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Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations

Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical...

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Autores principales: Antić, Željko, Yu, Jiangyan, van Reijmersdal, Simon V., van Dijk, Anke, Dekker, Linde, Segerink, Wouter H., Sonneveld, Edwin, Fiocco, Marta, Pieters, Rob, Hoogerbrugge, Peter M., van Leeuwen, Frank N., van Kessel, Ad Geurts, Waanders, Esmé, Kuiper, Roland P.
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Fondazione Ferrata Storti 2020
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634184/
https://www.ncbi.nlm.nih.gov/pubmed/33147938
http://dx.doi.org/10.3324/haematol.2020.259226
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author Antić, Željko
Yu, Jiangyan
van Reijmersdal, Simon V.
van Dijk, Anke
Dekker, Linde
Segerink, Wouter H.
Sonneveld, Edwin
Fiocco, Marta
Pieters, Rob
Hoogerbrugge, Peter M.
van Leeuwen, Frank N.
van Kessel, Ad Geurts
Waanders, Esmé
Kuiper, Roland P.
author_facet Antić, Željko
Yu, Jiangyan
van Reijmersdal, Simon V.
van Dijk, Anke
Dekker, Linde
Segerink, Wouter H.
Sonneveld, Edwin
Fiocco, Marta
Pieters, Rob
Hoogerbrugge, Peter M.
van Leeuwen, Frank N.
van Kessel, Ad Geurts
Waanders, Esmé
Kuiper, Roland P.
author_sort Antić, Željko
collection PubMed
description Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases. Using molecular inversion probe sequencing and breakpoint-spanning polymerase chain reaction analysis we reliably detected alterations with an allele frequency below 1%. We identified 660 genomic alterations in 285 diagnostic samples of which 495 (75%) were subclonal. RAS pathway mutations were common, particularly in minor subclones, and comparisons between RAS hotspot mutations revealed differences in their capacity to drive clonal expansion in ALL. We did not find an association of subclonal alterations with unfavorable outcome. Particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the subclonal alterations were preserved at relapse. We conclude that, for the genes tested, there is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment.
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spelling pubmed-86341842021-12-17 Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations Antić, Željko Yu, Jiangyan van Reijmersdal, Simon V. van Dijk, Anke Dekker, Linde Segerink, Wouter H. Sonneveld, Edwin Fiocco, Marta Pieters, Rob Hoogerbrugge, Peter M. van Leeuwen, Frank N. van Kessel, Ad Geurts Waanders, Esmé Kuiper, Roland P. Haematologica Article Genomic studies of pediatric acute lymphoblastic leukemia (ALL) have shown remarkable heterogeneity in initial diagnosis, with multiple (sub)clones harboring lesions in relapse-associated genes. However, the clinical relevance of these subclonal alterations remains unclear. We assessed the clinical relevance and prognostic value of subclonal alterations in the relapse-associated genes IKZF1, CREBBP, KRAS, NRAS, PTPN11, TP53, NT5C2, and WHSC1 in 503 ALL cases. Using molecular inversion probe sequencing and breakpoint-spanning polymerase chain reaction analysis we reliably detected alterations with an allele frequency below 1%. We identified 660 genomic alterations in 285 diagnostic samples of which 495 (75%) were subclonal. RAS pathway mutations were common, particularly in minor subclones, and comparisons between RAS hotspot mutations revealed differences in their capacity to drive clonal expansion in ALL. We did not find an association of subclonal alterations with unfavorable outcome. Particularly for IKZF1, an established prognostic marker in ALL, all clonal but none of the subclonal alterations were preserved at relapse. We conclude that, for the genes tested, there is no basis to consider subclonal alterations detected at diagnosis for risk group stratification of ALL treatment. Fondazione Ferrata Storti 2020-11-05 /pmc/articles/PMC8634184/ /pubmed/33147938 http://dx.doi.org/10.3324/haematol.2020.259226 Text en Copyright© 2021 Ferrata Storti Foundation https://creativecommons.org/licenses/by-nc/4.0/This article is distributed under the terms of the Creative Commons Attribution Noncommercial License (by-nc 4.0) which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited.
spellingShingle Article
Antić, Željko
Yu, Jiangyan
van Reijmersdal, Simon V.
van Dijk, Anke
Dekker, Linde
Segerink, Wouter H.
Sonneveld, Edwin
Fiocco, Marta
Pieters, Rob
Hoogerbrugge, Peter M.
van Leeuwen, Frank N.
van Kessel, Ad Geurts
Waanders, Esmé
Kuiper, Roland P.
Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
title Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
title_full Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
title_fullStr Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
title_full_unstemmed Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
title_short Multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
title_sort multiclonal complexity of pediatric acute lymphoblastic leukemia and the prognostic relevance of subclonal mutations
topic Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8634184/
https://www.ncbi.nlm.nih.gov/pubmed/33147938
http://dx.doi.org/10.3324/haematol.2020.259226
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