Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia

Abstract Background Relapsed acute myeloid leukemia (AML) is associated with the acquisition of additional somatic mutations which are thought to drive phenotypic adaptability, clonal selection and evolution of leukemic clones during treatment. We performed high throughput exome sequencing of matche...

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Main Authors: Yuslina Mat Yusoff, Fadly Ahid, Zahidah Abu Seman, Julia Abdullah, Nor Rizan Kamaluddin, Ezalia Esa, Zubaidah Zakaria
Format: Article
Language:English
Published: BMC 2021-09-01
Series:Molecular Cytogenetics
Subjects:
Online Access:https://doi.org/10.1186/s13039-021-00561-2
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spelling doaj-95524437b05b40a19d801d7d5300bc442021-09-26T11:05:57ZengBMCMolecular Cytogenetics1755-81662021-09-0114111310.1186/s13039-021-00561-2Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemiaYuslina Mat Yusoff0Fadly Ahid1Zahidah Abu Seman2Julia Abdullah3Nor Rizan Kamaluddin4Ezalia Esa5Zubaidah Zakaria6Hematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health MalaysiaCentre for Medical Laboratory Technology Studies, Faculty of Health Sciences, Universiti Teknologi MARAHematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health MalaysiaHematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health MalaysiaHematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health MalaysiaHematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health MalaysiaHematology Unit, Cancer Research Centre, Institute for Medical Research, National Institutes of Health, Ministry of Health MalaysiaAbstract Background Relapsed acute myeloid leukemia (AML) is associated with the acquisition of additional somatic mutations which are thought to drive phenotypic adaptability, clonal selection and evolution of leukemic clones during treatment. We performed high throughput exome sequencing of matched presentation and relapsed samples from 6 cytogenetically normal AML (CN-AML) patients treated with standard remission induction chemotherapy in order to contribute with the investigation of the mutational landscape of CN-AML and clonal evolution during AML treatment. Result A total of 24 and 32 somatic variants were identified in presentation and relapse samples respectively with an average of 4.0 variants per patient at presentation and 5.3 variants per patient at relapse, with SNVs being more frequent than indels at both disease stages. All patients have somatic variants in at least one gene that is frequently mutated in AML at both disease presentation and relapse, with most of these variants are classic AML and recurrent hotspot mutations including NPM1 p.W288fs, FLT3-ITD, NRAS p.G12D and IDH2 p.R140Q. In addition, we found two distinct clonal evolution patterns of relapse: (1) a leukemic clone at disease presentation acquires additional mutations and evolves into the relapse clone after the chemotherapy; (2) a leukemic clone at disease presentation persists at relapse without the addition of novel somatic mutations. Conclusions The findings of this study suggest that the relapse-initiating clones may pre-exist prior to therapy, which harbor or acquire mutations that confer selective advantage during chemotherapy, resulting in clonal expansion and eventually leading to relapse.https://doi.org/10.1186/s13039-021-00561-2Acute myeloid leukemiaClonal evolutionMutationRelapseWhole exome sequencing
collection DOAJ
language English
format Article
sources DOAJ
author Yuslina Mat Yusoff
Fadly Ahid
Zahidah Abu Seman
Julia Abdullah
Nor Rizan Kamaluddin
Ezalia Esa
Zubaidah Zakaria
spellingShingle Yuslina Mat Yusoff
Fadly Ahid
Zahidah Abu Seman
Julia Abdullah
Nor Rizan Kamaluddin
Ezalia Esa
Zubaidah Zakaria
Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia
Molecular Cytogenetics
Acute myeloid leukemia
Clonal evolution
Mutation
Relapse
Whole exome sequencing
author_facet Yuslina Mat Yusoff
Fadly Ahid
Zahidah Abu Seman
Julia Abdullah
Nor Rizan Kamaluddin
Ezalia Esa
Zubaidah Zakaria
author_sort Yuslina Mat Yusoff
title Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia
title_short Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia
title_full Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia
title_fullStr Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia
title_full_unstemmed Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia
title_sort comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia
publisher BMC
series Molecular Cytogenetics
issn 1755-8166
publishDate 2021-09-01
description Abstract Background Relapsed acute myeloid leukemia (AML) is associated with the acquisition of additional somatic mutations which are thought to drive phenotypic adaptability, clonal selection and evolution of leukemic clones during treatment. We performed high throughput exome sequencing of matched presentation and relapsed samples from 6 cytogenetically normal AML (CN-AML) patients treated with standard remission induction chemotherapy in order to contribute with the investigation of the mutational landscape of CN-AML and clonal evolution during AML treatment. Result A total of 24 and 32 somatic variants were identified in presentation and relapse samples respectively with an average of 4.0 variants per patient at presentation and 5.3 variants per patient at relapse, with SNVs being more frequent than indels at both disease stages. All patients have somatic variants in at least one gene that is frequently mutated in AML at both disease presentation and relapse, with most of these variants are classic AML and recurrent hotspot mutations including NPM1 p.W288fs, FLT3-ITD, NRAS p.G12D and IDH2 p.R140Q. In addition, we found two distinct clonal evolution patterns of relapse: (1) a leukemic clone at disease presentation acquires additional mutations and evolves into the relapse clone after the chemotherapy; (2) a leukemic clone at disease presentation persists at relapse without the addition of novel somatic mutations. Conclusions The findings of this study suggest that the relapse-initiating clones may pre-exist prior to therapy, which harbor or acquire mutations that confer selective advantage during chemotherapy, resulting in clonal expansion and eventually leading to relapse.
topic Acute myeloid leukemia
Clonal evolution
Mutation
Relapse
Whole exome sequencing
url https://doi.org/10.1186/s13039-021-00561-2
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