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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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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