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Genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in China using exon sequencing
BACKGROUND: Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by recurring structural chromosomal alterations and genetic alterations, whose detection is critical in diagnosis, risk stratification and prognostication. However, the genetic mechanisms that give...
Autores principales: | , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
BioMed Central
2020
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068927/ https://www.ncbi.nlm.nih.gov/pubmed/32164600 http://dx.doi.org/10.1186/s12885-020-6709-7 |
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author | Zhang, Honghong Wang, Hongsheng Qian, Xiaowen Gao, Shuai Xia, Jieqi Liu, Junwen Cheng, Yanqin Man, Jie Zhai, Xiaowen |
author_facet | Zhang, Honghong Wang, Hongsheng Qian, Xiaowen Gao, Shuai Xia, Jieqi Liu, Junwen Cheng, Yanqin Man, Jie Zhai, Xiaowen |
author_sort | Zhang, Honghong |
collection | PubMed |
description | BACKGROUND: Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by recurring structural chromosomal alterations and genetic alterations, whose detection is critical in diagnosis, risk stratification and prognostication. However, the genetic mechanisms that give rise to ALL remain poorly understood. METHODS: Using next-generation sequencing (NGS) in matched germline and tumor samples from 140 pediatric Chinese patients with ALL, we landscaped the gene mutations and estimated the mutation frequencies in this disease. RESULTS: Our results showed that the top driver oncogenes having a mutation prevalence over 5% in childhood ALL included KRAS (8.76%), NRAS (6.4%), FLT3 (5.7%) and KMT2D (5.0%). While the most frequently mutated genes were KRAS, NRAS and FLT3 in B cell ALL (B-ALL), the most common mutations were enriched in NOTCH1 (23.1%), FBXW7 (23.1%) and PHF6 (11.5%) in T cell ALL (T-ALL). These mutant genes are involved in key molecular processes, including the Ras pathway, the Notch pathway, epigenetic modification, and cell-cycle regulation. Strikingly, more than 50% of mutations occurred in the high-hyperdiploid (HeH) ALL existed in Ras pathway, especially FLT3 (20%). We also found that the epigenetic regulator gene KMT2D, which is frequently mutated in ALL, may be involved in driving leukemia transformation, as evidenced by an in vitro functional assay. CONCLUSION: Overall, this study provides further insights into the genetic basis of ALL and shows that Ras mutations are predominant in childhood ALL, especially in the high-hyperdiploid subtype in our research. |
format | Online Article Text |
id | pubmed-7068927 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2020 |
publisher | BioMed Central |
record_format | MEDLINE/PubMed |
spelling | pubmed-70689272020-03-18 Genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in China using exon sequencing Zhang, Honghong Wang, Hongsheng Qian, Xiaowen Gao, Shuai Xia, Jieqi Liu, Junwen Cheng, Yanqin Man, Jie Zhai, Xiaowen BMC Cancer Research Article BACKGROUND: Acute lymphoblastic leukemia (ALL), the most common childhood malignancy, is characterized by recurring structural chromosomal alterations and genetic alterations, whose detection is critical in diagnosis, risk stratification and prognostication. However, the genetic mechanisms that give rise to ALL remain poorly understood. METHODS: Using next-generation sequencing (NGS) in matched germline and tumor samples from 140 pediatric Chinese patients with ALL, we landscaped the gene mutations and estimated the mutation frequencies in this disease. RESULTS: Our results showed that the top driver oncogenes having a mutation prevalence over 5% in childhood ALL included KRAS (8.76%), NRAS (6.4%), FLT3 (5.7%) and KMT2D (5.0%). While the most frequently mutated genes were KRAS, NRAS and FLT3 in B cell ALL (B-ALL), the most common mutations were enriched in NOTCH1 (23.1%), FBXW7 (23.1%) and PHF6 (11.5%) in T cell ALL (T-ALL). These mutant genes are involved in key molecular processes, including the Ras pathway, the Notch pathway, epigenetic modification, and cell-cycle regulation. Strikingly, more than 50% of mutations occurred in the high-hyperdiploid (HeH) ALL existed in Ras pathway, especially FLT3 (20%). We also found that the epigenetic regulator gene KMT2D, which is frequently mutated in ALL, may be involved in driving leukemia transformation, as evidenced by an in vitro functional assay. CONCLUSION: Overall, this study provides further insights into the genetic basis of ALL and shows that Ras mutations are predominant in childhood ALL, especially in the high-hyperdiploid subtype in our research. BioMed Central 2020-03-12 /pmc/articles/PMC7068927/ /pubmed/32164600 http://dx.doi.org/10.1186/s12885-020-6709-7 Text en © The Author(s). 2020 Open AccessThis article is licensed under a Creative Commons Attribution 4.0 International License, which permits use, sharing, adaptation, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if changes were made. The images or other third party material in this article are included in the article's Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article's Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit http://creativecommons.org/licenses/by/4.0/. The Creative Commons Public Domain Dedication waiver (http://creativecommons.org/publicdomain/zero/1.0/) applies to the data made available in this article, unless otherwise stated in a credit line to the data. |
spellingShingle | Research Article Zhang, Honghong Wang, Hongsheng Qian, Xiaowen Gao, Shuai Xia, Jieqi Liu, Junwen Cheng, Yanqin Man, Jie Zhai, Xiaowen Genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in China using exon sequencing |
title | Genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in China using exon sequencing |
title_full | Genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in China using exon sequencing |
title_fullStr | Genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in China using exon sequencing |
title_full_unstemmed | Genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in China using exon sequencing |
title_short | Genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in China using exon sequencing |
title_sort | genetic mutational analysis of pediatric acute lymphoblastic leukemia from a single center in china using exon sequencing |
topic | Research Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC7068927/ https://www.ncbi.nlm.nih.gov/pubmed/32164600 http://dx.doi.org/10.1186/s12885-020-6709-7 |
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