The genomic landscape of teenage and young adult T-cell acute lymphoblastic leukemia

Abstract

Background: Treatment on risk adapted intensive pediatric protocols has improved outcome for teenagers and young adults (TYA) with T-cell acute lymphoblastic leukemia (T-ALL). Understanding the biology of disease in this age group and the genetic basis of relapse is a key goal as patients with relapsed/refractory disease have poor outcomes with conventional chemotherapy and novel molecular targets are required. This study examines the question of whether TYA T-ALL has a specific biological-molecular profile distinct from pediatric or adult T-ALL.

Methods: Genomic characterization was undertaken of a retrospective discovery cohort of 80 patients aged 15-26 years with primary or relapsed T-ALL, using a combination of Genome-Wide Human SNP Array 6.0, targeted gene mutation and promoter methylation analyses. Findings were confirmed by MLPA, real-time quantitative PCR, and FISH. Whole Exome Sequencing was performed in 4 patients with matched presentation and relapse to model clonal evolution. A prevalence analysis was performed on a final data set of 1,792 individual cases to identify genetic lesions with age specific frequency patterns, including 972 pediatric (1-14 years), 439 TYA (15-24 years) and 381 adult (≥25 years) cases. These cases were extracted from 19 publications with comparable genomic data identified through a PubMed search.

Results: Genomic characterization of this large cohort of TYA T-ALL patients identified recurrent isochromosome 7q i(7q) in our discovery cohort (n = 3). Prevalence analysis did not identify any age specific genetic abnormalities. Genomic analysis of 6 pairs of matched presentation - relapsed T-ALL established that all relapses were clonally related to the initial leukemia. Whole exome sequencing analysis revealed recurrent, targetable, mutations disrupting NOTCH, PI3K/AKT/mTOR, FLT3, NRAS as well as drug metabolism pathways.

Conclusions: All genetic aberrations in TYA T-ALL occurred with an incidence similar or intermediate to that reported in the pediatric and adult literature, demonstrating that overall TYA T-ALL exhibits a transitional genomic profile. Analysis of matched presentation - relapse supported the hypothesis that relapse is driven by the Darwinian evolution of sub-clones associated with drug resistance (NT5C2 and TP53 mutations) and re-iterative mutation of known key T-ALL drivers, including NOTCH1.

Keywords: T-ALL; clonal selection; genomics; relapse; teenagers and young adults.

FIGURE 1

Recurrent isochromosome 7q in TYA T‐ALL. Nexus copy number analysis of chromosome 7 in 6 TYA T‐ALL samples. Analysis of UNP49 (trisomy 7) and UPN50 (disomy 7) are shown for comparative reasons. The location of MLPA probes for IKZF1, POR and EZH2 is indicated by the black arrows at the top. The color scale represents change in DNA copy number—red and blue represent gain and loss respectively. T‐ALL, T‐cell acute lymphoblastic leukemia; TYA, teenagers and young adults

FIGURE 2

Incidence of gene abnormalities with significant enrichment in T‐ALL age groups. Bar diagrams depict the relative incidence of gene deletions and mutations (mGene) with significant enrichment in Paediatric, TYA and/or Adult patients with T‐ALL. T‐ALL, T‐cell acute lymphoblastic leukemia; TYA, teenagers and young adults

FIGURE 3

Heatmap of recurrently targeted pathways in matched presentation and relapsed TYA T‐ALL. Heatmap of selected genes affecting cellular pathways in T‐ALL. Validated and presumed protein‐altering mutations are shown. Green boxes indicate deletions; blue boxes missense mutations; yellow boxes in‐frame insertions; red boxes frameshift mutations; orange boxes nonsense mutations. T‐ALL, T‐cell acute lymphoblastic leukemia; TF, transcription factor; TYA, teenagers and young adults

FIGURE 4

Comparative genetic composition of UPN38 at presentation and subsequent relapses. Top, variant allele frequency (VAF) of missense mutations in presentation, relapse 1 and 2. Bottom, Inferred clonal evolution from a single hematopoietic stem cell to presentation (P), relapse 1 (R1) and relapse 2 (R2). Phylogenetic tree depicting shared and acquired gene mutations