93MO - Whole genome sequencing advances aiding clinical care of patients with acute lymphoblastic leukaemia

Background

The NHS Genomic Medicine Service (GMS) was launched in 2019 to enable equitable access to comprehensive genomic testing using a standardised National Genomic Test Directory (NGTD). Building on the work of the 100,000 Genomes Project, WGS is now offered as routine care through the GMS for specific clinical indications including Acute Lymphoblastic Leukaemia (ALL). Here we discuss challenges and success of providing “one stop shop” genomic test for patients with ALL.

Methods

A standard experimental design for tumour WGS analysis requires individual tumour samples to be matched with a reference “normal” sample from the same patient. For ALLs, obtaining a high-quality normal sample not contaminated with tumour cells may require a long time. To provide faster access to the results, we created a “tumour first – germline late” pipeline, where tumour only results can be produced quickly and highlight clinically relevant variants in the mixture of somatic and germline variants, and a high-precision tumour-normal analysis would be produced when a high-quality normal sample is received.

Results

Despite high overall concordance between the results of the genomic tests commissioned through the NGTD and WGS analysis, calling variants in some genomic regions remains challenging. Recent advances in genome alignment allowed us to start detecting DUX4 rearrangements from WGS data, which is a clinically relevant rearrangement activating expression of DUX4 transcription factor associated with favourable outcomes, and describe its prevalence across 100,000 Genomes and GMS cohorts. Minimal residual disease (MRD) monitoring targeting individual immunoglobulin and T-cell receptor (IG/TCR) gene rearrangements is crucial for risk stratification and treatment of patients with ALL. In standard-of-care targeted IG/TCR high-throughput sequencing, only rearrangements covered by the panels can be detected, and the techniques are labour intensive and expensive. We show that WGS has the potential to discover all IG/TCR rearrangements in a single assay which can be utilised for follow up MRD monitoring.

Conclusions

To summarise, WGS delivers all germline and somatic findings that provide diagnostic and prognostic information for patients with ALL.

Editorial acknowledgement

Clinical trial identification

Legal entity responsible for the study

The authors.

Funding

Genomics England.

Disclosure

All authors have declared no conflicts of interest.