dc.contributor.author | Mansur, MB | |
dc.contributor.author | Furness, CL | |
dc.contributor.author | Nakjang, S | |
dc.contributor.author | Enshaei, A | |
dc.contributor.author | Alpar, D | |
dc.contributor.author | Colman, SM | |
dc.contributor.author | Minto, L | |
dc.contributor.author | Irving, J | |
dc.contributor.author | Poole, BV | |
dc.contributor.author | Noronha, EP | |
dc.contributor.author | Savola, S | |
dc.contributor.author | Iqbal, S | |
dc.contributor.author | Gribben, J | |
dc.contributor.author | Pombo-de-Oliveira, MS | |
dc.contributor.author | Ford, TM | |
dc.contributor.author | Greaves, MF | |
dc.contributor.author | van Delft, FW | |
dc.date.accessioned | 2021-08-12T11:14:22Z | |
dc.date.available | 2021-08-12T11:14:22Z | |
dc.date.issued | 2021-07-01 | |
dc.identifier.citation | Cancer Medicine, 2021, 10 (14), pp. 4864 - 4873 | |
dc.identifier.issn | 2045-7634 | |
dc.identifier.uri | https://repository.icr.ac.uk/handle/internal/4752 | |
dc.identifier.eissn | 2045-7634 | |
dc.identifier.doi | 10.1002/cam4.4024 | |
dc.description.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. | |
dc.format.extent | 4864 - 4873 | |
dc.language | eng | |
dc.language.iso | eng | |
dc.publisher | WILEY | |
dc.rights.uri | https://creativecommons.org/licenses/by/4.0 | |
dc.title | The genomic landscape of teenage and young adult T-cell acute lymphoblastic leukemia. | |
dc.type | Journal Article | |
dcterms.dateAccepted | 2021-05-11 | |
rioxxterms.version | VoR | |
rioxxterms.versionofrecord | 10.1002/cam4.4024 | |
rioxxterms.licenseref.uri | https://creativecommons.org/licenses/by/4.0 | |
rioxxterms.type | Journal Article/Review | |
dc.relation.isPartOf | Cancer Medicine | |
pubs.issue | 14 | |
pubs.notes | Not 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-status | Published | |
pubs.volume | 10 | |
pubs.embargo.terms | Not known | |
icr.researchteam | Biology of Childhood Leukaemia | |
icr.researchteam | Biology of Childhood Leukaemia | |
dc.contributor.icrauthor | Ford, Anthony | |
dc.contributor.icrauthor | Greaves, Melvyn | |