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

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...

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Autores principales:	Shumaila Sayyab, Anders Lundmark, Malin Larsson, Markus Ringnér, Sara Nystedt, Yanara Marincevic-Zuniga, Katja Pokrovskaja Tamm, Jonas Abrahamsson, Linda Fogelstrand, Mats Heyman, Ulrika Norén-Nyström, Gudmar Lönnerholm, Arja Harila-Saari, Eva C. Berglund, Jessica Nordlund, Ann-Christine Syvänen
Formato:	article
Lenguaje:	EN
Publicado:	Nature Portfolio 2021
Materias:	Medicine R Science Q
Acceso en línea:	https://doaj.org/article/df7f00d635d847359cec38029b48a552
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spelling	oai:doaj.org-article:df7f00d635d847359cec38029b48a5522021-12-02T14:53:34ZMutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia10.1038/s41598-021-95109-02045-2322https://doaj.org/article/df7f00d635d847359cec38029b48a5522021-08-01T00:00:00Zhttps://doi.org/10.1038/s41598-021-95109-0https://doaj.org/toc/2045-2322Abstract 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.Shumaila SayyabAnders LundmarkMalin LarssonMarkus RingnérSara NystedtYanara Marincevic-ZunigaKatja Pokrovskaja TammJonas AbrahamssonLinda FogelstrandMats HeymanUlrika Norén-NyströmGudmar LönnerholmArja Harila-SaariEva C. BerglundJessica NordlundAnn-Christine SyvänenNature PortfolioarticleMedicineRScienceQENScientific Reports, Vol 11, Iss 1, Pp 1-17 (2021)
institution	DOAJ
collection	DOAJ
language	EN
topic	Medicine R Science Q
spellingShingle	Medicine R Science Q Shumaila Sayyab Anders Lundmark Malin Larsson Markus Ringnér Sara Nystedt Yanara Marincevic-Zuniga Katja Pokrovskaja Tamm Jonas Abrahamsson Linda Fogelstrand Mats Heyman Ulrika Norén-Nyström Gudmar Lönnerholm Arja Harila-Saari Eva C. Berglund Jessica Nordlund Ann-Christine Syvänen Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
description	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 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.
format	article
author	Shumaila Sayyab Anders Lundmark Malin Larsson Markus Ringnér Sara Nystedt Yanara Marincevic-Zuniga Katja Pokrovskaja Tamm Jonas Abrahamsson Linda Fogelstrand Mats Heyman Ulrika Norén-Nyström Gudmar Lönnerholm Arja Harila-Saari Eva C. Berglund Jessica Nordlund Ann-Christine Syvänen
author_facet	Shumaila Sayyab Anders Lundmark Malin Larsson Markus Ringnér Sara Nystedt Yanara Marincevic-Zuniga Katja Pokrovskaja Tamm Jonas Abrahamsson Linda Fogelstrand Mats Heyman Ulrika Norén-Nyström Gudmar Lönnerholm Arja Harila-Saari Eva C. Berglund Jessica Nordlund Ann-Christine Syvänen
author_sort	Shumaila Sayyab
title	Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
title_short	Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
title_full	Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
title_fullStr	Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
title_full_unstemmed	Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
title_sort	mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia
publisher	Nature Portfolio
publishDate	2021
url	https://doaj.org/article/df7f00d635d847359cec38029b48a552
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Mutational patterns and clonal evolution from diagnosis to relapse in pediatric acute lymphoblastic leukemia

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