Integrative genomic analysis of childhood acute lymphoblastic leukaemia lacking a genetic biomarker in the UKALL2003 clinical trial.

Abstract

Incorporating genetics into risk-stratification for treatment of childhood B-progenitor acute lymphoblastic leukaemia (B-ALL) has contributed significantly to improved survival. In about 30% B-ALL (B-other-ALL) without well-established chromosomal changes, new genetic subtypes have recently emerged, yet their true prognostic relevance largely remains unclear. We integrated next generation sequencing (NGS): whole genome sequencing (WGS) (n = 157) and bespoke targeted NGS (t-NGS) (n = 175) (overlap n = 36), with existing genetic annotation in a representative cohort of 351 B-other-ALL patients from the childhood ALL trail, UKALL2003. PAX5alt was most frequently observed (n = 91), whereas PAX5 P80R mutations (n = 11) defined a distinct PAX5 subtype. DUX4-r subtype (n = 80) was defined by DUX4 rearrangements and/or ERG deletions. These patients had a low relapse rate and excellent survival. ETV6::RUNX1-like subtype (n = 21) was characterised by multiple abnormalities of ETV6 and IKZF1, with no reported relapses or deaths, indicating their excellent prognosis in this trial. An inferior outcome for patients with ABL-class fusions (n = 25) was confirmed. Integration of NGS into genomic profiling of B-other-ALL within a single childhood ALL trial, UKALL2003, has shown the added clinical value of NGS-based approaches, through improved accuracy in detection and classification into the range of risk stratifying genetic subtypes, while validating their prognostic significance.

Feasibility to use whole-genome sequencing as a sole diagnostic method to detect genomic aberrations in pediatric B-cell acute lymphoblastic leukemia

“…Most studies have used target sequencing depths ranging from 60× to 90× to assess the diagnostic yield of WGS in hematological malignancies ( 15 , 19 , 20 , 60 ). In a study with an effective mean coverage of 50×, Duncavage and coworkers found that the sensitivity was 100% for the detection of CNVs and SVs but decreased to 84.6% for SNVs ( 19 ).…”

“…Of note, restricted analysis of leukemic samples (L-only) could call primary genetic abnormalities in 37 out of 38 patients ( 20 ). A further study based on WGS investigated a subset of pediatric B-other ALL patients from the UKALL2003 trial and identified a subtype-defining lesion in 94% of the patients ( 15 ), whereas a similar study of 47 adult B-other ALL patients detected a class-defining aberration in 87% of patients ( 21 ).…”