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Genetic heterogeneity and mutational signature in Chinese Epstein-Barr virus-positive diffuse large B-cell lymphoma

Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is typically an aggressive tumor in elderly patients. However, in a subset of young patients, EBV+ DLBCL follows a relatively indolent clinical course and exhibits a good response to chemotherapy. This lymphoma comprises po...

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Autores principales: Liu, Fang, Wang, Zhe, Zhou, Xiaoge, Liu, Qing, Chen, Gang, Xiao, Hualiang, Yin, Weihua, Nakamura, Shigeo, Rao, Huilan
Formato: Online Artículo Texto
Lenguaje:English
Publicado: Public Library of Science 2018
Materias:
Acceso en línea:https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091946/
https://www.ncbi.nlm.nih.gov/pubmed/30106962
http://dx.doi.org/10.1371/journal.pone.0201546
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author Liu, Fang
Wang, Zhe
Zhou, Xiaoge
Liu, Qing
Chen, Gang
Xiao, Hualiang
Yin, Weihua
Nakamura, Shigeo
Rao, Huilan
author_facet Liu, Fang
Wang, Zhe
Zhou, Xiaoge
Liu, Qing
Chen, Gang
Xiao, Hualiang
Yin, Weihua
Nakamura, Shigeo
Rao, Huilan
author_sort Liu, Fang
collection PubMed
description Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is typically an aggressive tumor in elderly patients. However, in a subset of young patients, EBV+ DLBCL follows a relatively indolent clinical course and exhibits a good response to chemotherapy. This lymphoma comprises polymorphous lymphoma and large cell lymphomas subtypes, with the latter subtype showing a significantly poorer prognosis. It is unknown whether the genetic background differs between age groups and histopathological subtypes. To investigate the genetic basis, heterogeneity, and recurrently mutated genes in EBV+ DLBCL, we performed whole-exome sequencing of DNA from 11 tissue samples of this lymphoma. Sequencing revealed that the most common substitution was the transition C>T/G>A. Genetic features—including the numbers of mutated genes in exonic region, single-nucleotide variants (SNV), and indels—did not significantly differ between age groups or histological subtypes. Matching with the COSMIC database revealed that the main mutational signature was signature 3, which is associated with failure of DNA double-strand break-repair by homologous recombination. Mutant-Allele Tumor Heterogeneity (MATH) scores showed that EBV+ DLBCL exhibited broad intratumor heterogeneity, and were positively correlated with Ann Arbor Stage and ≥2 extranodal lesion sites. We identified 57 selected recurrently mutated genes. The most commonly mutated five genes—LNP1 (11/11), PRSS3 (10/11), MUC3A (9/11), FADS6 (9/11), and TRAK1 (8/11)—were validated by Sanger sequencing. These mutated genes have not previously been identified. Overall, our present results demonstrate the tremendous genetic heterogeneity underlying EBV+ DLBCLs, and highlight the need for personalized therapeutic approaches to treating these patients.
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spelling pubmed-60919462018-08-30 Genetic heterogeneity and mutational signature in Chinese Epstein-Barr virus-positive diffuse large B-cell lymphoma Liu, Fang Wang, Zhe Zhou, Xiaoge Liu, Qing Chen, Gang Xiao, Hualiang Yin, Weihua Nakamura, Shigeo Rao, Huilan PLoS One Research Article Epstein-Barr virus (EBV)-positive diffuse large B-cell lymphoma (EBV+ DLBCL) is typically an aggressive tumor in elderly patients. However, in a subset of young patients, EBV+ DLBCL follows a relatively indolent clinical course and exhibits a good response to chemotherapy. This lymphoma comprises polymorphous lymphoma and large cell lymphomas subtypes, with the latter subtype showing a significantly poorer prognosis. It is unknown whether the genetic background differs between age groups and histopathological subtypes. To investigate the genetic basis, heterogeneity, and recurrently mutated genes in EBV+ DLBCL, we performed whole-exome sequencing of DNA from 11 tissue samples of this lymphoma. Sequencing revealed that the most common substitution was the transition C>T/G>A. Genetic features—including the numbers of mutated genes in exonic region, single-nucleotide variants (SNV), and indels—did not significantly differ between age groups or histological subtypes. Matching with the COSMIC database revealed that the main mutational signature was signature 3, which is associated with failure of DNA double-strand break-repair by homologous recombination. Mutant-Allele Tumor Heterogeneity (MATH) scores showed that EBV+ DLBCL exhibited broad intratumor heterogeneity, and were positively correlated with Ann Arbor Stage and ≥2 extranodal lesion sites. We identified 57 selected recurrently mutated genes. The most commonly mutated five genes—LNP1 (11/11), PRSS3 (10/11), MUC3A (9/11), FADS6 (9/11), and TRAK1 (8/11)—were validated by Sanger sequencing. These mutated genes have not previously been identified. Overall, our present results demonstrate the tremendous genetic heterogeneity underlying EBV+ DLBCLs, and highlight the need for personalized therapeutic approaches to treating these patients. Public Library of Science 2018-08-14 /pmc/articles/PMC6091946/ /pubmed/30106962 http://dx.doi.org/10.1371/journal.pone.0201546 Text en © 2018 Liu et al http://creativecommons.org/licenses/by/4.0/ This is an open access article distributed under the terms of the Creative Commons Attribution License (http://creativecommons.org/licenses/by/4.0/) , which permits unrestricted use, distribution, and reproduction in any medium, provided the original author and source are credited.
spellingShingle Research Article
Liu, Fang
Wang, Zhe
Zhou, Xiaoge
Liu, Qing
Chen, Gang
Xiao, Hualiang
Yin, Weihua
Nakamura, Shigeo
Rao, Huilan
Genetic heterogeneity and mutational signature in Chinese Epstein-Barr virus-positive diffuse large B-cell lymphoma
title Genetic heterogeneity and mutational signature in Chinese Epstein-Barr virus-positive diffuse large B-cell lymphoma
title_full Genetic heterogeneity and mutational signature in Chinese Epstein-Barr virus-positive diffuse large B-cell lymphoma
title_fullStr Genetic heterogeneity and mutational signature in Chinese Epstein-Barr virus-positive diffuse large B-cell lymphoma
title_full_unstemmed Genetic heterogeneity and mutational signature in Chinese Epstein-Barr virus-positive diffuse large B-cell lymphoma
title_short Genetic heterogeneity and mutational signature in Chinese Epstein-Barr virus-positive diffuse large B-cell lymphoma
title_sort genetic heterogeneity and mutational signature in chinese epstein-barr virus-positive diffuse large b-cell lymphoma
topic Research Article
url https://www.ncbi.nlm.nih.gov/pmc/articles/PMC6091946/
https://www.ncbi.nlm.nih.gov/pubmed/30106962
http://dx.doi.org/10.1371/journal.pone.0201546
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