Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical...
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Language: | English |
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Taylor & Francis Group
2021-01-01
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Series: | OncoImmunology |
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Online Access: | http://dx.doi.org/10.1080/2162402X.2021.1928365 |
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DOAJ |
language |
English |
format |
Article |
sources |
DOAJ |
author |
Hua You Zijun Y. Xu-Monette Li Wei Harry Nunns Máté L. Nagy Govind Bhagat Xiaosheng Fang Feng Zhu Carlo Visco Alexandar Tzankov Karen Dybkaer April Chiu Wayne Tam Youli Zu Eric D. Hsi Fredrick B. Hagemeister Jooryung Huh Maurilio Ponzoni Andrés J.M. Ferreri Michael B. Møller Benjamin M. Parsons J. Han Van Krieken Miguel A. Piris Jane N. Winter Yong Li Qingyan Au Bing Xu Maher Albitar Ken H. Young |
spellingShingle |
Hua You Zijun Y. Xu-Monette Li Wei Harry Nunns Máté L. Nagy Govind Bhagat Xiaosheng Fang Feng Zhu Carlo Visco Alexandar Tzankov Karen Dybkaer April Chiu Wayne Tam Youli Zu Eric D. Hsi Fredrick B. Hagemeister Jooryung Huh Maurilio Ponzoni Andrés J.M. Ferreri Michael B. Møller Benjamin M. Parsons J. Han Van Krieken Miguel A. Piris Jane N. Winter Yong Li Qingyan Au Bing Xu Maher Albitar Ken H. Young Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma OncoImmunology tumor mutation burden kmt2d genomic instability tumor microenvironment pd-1 pd-l1 tp53 epigenetic dlbcl indel |
author_facet |
Hua You Zijun Y. Xu-Monette Li Wei Harry Nunns Máté L. Nagy Govind Bhagat Xiaosheng Fang Feng Zhu Carlo Visco Alexandar Tzankov Karen Dybkaer April Chiu Wayne Tam Youli Zu Eric D. Hsi Fredrick B. Hagemeister Jooryung Huh Maurilio Ponzoni Andrés J.M. Ferreri Michael B. Møller Benjamin M. Parsons J. Han Van Krieken Miguel A. Piris Jane N. Winter Yong Li Qingyan Au Bing Xu Maher Albitar Ken H. Young |
author_sort |
Hua You |
title |
Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma |
title_short |
Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma |
title_full |
Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma |
title_fullStr |
Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma |
title_full_unstemmed |
Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphoma |
title_sort |
genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large b-cell lymphoma |
publisher |
Taylor & Francis Group |
series |
OncoImmunology |
issn |
2162-402X |
publishDate |
2021-01-01 |
description |
Diffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that KMT2D and TP53 nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUThigh) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type TP53. To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUThigh with decreased T cells in DLBCL patients with wild-type TP53. On the other hand, in overall cohort, MUThigh was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUThigh in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT-KMT2D with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell–like DLBCL with wild-type TP53. Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL. |
topic |
tumor mutation burden kmt2d genomic instability tumor microenvironment pd-1 pd-l1 tp53 epigenetic dlbcl indel |
url |
http://dx.doi.org/10.1080/2162402X.2021.1928365 |
work_keys_str_mv |
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doaj-4cc601ce935d46d6bdaa5d24f1fab4232021-09-06T13:15:34ZengTaylor & Francis GroupOncoImmunology2162-402X2021-01-0110110.1080/2162402X.2021.19283651928365Genomic complexity is associated with epigenetic regulator mutations and poor prognosis in diffuse large B-cell lymphomaHua You0Zijun Y. Xu-Monette1Li Wei2Harry Nunns3Máté L. Nagy4Govind Bhagat5Xiaosheng Fang6Feng Zhu7Carlo Visco8Alexandar Tzankov9Karen Dybkaer10April Chiu11Wayne Tam12Youli Zu13Eric D. Hsi14Fredrick B. Hagemeister15Jooryung Huh16Maurilio Ponzoni17Andrés J.M. Ferreri18Michael B. Møller19Benjamin M. Parsons20J. Han Van Krieken21Miguel A. Piris22Jane N. Winter23Yong Li24Qingyan Au25Bing Xu26Maher Albitar27Ken H. Young28Affiliated Cancer Hospital & Institute of Guangzhou Medical UniversityDuke University Medical CenterAffiliated Cancer Hospital & Institute of Guangzhou Medical UniversityNeoGenomics LaboratoriesNeoGenomics LaboratoriesDepartment of Pathology and Cell Biology, Columbia University Irving Medical Center and New York Presbyterian Hospital, New York, New York, USADuke University Medical CenterDuke University Medical CenterDepartment of Medicine, Section of Hematology, University of VeronaDepartment of Pathology, Institute of Pathology,University Hospital BaselClinical Department, Aalborg University HospitalHematopathology Department, Mayo ClinicDepartment of Pathology, Weill Medical College of Cornell UniversityDepartment of Pathology and Genomic Medicine, The Methodist HospitalDepartment of Pathology, Cleveland ClinicDepartment of Lymphoma and Myeloma, The University of Texas MD Anderson Cancer CenterDepartment of Pathology, Asan Medical Center, Ulsan University College of MedicineLymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific InstituteLymphoma Unit, Department of Onco-Hematology, IRCCS San Raffaele Scientific InstituteDepartment of Pathology, Odense University HospitalHematology & Oncology, Gundersen Lutheran Health SystemDepartment of Pathology, Radboud University Nijmegen Medical CentrePathology Department, Hospital Universitario Marqués de ValdecillaDepartment of Medicine (Hematology and Oncology), Feinberg School of Medicine, Northwestern UniversityDepartment of Medicine, Baylor College of MedicineNeoGenomics LaboratoriesDepartment of Hematology, The First Affiliated Hospital of Xiamen UniversityGenomic Testing Cooperative, LCADuke University Medical CenterDiffuse large B-cell lymphoma (DLBCL) is the most common type of lymphoma with high mutation burdens but a low response rate to immune checkpoint inhibitors. In this study, we performed targeted next-generation sequencing and fluorescent multiplex immunohistochemistry, and investigated the clinical significance and immunological effect of mutation numbers in 424 DLBCL patients treated with standard immunochemotherapy. We found that KMT2D and TP53 nonsynonymous mutations (MUT) were significantly associated with increased nonsynonymous mutation numbers, and that high mutation numbers (MUThigh) were associated with significantly poorer clinical outcome in germinal center B-cell-like DLBCL with wild-type TP53. To understand the underlying mechanisms, we identified a gene-expression profiling signature and the association of MUThigh with decreased T cells in DLBCL patients with wild-type TP53. On the other hand, in overall cohort, MUThigh was associated with lower PD-1 expression in T cells and PD-L1 expression in macrophages, suggesting a positive role of MUThigh in immune responses. Analysis in a whole-exome sequencing dataset of 304 patients deposited by Chapuy et al. validated the correlation of MUT-KMT2D with genomic complexity and the significantly poorer survival associated with higher numbers of genomic single nucleotide variants in activated B-cell–like DLBCL with wild-type TP53. Together, these results suggest that KMT2D inactivation or epigenetic dysregulation has a role in driving DLBCL genomic instability, and that genomic complexity has adverse impact on clinical outcome in DLBCL patients with wild-type TP53 treated with standard immunochemotherapy. The oncoimmune data in this study have important implications for biomarker and therapeutic studies in DLBCL.http://dx.doi.org/10.1080/2162402X.2021.1928365tumor mutation burdenkmt2dgenomic instabilitytumor microenvironmentpd-1pd-l1tp53epigeneticdlbclindel |