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Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

Sayyab, Shumaila ; Lundmark, Anders ; Larsson, Malin ; Ringnér, Markus LU orcid ; Nystedt, Sara ; Marincevic-Zuniga, Yanara ; Tamm, Katja Pokrovskaja ; Abrahamsson, Jonas ; Fogelstrand, Linda and Heyman, Mats , et al. (2021) In Scientific Reports 11.
Abstract

The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we... (More)

The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.

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type
Contribution to journal
publication status
published
subject
in
Scientific Reports
volume
11
article number
15988
publisher
Nature Publishing Group
external identifiers
  • scopus:85112608376
  • pmid:34362951
ISSN
2045-2322
DOI
10.1038/s41598-021-95109-0
language
English
LU publication?
yes
id
40461752-0726-42ad-81ad-0e365cc29937
date added to LUP
2021-08-16 16:20:24
date last changed
2024-04-06 05:38:28
@article{40461752-0726-42ad-81ad-0e365cc29937,
  abstract     = {{<p>The mechanisms driving clonal heterogeneity and evolution in relapsed pediatric acute lymphoblastic leukemia (ALL) are not fully understood. We performed whole genome sequencing of samples collected at diagnosis, relapse(s) and remission from 29 Nordic patients. Somatic point mutations and large-scale structural variants were called using individually matched remission samples as controls, and allelic expression of the mutations was assessed in ALL cells using RNA-sequencing. We observed an increased burden of somatic mutations at relapse, compared to diagnosis, and at second relapse compared to first relapse. In addition to 29 known ALL driver genes, of which nine genes carried recurrent protein-coding mutations in our sample set, we identified putative non-protein coding mutations in regulatory regions of seven additional genes that have not previously been described in ALL. Cluster analysis of hundreds of somatic mutations per sample revealed three distinct evolutionary trajectories during ALL progression from diagnosis to relapse. The evolutionary trajectories provide insight into the mutational mechanisms leading relapse in ALL and could offer biomarkers for improved risk prediction in individual patients.</p>}},
  author       = {{Sayyab, Shumaila and Lundmark, Anders and Larsson, Malin and Ringnér, Markus and Nystedt, Sara and Marincevic-Zuniga, Yanara and Tamm, Katja Pokrovskaja and Abrahamsson, Jonas and Fogelstrand, Linda and Heyman, Mats and Norén-Nyström, Ulrika and Lönnerholm, Gudmar and Harila-Saari, Arja and Berglund, Eva C and Nordlund, Jessica and Syvänen, Ann-Christine}},
  issn         = {{2045-2322}},
  language     = {{eng}},
  month        = {{08}},
  publisher    = {{Nature Publishing Group}},
  series       = {{Scientific Reports}},
  title        = {{Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia}},
  url          = {{http://dx.doi.org/10.1038/s41598-021-95109-0}},
  doi          = {{10.1038/s41598-021-95109-0}},
  volume       = {{11}},
  year         = {{2021}},
}