Genes commonly deleted in childhood B-cell precursor acute lymphoblastic leukemia: association with cytogenetics and clinical features

Abstract

In childhood B-cell precursor acute lymphoblastic leukemia, cytogenetics is important in diagnosis and as an indicator of response to therapy, thus playing a key role in risk stratification of patients for treatment. Little is known of the relationship between different cytogenetic subtypes in B-cell precursor acute lymphoblastic leukemia and the recently reported copy number abnormalities affecting significant leukemia associated genes. In a consecutive series of 1427 childhood B-cell precursor acute lymphoblastic leukemia patients, we have determined the incidence and type of copy number abnormalities using multiplex ligation-dependent probe amplification. We have shown strong links between certain deletions and cytogenetic subtypes, including the novel association between RB1 deletions and intrachromosomal amplification of chromosome 21. In this study, we characterized the different copy number abnormalities and show heterogeneity of PAX5 and IKZF1 deletions and the recurrent nature of RB1 deletions. Whole gene losses are often indicative of larger deletions, visible by conventional cytogenetics. An increased number of copy number abnormalities is associated with NCI high risk, specifically deletions of IKZF1 and CDKN2A/B, which occur more frequently among these patients. IKZF1 deletions and rearrangements of CRLF2 among patients with undefined karyotypes may point to the poor risk BCR-ABL1-like group. In conclusion, this study has demonstrated in a large representative cohort of children with B-cell precursor acute lymphoblastic leukemia that the pattern of copy number abnormalities is highly variable according to the primary genetic abnormality.

Figure 1.

Bar chart showing the percentage of patients within NCI high and standard risk groups with increasing numbers of CNA.

Figure 2.

Graphs showing the proportion of cases with IKZF1 and CDKN2A/B deletions according to age among BCR-ABL1 negative patients. As it is known that there is a strong association between IKZF1 deletions and BCR-ABL1 positive ALL and that the incidence of BCR-ABL1 positive ALL increases with age, childhood BCR-ABL1 positive patients were excluded from this age association analysis of IKZF1 and CDKN2A/B for direct comparison with the MLPA tested adult BCR-ABL1 negative series.

Figure 3.

Bar chart showing the proportion of patients within each cytogenetic subgroup with increasing numbers of CNA.

Figure 4.

Circos plots showing the relative incidence and distribution of CNA within the overall cohort and the individual cytogenetic groups. The proportions of cases with and without CNA are indicated in black and gray, respectively, around the perimeter and the ribbons representing the individual CNA are color coded. The width of the ribbons reflects the frequency of each CNA.