(P 146) EXPLORING THE CLINICAL UTILITY OF WHOLE GENOME SEQUENCING FOR PAEDIATRIC, TYA AND ADULT SARCOMA PATIENTS WITHIN THE LONDON SARCOMA SERVICE: A RETROSPECTIVE COHORT ANALYSIS

Objective: Sarcomas are rare, mesenchymal tumours exhibiting significant heterogeneity, with over 100 subtypes recognised by the WHO classification (1). Due to the complex nature and variability of these tumours, diagnostic errors are relatively common and there have been minimal advancements in therapeutic options over the last three decades, highlighting an urgent need for precision diagnostics and new treatment strategies. Following the 100,000 genomes project, the National Health Service England (NHSE) initiated the implementation of whole genome sequencing (WGS) for sarcoma patients in 2018. WGS is a useful tool for refining diagnoses and identifying novel genomic alterations (2).
The real-world clinical utility, feasibility and potential implications of WGS at diagnosis for paediatric, teenage and young adult (TYA) and adult sarcoma patients requires further elucidation.

Methods: A retrospective analysis of clinical data for two patient cohorts treated within the London Sarcoma Service between 2019 and 2023 was completed.
Cohort 1: paediatric and TYA patients, Cohort 2: adult patients.
Patients were identified using a local electronic healthcare record system. Clinical data was extracted from electronic healthcare records and WGS reports. Patients without available WGS reports were excluded from the data analysis. WGS pathway length was analysed, along with genetic findings and genomic tumour advisory board (GTAB) outcomes.

Results: WGS was completed and results available for 69 patients - Cohort 1: 46 patients, Cohort 2: 23 patients.

Cohort 1: Paediatric and TYA Patients

Among the 46 patients, histological subtypes were osteosarcoma (OS) (n=29), ewing sarcoma (n=8), rhabdomyosarcoma (n=1), round cell sarcoma (n=2), malignant peripheral nerve sheath tumour (MPNST) (n=2), synovial sarcoma (n=2), spindle cell sarcoma (n=1) and epithelioid sarcoma (n=1). WGS identified 207 genomic alterations, with 72% of these variants categorised as Tier 1A or 1B. One novel somatic gene fusion (PMSC1::NFATC2) was identified and another novel fusion not previously observed in the MPNST sarcoma subtype (KAT6B::KANSL1). WGS identified 2 patients with germline variants: one with an MLH1 variant and the other with a TP53 variant, both diagnosed with osteosarcoma. Both patients were referred to clinical genetics services, confirming diagnoses of Lynch syndrome and Li-Fraumeni syndrome, respectively. The patient with Lynch syndrome subsequently received compassionate access to immunotherapy based on this result.

The most common somatic genetic variants were MYC gains (n=10) and copy-neutral loss of heterozygosity of TP53 (n=10). Deletions of RB1 and TP53 were found in 20% (n=9) of the cohort. Approximately 25% of the identified mutations lacked well-established research or clinical guidelines.

The median interval from the time tissue was sent to the Genomic Laboratory Hub (GLH) for WGS to the GTAB discussion was 13.5 weeks (range 4 - 61 weeks).

Cohort 2: Adult Patients

Among the 23 adult patients, histological subtypes were spindle cell sarcoma (n=7), OS (n=3), chondrosarcoma (n=2), chordoma (n=2), synovial sarcoma (n=1) and leiomyosarcoma (n=1). Other diagnoses included MPNST and desmoplastic small round cell sarcoma.

WGS identified 87 mutations. The most common somatic genetic variants were TP53 (n=19) followed by RB1, CDKN2A and PTEN, with 52.9% of mutations classified as Tier 1A or 1B. One MPNST patient had a germline TP53 missense mutation enabling them to access genetic services and Li-Fraumeni syndrome was confirmed. One OS patient had a potentially actionable FGFR1 mutation and was referred to a clinical trial, although they were not eligible for the study.

The median interval from the time tissue was sent to the Genomic Laboratory Hub (GLH) for WGS to the GTAB discussion was 15 weeks (range of 5 - 51 weeks).

Conclusion: WGS proves to be a valuable tool for identifying pathogenic germline variants. Based on germline MLH1 variant confirmation, one patient received compassionate access immunotherapy.

WGS holds promise in elucidating novel genomic alterations which pave the way to informing clinical decision-making and guiding personalised treatment strategies. However, although 75% of patients had a clinically relevant somatic genetic alteration (eg. TP53 variant), these mostly remain non-actionable for sarcoma patients. One patient was referred to a clinical trial based on somatic FGFR1 mutation. Two novel somatic gene fusions were identified.

Long intervals from sampling to issuing of results, complexities of tissue storage and inadequate data integration across different NHS trusts remain challenges within the WGS pathway. To enhance understanding and communication, in October 2022 our local pathway protocol formalised that all WGS results are discussed at the LSS genomic tumour advisory board meeting (GTAB). Continued optimisation and refinement of the pathways are ongoing to enable utilisation of WGS to full potential.

In future, establishment of a WGS database and collaboration with national and international centres will improve access to clinical trials for sarcoma patients.