrienne M. , Van Loo Peter 
Published: June 2022

Genomic rearrangements are key mutational processes in a number of bone and soft tissue tumors (sarcomas). These events are used for both disease classification and as prognostic and predictive biomarkers. However, the rearrangement architecture and mutational processes giving rise to many of these events remain poorly characterized. Recent data indicate that sarcomas show particularly high frequencies of complex structural rearrangements, including patterns which do not fit those of known mutational mechanisms. As the largest whole genome sequencing (WGS) dataset of sarcomas to date, the Genomics England (GE) 100,000 Genomes Project represents a unique cohort in which to examine these events.

Structural variants (SVs) were identified using five SV callers (Manta, Delly, LUMPY, SvABA and GRIDSS) in WGS data from 1330 GE samples. SVs were filtered to retain only those passing the quality filter, and to remove variants present in either matched germline samples or &gt;1% of a panel of normal variants. Caller performance was evaluated by comparison of distances between SV and copy number call breakpoints generated by Battenberg. SVs identified by at least two callers were taken forward as high-quality calls. Chromothriptic events, extrachromosomal DNA (ecDNA) and breakage-fusion-bridges were identified using established algorithms.

In keeping with previous data, the prevalence of structural variants varies by tumor type, with particularly high numbers of SVs observed in liposarcoma and osteosarcoma. Many tumor types included notable outlier samples; these were more likely to show evidence of chromothripsis, as identified by a dedicated chromothripsis caller. Liposarcomas show the highest frequency of chromothripsis, as described previously. In addition, we have examined some tumor types at higher granularity than previously available, demonstrating directly that the prevalence of chromothripsis varies by histological subtype. For example, chromothriptic events are identified in 100% of well-differentiated liposarcomas, but less than 10% of myxoid liposarcomas. Similarly, the presence of ecDNA varies by tumor type, with the novel observation of particularly high rates in angiosarcoma.

Despite recent advances in histological classification, the survival for patients with sarcoma has remained largely static for over 40 years. Determination of the mutational processes generating these rearrangements will shed light on the pathogenesis of these tumors.

Citation Format: Sara Waise, Tom Lesluyes, Jonas Demeulemeester, Maxime Tarabichi, Sarcoma Genomics England Clinical Interpretation Partnership, Nischalan Pillay, Adrienne M. Flanagan, Peter Van Loo. Profiling the complex rearrangement landscape of sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2286.