Unravelling the genomic landscape of acute lymphoblastic leukaemia in older adults

Abstract

The objectives of this study were to characterise the primary genetic abnormalities, genomic copy number changes and mutational landscape of ALL in older adults. The primary chromosomal abnormalities from patients aged ≥60 years recruited into the UKALL14 (n=94) and UKALL60+ (N=116) trials were first evaluated. B-cell precursor (BCP) ALL patients lacking a primary chromosomal abnormality (B-other ALL) were screened for ABL-class fusions, JAK-STAT abnormalities and other rearrangements using fluorescence in situ hybridisation (FISH). CRLF2 and ZNF384 rearrangements were detected in 17% and 7% of tested patients respectively. ABLclass fusions were notably absent. Next, single nucleotide polymorphism (SNP) arrays were performed to identify copy number abnormalities in patients with suitable material (n=83). Deletions were detected in IKZF1 (52%), CDKN2A/B (45%) and PAX5 (39%), as well as arm level events including del(9p) (21%), monosomy 7 (10%) and gain 1q (10%). Selected novel abnormalities were then validated using a customised sequencing approach. Recurrent novel deletions were confirmed in LEMD3, KDM6A and CXCR4, potentially contributing to leukaemogenesis. Separately, SNP arrays were performed on DNA from patients with low hypodiploidy or high hyperdiploidy (n=88) and machine-learning techniques were used to cluster cases based on log2 ratio data. Discrepancies between the cytogenetic-derived and SNP array-derived genetic subgroup were identified. A diagnostic classifier based on chromosomal log2 ratios was then designed using classification and regression tree analysis (CART). Finally, the mutational landscape of ALL in older adults was characterised in selected patients using exome sequencing (n=6) and a customised sequencing panel (n=30). Pathogenic variants were identified in TP53, NF1, JAK2 as well as members of the RAS signalling pathway, and were closely related to specific primary chromosomal abnormalities. This project has helped characterise the landscape of genetic prognostic biomarkers in older adults with ALL, and identified novel therapeutically actionable abnormalities meriting further assessment.