Genomic variant profiling in blast-phase paediatric chronic myeloid leukaemia: Predisposing and driving alterations

Abstract

Paediatric blast-phase chronic myeloid leukaemia (CML-BP) is a rare and serious condition. Of 231 paediatric patients enrolled in the German CML-PAED-II registry between January 2007 and September 2023, 25 individuals (11%) were diagnosed with CML-BP. To identify genetic variants associated with early onset and disease transformation, we performed whole genome sequencing (WGS), deep targeted sequencing and cytogenetic analyses in 19 cases with de novo (n = 11) or secondary (n = 8) CML-BP and sufficient available biomaterial. Copy number variants (CNVs) were more frequent than single nucleotide variants (SNVs) and more prevalent in secondary than in de novo CML-BP. Recurrent pathogenic somatic SNVs were observed in ABL1 (n = 5, 24%), RUNX1 (n = 2, 12%) and ASXL1 (n = 2, 12%). Nine patients (47%) carried pathogenic germline (n = 8) or somatic (n = 1) variants in either of the genes ATM, CHEK2, FANCM, HERC2, NBN, RAD54B, RECQL4, SETD2 or TP63 belonging to the DNA damage response (DDR). Within a comparison cohort of 19 patients with chronic phase paediatric CML, only one individual (5%) exhibited a pathogenic DDR germline variant. Our study provides novel pathogenetic insights into paediatric CML-BP. The identification of pathogenic DDR-associated germline variants suggests a genetic predisposition with potential implications for patients and families concerning cancer treatment and surveillance.

Keywords: DNA damage repair; blast phase; molecular response; paediatric chronic myeloid leukaemia; somatic variant profile; whole genome sequencing.

FIGURE 1

Variant filter strategy and variant evaluation of whole genome sequencing in the study cohort of (n = 19) paediatric patients with blast‐phase chronic myeloid leukaemia (CML‐BP).

FIGURE 2

Somatic genetic landscape of de novo and secondary blast phase in CML. Frequencies of somatic variants in 19 paediatric patients with de novo (n = 11; left panel) or secondary (n = 8; right panel) blast‐phase chronic myeloid leukaemia (CML‐BP). Categories of variants [t(9;22) without ACA, high‐risk ACA, large CNVs (low‐risk ACA), small CNVs, SNVs] are highlighted in different colours. ACA, additional chromosomal aberration; CNV, copy number variant.

FIGURE 3

Overview of pathogenic somatic and germline variants. Categorical presentation of pathogenic somatic and germline variants detected in 19 paediatric individuals with blast‐phase chronic myeloid leukaemia (CML‐BP) (lower panel) shown in relation to blast phase, phenotype and cytogenetics with respect to additional chromosomal aberrations (ACAs) (upper panels). Graduation of variant allele frequency (VAF) is illustrated by colour intensities.

FIGURE 4

Illustration of genes and gene networks as analysed by the ‘String: function protein association networks’ version 12.0 (string‐db.org) for all pathogenic germline variants (A) and specifically for the nine pathogenic variants affecting DNA damage response genes (B). Known functional interactions between the affected genes are represented by lines, the strength of which reflects the functional association.