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Lookup NU author(s): Dr Amir EnshaeiORCiD, Dr Sirintra Nakjang, Lynne Minto, Professor Julie Irving, Beth Poole, Dr Frederik van DelftORCiD
This work is licensed under a Creative Commons Attribution 4.0 International License (CC BY 4.0).
BackgroundTreatment 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.MethodsGenomic 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.ResultsGenomic 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.ConclusionsAll 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.
Author(s): Mansur M, Furness CL, Enshaei A, Nakjang S, Alpar D, Colman SM, Minto L, Irving J, Poole BV, Noronha LP, Savola S, Iqbal S, Gribben J, Pombo-de-Oliveira MS, Ford TM, Greaves M, van Delft F
Publication type: Article
Publication status: Published
Journal: Cancer Medicine
Year: 2021
Volume: 10
Issue: 14
Pages: 4864-4873
Print publication date: 01/07/2021
Online publication date: 02/06/2021
Acceptance date: 11/05/2021
Date deposited: 06/11/2023
ISSN (electronic): 2045-7634
Publisher: Wiley
URL: https://doi.org/10.1002/cam4.4024
DOI: 10.1002/cam4.4024
Data Access Statement: The raw data CEL and fastq files are available upon request and will be accessible through the Newcastle University data repository (data.NCL).
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