Validation of the United Kingdom copy-number alteration classifier in 3239 children with B-cell precursor ALL

Abstract

Genetic abnormalities provide vital diagnostic and prognostic information in pediatric acute lymphoblastic leukemia (ALL) and are increasingly used to assign patients to risk groups. We recently proposed a novel classifier based on the copy-number alteration (CNA) profile of the 8 most commonly deleted genes in B-cell precursor ALL. This classifier defined 3 CNA subgroups in consecutive UK trials and was able to discriminate patients with intermediate-risk cytogenetics. In this study, we sought to validate the United Kingdom ALL (UKALL)–CNA classifier and reevaluate the interaction with cytogenetic risk groups using individual patient data from 3239 cases collected from 12 groups within the International BFM Study Group. The classifier was validated and defined 3 risk groups with distinct event-free survival (EFS) rates: good (88%), intermediate (76%), and poor (68%) (P < .001). There was no evidence of heterogeneity, even within trials that used minimal residual disease to guide therapy. By integrating CNA and cytogenetic data, we replicated our original key observation that patients with intermediate-risk cytogenetics can be stratified into 2 prognostic subgroups. Group A had an EFS rate of 86% (similar to patients with good-risk cytogenetics), while group B patients had a significantly inferior rate (73%, P < .001). Finally, we revised the overall genetic classification by defining 4 risk groups with distinct EFS rates: very good (91%), good (81%), intermediate (73%), and poor (54%), P < .001. In conclusion, the UKALL-CNA classifier is a robust prognostic tool that can be deployed in different trial settings and used to refine established cytogenetic risk groups.

Concordance of copy number abnormality detection using SNP arrays and Multiplex Ligation-dependent Probe Amplification (MLPA) in acute lymphoblastic leukaemia

“…In this study, we have validated the use of SNP arrays to call MLPA defined UKALL-CNA profiles, which have been previously validated across several patient cohorts 22 . We investigated concordance between two different techniques: SNP6.0 array and MLPA for the detection of copy number alterations across key genes somatically altered in B-ALL.…”

“…Effect of using SNP6.0 array data with the UKALL-CNA classifier. Previously, we designed 4 and validated 22 a copy number based ALL risk classifier (UKALL-CNA classifier), which segregates patients based on the copy number states of the eight genes and the PAR1 region included in the MLPA P335 kit. This classifier assigns patients into three groups: good risk (GR), intermediate risk (IR), and poor risk (PR), with significantly different outcomes.…”

“…We investigated concordance between two different techniques: SNP6.0 array and MLPA for the detection of copy number alterations across key genes somatically altered in B-ALL. Our aim was to investigate how well SNP arrays perform for risk classification of B-other-ALL using the UKALL-CNA classifier 4,22 in comparison to the MLPA kit 19 . These results are important because they provide good evidence that the UKALL-CNA profile can be reliably called using a different platform.…”

Complex karyotype with cryptic FUS gene rearrangement and deletion of NR3C1 and VPREB1 genes in childhood B‑cell acute lymphoblastic leukemia: A case report

“…ii) Chromosome specific high resolution array-proven multicolor-banding (aMCB) probes sets for #5, #9, #16, #19 and X were used. In combination with whole chromosome painting (WCP) for chromosomes 5,6,9,16,17,18,19,20,21,22, X were applied as well (15,16).…”

Identifying novel genetic alterations in pediatric acute lymphoblastic leukemia based on copy number analysis

“…Additional CNVs could be helpful to refine ALL prognostic. The prognostic effect of CNVs depends on the other factors, such as the presence of additional molecular or cytogenetic aberrations; this situation reinforces the need to analyze these combined alterations [5].…”