Pillay, Nischalan; Farswan, Akanksha; Davies, Christopher; Zaccaria, Simone; Demeulemeester, Jonas; Strauss, Sandra; Tirabosco, Roberto; ... Rogan, Gabrielle; + view all Pillay, Nischalan; Farswan, Akanksha; Davies, Christopher; Zaccaria, Simone; Demeulemeester, Jonas; Strauss, Sandra; Tirabosco, Roberto; Amary, Fernanda; Flanagan, Adrienne; Siebenlist, Jana; Rogan, Gabrielle; - view fewer (2024) Genomic Biomarkers of Disease Progression in Clear Sarcoma. In: Proceedings of the XXXV International Academy of Pathology congress (IAP 2024). International Academy of Pathology (In press).

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Abstract

Background: Clear cell sarcoma of soft tissue (CCS) is a rare, aggressive tumour with local recurrence rates approaching 40% and metastasis rates of 70%. There is a limited understanding of the factors leading to disease progression and the poor overall survival in CCS and therapeutic options for patients are limited. Previous studies have established that the gene fusions between EWSR1 and ATF1 or other members of the CREB family are the genetic hallmarks of CCS. However, the processes which initiate these fusion events are not known and the role that other driver events play in tumour progression such as gains in chromosome 7 and 8 are not established. There is also varied heterogeneity of treatment responses and survival in patients with CCS, the mechanisms of which are not known. Moreover, histological grading has no prognostic value in CCS. In this study, we investigated the temporal dynamics of genome evolution that contribute to disease progression using a combination of judicious pathology assessment, whole genome , single cell RNA and long-read sequencing.// Aims: Determine the genomic correlates of tumour progression in CCS.// Methods: Careful pathological evaluation and clinical annotation was undertaken for 45 CCS samples (28 primaries, 4 local recurrences and 13 metastases) where fresh frozen tumour with matching germline DNA were available. These were sequenced at high resolution using whole genome sequencing. Similarly, frozen tissue of 37 cases (23 primaries, 2 local recurrences and 12 metastases) underwent bulk RNA sequencing, with 6 primary-metastatic pairs undergoing single-cell RNA sequencing. Somatic single nucleotide variants, indels, copy number variants and structural variants underwent consensus mutation calling and manual curation. Clonal inference and timing were undertaken using software tools namely, DPClust and Hatchet 2.0.// Results: Frequent copy number alterations were observed in chromosomes 8, 7, 9 and 17. These copy number events served as beacons for timing the evolution of gains across the genome that contributed to disease progression and were validated at the single cell RNA level. >90% samples harbored the EWSR1::ATF fusion followed by EWSR1::CREM and EWSR1::CREB fusions. Unexpectedly, complex structural events of chromothripsis and chromoplexy were identified in 8 CCS patients, many of which underpinned the fusions. Frequent gains of chr17 and expression of the CINSARC signature were markers of poor prognosis.// Conclusion: Integration of the multi-modal data revealed hitherto unknown patterns of genetic intra and intertumour heterogeneity. Overall, this integrative analyses was distilled into a composite genomic biomarker to guide prognosis and inform on disease progression.

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