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Article

Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia

1
Princess Máxima Center for Pediatric Oncology, 3584 CS Utrecht, The Netherlands
2
Dutch Childhood Oncology Group, 3584 CS Utrecht, The Netherlands
3
Department of Genetics, University Medical Center Utrecht, 3508 AB Utrecht, The Netherlands
*
Author to whom correspondence should be addressed.
These authors contributed equally to this work.
Academic Editor: Linda Holmfeldt
Genes 2021, 12(2), 214; https://doi.org/10.3390/genes12020214
Received: 31 December 2020 / Revised: 22 January 2021 / Accepted: 28 January 2021 / Published: 2 February 2021
(This article belongs to the Special Issue Genetics and Epigenetics of Pediatric Leukemia)
Pediatric acute lymphoblastic leukemia (ALL) is the most common pediatric malignancy and is characterized by clonal heterogeneity. Genomic mutations can increase proliferative potential of leukemic cells and cause treatment resistance. However, mechanisms driving mutagenesis and clonal diversification in ALL are not fully understood. In this proof of principle study, we performed whole genome sequencing of two cases with multiple relapses in order to investigate whether groups of mutations separated in time show distinct mutational signatures. Based on mutation allele frequencies at diagnosis and subsequent relapses, we clustered mutations into groups and performed cluster-specific mutational profile analysis and de novo signature extraction. In patient 1, who experienced two relapses, the analysis unraveled a continuous interplay of aberrant activation induced cytidine deaminase (AID)/apolipoprotein B editing complex (APOBEC) activity. The associated signatures SBS2 and SBS13 were present already at diagnosis, and although emerging mutations were lost in later relapses, the process remained active throughout disease evolution. Patient 2 had three relapses. We identified episodic mutational processes at diagnosis and first relapse leading to mutations resembling ultraviolet light-driven DNA damage, and thiopurine-associated damage at first relapse. In conclusion, our data shows that investigation of mutational processes in clusters separated in time may aid in understanding the mutational mechanisms and discovery of underlying causes. View Full-Text
Keywords: pediatric acute lymphoblastic leukemia; mutational signatures; clonal evolution; relapse development; APOBEC activity; thiopurine-associated DNA damage pediatric acute lymphoblastic leukemia; mutational signatures; clonal evolution; relapse development; APOBEC activity; thiopurine-associated DNA damage
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MDPI and ACS Style

Antić, Ž.; Lelieveld, S.H.; van der Ham, C.G.; Sonneveld, E.; Hoogerbrugge, P.M.; Kuiper, R.P. Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia. Genes 2021, 12, 214. https://doi.org/10.3390/genes12020214

AMA Style

Antić Ž, Lelieveld SH, van der Ham CG, Sonneveld E, Hoogerbrugge PM, Kuiper RP. Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia. Genes. 2021; 12(2):214. https://doi.org/10.3390/genes12020214

Chicago/Turabian Style

Antić, Željko, Stefan H. Lelieveld, Cédric G. van der Ham, Edwin Sonneveld, Peter M. Hoogerbrugge, and Roland P. Kuiper 2021. "Unravelling the Sequential Interplay of Mutational Mechanisms during Clonal Evolution in Relapsed Pediatric Acute Lymphoblastic Leukemia" Genes 12, no. 2: 214. https://doi.org/10.3390/genes12020214

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