(P 011) TACKLE A RARE SARCOMA THROUGH A COLLABORATIVE APPROACH

Objective: Background: Epithelioid sarcoma (EpS) is a rare soft tissue and bone sarcoma, occurring most commonly in children and young adults. The prognosis of these tumours is poor, with a 10-year-survival rate of 50% and a high-rate of locoregional recurrences. Traditionally, EpS has been divided into two subtypes with distinct clinical and histopathological features: the classical EpS (cEpS) and the proximal EpS (pEpS). They are thought to represent the same disease spectrum with both sharing the same molecular hallmark - recurrent inactivation of SMARCB1. Notably there are a few other SMARCB1-deficient tumours, malignant rhabdoid tumour, epithelioid malignant peripheral nerve sheet tumour, poorly differentiated chordoma, and these have not been investigated alongside EpS. The rarity of EpS has hampered research, and little is known about the pathogenesis of this disease. Hence there is an unmet need to understand better the biology of EpS with the aim of providing benefit for patients.

Hypothesis: We hypothesise that comprehensive molecular analysis of SMARB1-deficient tumours will provide insight into their development and lead to the identification of vulnerabilities which can be targeted therapeutically.

Methods: Methods: In collaboration with the Genomics England Clinical Interpretation Partnership (GECIP) and four tumours biobank centres we established a cohort of patients with EpS. We performed whole genome sequencing (WGS) of the primary tumour DNA (60-100X depth of coverage) and matching germline DNA (40X depth of coverage) from 13 patients. We will also analyse 10 EpS (matched tumour and normal samples) by whole exome sequencing (WES) (150-250X depth of coverage). Bulk RNA sequencing and methylation array analyses (EPIC array) are also being undertaken on 20 of these cases. Publicly available data from about 100 cases of other SMARCB1-deficient tumours were employed to study the other SMARCB1-deficient tumours.

Results: Results: Our preliminary results highlight the complexity and heterogeneity of EpS at the genomic level and suggest that the two histological subtypes of Eps which are traditionally considered to be part of the same disease spectrum are probably biologically more different than previously thought. This could play an important role for enrolment and stratification in clinical studies.

Conclusion: Conclusion: This initiative will provide a publicly available resource for data and samples for the study of EpS. Through our extensive multi-omic analysis of EpS we will gain a greater understanding of this disease and unlock the biological processes underlying one of the rarest of sarcomas from which patients can potentially benefit. The full potential of this work will only be realized through a collaborative approach which we wish to extend.