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

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 presen...

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Published in:Molecular Cytogenetics
Main Author: Mat Yusoff Y.; Ahid F.; Abu Seman Z.; Abdullah J.; Kamaluddin N.R.; Esa E.; Zakaria Z.
Format: Article
Language:English
Published: BioMed Central Ltd 2021
Online Access:https://www.scopus.com/inward/record.uri?eid=2-s2.0-85115642717&doi=10.1186%2fs13039-021-00561-2&partnerID=40&md5=2df67e2c9fb6c62b4fb2d74fdcb54952
id 2-s2.0-85115642717
spelling 2-s2.0-85115642717
Mat Yusoff Y.; Ahid F.; Abu Seman Z.; Abdullah J.; Kamaluddin N.R.; Esa E.; Zakaria Z.
Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia
2021
Molecular Cytogenetics
14
1
10.1186/s13039-021-00561-2
https://www.scopus.com/inward/record.uri?eid=2-s2.0-85115642717&doi=10.1186%2fs13039-021-00561-2&partnerID=40&md5=2df67e2c9fb6c62b4fb2d74fdcb54952
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. © 2021, The Author(s).
BioMed Central Ltd
17558166
English
Article
All Open Access; Gold Open Access
author Mat Yusoff Y.; Ahid F.; Abu Seman Z.; Abdullah J.; Kamaluddin N.R.; Esa E.; Zakaria Z.
spellingShingle Mat Yusoff Y.; Ahid F.; Abu Seman Z.; Abdullah J.; Kamaluddin N.R.; Esa E.; Zakaria Z.
Comprehensive analysis of mutations and clonal evolution patterns in a cohort of patients with cytogenetically normal acute myeloid leukemia
author_facet Mat Yusoff Y.; Ahid F.; Abu Seman Z.; Abdullah J.; Kamaluddin N.R.; Esa E.; Zakaria Z.
author_sort Mat Yusoff Y.; Ahid F.; Abu Seman Z.; Abdullah J.; Kamaluddin N.R.; Esa E.; Zakaria Z.
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
publishDate 2021
container_title Molecular Cytogenetics
container_volume 14
container_issue 1
doi_str_mv 10.1186/s13039-021-00561-2
url https://www.scopus.com/inward/record.uri?eid=2-s2.0-85115642717&doi=10.1186%2fs13039-021-00561-2&partnerID=40&md5=2df67e2c9fb6c62b4fb2d74fdcb54952
description 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. © 2021, The Author(s).
publisher BioMed Central Ltd
issn 17558166
language English
format Article
accesstype All Open Access; Gold Open Access
record_format scopus
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