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dc.contributor.authorMansur, MB
dc.contributor.authorFurness, CL
dc.contributor.authorNakjang, S
dc.contributor.authorEnshaei, A
dc.contributor.authorAlpar, D
dc.contributor.authorColman, SM
dc.contributor.authorMinto, L
dc.contributor.authorIrving, J
dc.contributor.authorPoole, BV
dc.contributor.authorNoronha, EP
dc.contributor.authorSavola, S
dc.contributor.authorIqbal, S
dc.contributor.authorGribben, J
dc.contributor.authorPombo-de-Oliveira, MS
dc.contributor.authorFord, TM
dc.contributor.authorGreaves, MF
dc.contributor.authorvan Delft, FW
dc.date.accessioned2021-08-12T11:14:22Z
dc.date.available2021-08-12T11:14:22Z
dc.date.issued2021-07-01
dc.identifier.citationCancer Medicine, 2021, 10 (14), pp. 4864 - 4873
dc.identifier.issn2045-7634
dc.identifier.urihttps://repository.icr.ac.uk/handle/internal/4752
dc.identifier.eissn2045-7634
dc.identifier.doi10.1002/cam4.4024
dc.description.abstractBACKGROUND: 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.
dc.format.extent4864 - 4873
dc.languageeng
dc.language.isoeng
dc.publisherWILEY
dc.rights.urihttps://creativecommons.org/licenses/by/4.0
dc.titleThe genomic landscape of teenage and young adult T-cell acute lymphoblastic leukemia.
dc.typeJournal Article
dcterms.dateAccepted2021-05-11
rioxxterms.versionVoR
rioxxterms.versionofrecord10.1002/cam4.4024
rioxxterms.licenseref.urihttps://creativecommons.org/licenses/by/4.0
rioxxterms.typeJournal Article/Review
dc.relation.isPartOfCancer Medicine
pubs.issue14
pubs.notesNot known
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Biology of Childhood Leukaemia
pubs.organisational-group/ICR
pubs.organisational-group/ICR/Primary Group
pubs.organisational-group/ICR/Primary Group/ICR Divisions
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology
pubs.organisational-group/ICR/Primary Group/ICR Divisions/Molecular Pathology/Biology of Childhood Leukaemia
pubs.publication-statusPublished
pubs.volume10
pubs.embargo.termsNot known
icr.researchteamBiology of Childhood Leukaemia
icr.researchteamBiology of Childhood Leukaemia
dc.contributor.icrauthorFord, Anthony
dc.contributor.icrauthorGreaves, Melvyn


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