The genomic landscape of teenage and young adult T-cell acute lymphoblastic leukemia.
T-ALL
clonal selection
genomics
relapse
teenagers and young adults
Journal
Cancer medicine
ISSN: 2045-7634
Titre abrégé: Cancer Med
Pays: United States
ID NLM: 101595310
Informations de publication
Date de publication:
07 2021
07 2021
Historique:
revised:
09
04
2021
received:
24
12
2020
accepted:
11
05
2021
pubmed:
4
6
2021
medline:
1
1
2022
entrez:
3
6
2021
Statut:
ppublish
Résumé
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. 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. 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. 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.
Sections du résumé
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.
Identifiants
pubmed: 34080325
doi: 10.1002/cam4.4024
pmc: PMC8290240
doi:
Types de publication
Journal Article
Research Support, Non-U.S. Gov't
Review
Langues
eng
Sous-ensembles de citation
IM
Pagination
4864-4873Subventions
Organisme : Kay Kendall Leukaemia Fund
ID : KKLF417
Organisme : Fundação do Cancer, SwissBridge Fund
Organisme : The Hungarian National Research, Development and Innovation Office-NKFIH
ID : 134253
Organisme : FAPERJ
ID : E-26/202.577/2019
Organisme : Hungarian Academy of Sciences
ID : BO/00320/18/5
Organisme : INCA, CNPq
ID : 310877/2019-5
Organisme : New National Excellence Program of the Ministry for Innovation and Technology
ID : ÚNKP-20-5-SE-22
Organisme : The Institute of Cancer Research
Organisme : Lady Tata Memorial Trust-LTMT International Award for Research in Leukaemia and the Ministry of Health, INCA-Brazil
Organisme : The European Hematology Association-EHA Partner Fellowship
ID : 2011/01
Organisme : The Hungarian National Research, Development and Innovation Office-NKFIH
ID : 119950
Organisme : Leukaemia & Lymphoma Research
Organisme : EU's Horizon 2020 Research and Innovation Program
ID : 739593
Organisme : Wellcome Trust
ID : 105104/Z/14/Z
Pays : United Kingdom
Organisme : Bloodwise
Organisme : FAPERJ
ID : E-26/110.712/2012
Organisme : INCA, CNPq
ID : 301594/2015-5
Organisme : Wellcome Trust
Pays : United Kingdom
Informations de copyright
© 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd.
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