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The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia
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 relap...
Autores principales: | , , , , , , , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
John Wiley and Sons Inc.
2021
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290240/ https://www.ncbi.nlm.nih.gov/pubmed/34080325 http://dx.doi.org/10.1002/cam4.4024 |
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author | Mansur, Marcela B. Furness, Caroline L. Nakjang, Sirintra Enshaei, Amir Alpar, Donat Colman, Sue M. Minto, Lynne Irving, Julie Poole, Beth V. Noronha, Elda P. Savola, Suvi Iqbal, Sameena Gribben, John Pombo‐de‐Oliveira, Maria S. Ford, Tony M. Greaves, Mel F. van Delft, Frederik W. |
author_facet | Mansur, Marcela B. Furness, Caroline L. Nakjang, Sirintra Enshaei, Amir Alpar, Donat Colman, Sue M. Minto, Lynne Irving, Julie Poole, Beth V. Noronha, Elda P. Savola, Suvi Iqbal, Sameena Gribben, John Pombo‐de‐Oliveira, Maria S. Ford, Tony M. Greaves, Mel F. van Delft, Frederik W. |
author_sort | Mansur, Marcela B. |
collection | PubMed |
description | 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. |
format | Online Article Text |
id | pubmed-8290240 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2021 |
publisher | John Wiley and Sons Inc. |
record_format | MEDLINE/PubMed |
spelling | pubmed-82902402021-07-21 The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia Mansur, Marcela B. Furness, Caroline L. Nakjang, Sirintra Enshaei, Amir Alpar, Donat Colman, Sue M. Minto, Lynne Irving, Julie Poole, Beth V. Noronha, Elda P. Savola, Suvi Iqbal, Sameena Gribben, John Pombo‐de‐Oliveira, Maria S. Ford, Tony M. Greaves, Mel F. van Delft, Frederik W. Cancer Med Cancer Biology 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. John Wiley and Sons Inc. 2021-06-02 /pmc/articles/PMC8290240/ /pubmed/34080325 http://dx.doi.org/10.1002/cam4.4024 Text en © 2021 The Authors. Cancer Medicine published by John Wiley & Sons Ltd. https://creativecommons.org/licenses/by/4.0/This is an open access article under the terms of the http://creativecommons.org/licenses/by/4.0/ (https://creativecommons.org/licenses/by/4.0/) License, which permits use, distribution and reproduction in any medium, provided the original work is properly cited. |
spellingShingle | Cancer Biology Mansur, Marcela B. Furness, Caroline L. Nakjang, Sirintra Enshaei, Amir Alpar, Donat Colman, Sue M. Minto, Lynne Irving, Julie Poole, Beth V. Noronha, Elda P. Savola, Suvi Iqbal, Sameena Gribben, John Pombo‐de‐Oliveira, Maria S. Ford, Tony M. Greaves, Mel F. van Delft, Frederik W. The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia |
title | The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia |
title_full | The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia |
title_fullStr | The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia |
title_full_unstemmed | The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia |
title_short | The genomic landscape of teenage and young adult T‐cell acute lymphoblastic leukemia |
title_sort | genomic landscape of teenage and young adult t‐cell acute lymphoblastic leukemia |
topic | Cancer Biology |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8290240/ https://www.ncbi.nlm.nih.gov/pubmed/34080325 http://dx.doi.org/10.1002/cam4.4024 |
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