Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma
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Follicular lymphoma (FL) and diffuse large B-cell lymphoma (DLBCL) are the two most common non-Hodgkin lymphomas (NHLs). Here we sequenced tumour and matched normal DNA from 13 DLBCL cases and one FL case to identify genes with mutations in B-cell NHL. We analysed RNA-seq data from these and another 113 NHLs to identify genes with candidate mutations, and then re-sequenced tumour and matched normal DNA from these cases to confirm 109 genes with multiple somatic mutations. Genes with roles in histone modification were frequent targets of somatic mutation. For example, 32% of DLBCL and 89% of FL cases had somatic mutations in MLL2, which encodes a histone methyltransferase, and 11.4% and 13.4% of DLBCL and FL cases, respectively, had mutations in MEF2B, a calcium-regulated gene that cooperates with CREBBP and EP300 in acetylating histones. Our analysis suggests a previously unappreciated disruption of chromatin biology in lymphomagenesis. Despite being a focus of research activity for many years, the mutations driving the two most common non-Hodgkin lymphomas — follicular lymphoma and diffuse large B-cell lymphoma — have remained cryptic. Whole genome sequencing, combined with transcriptome analysis and further resequencing of candidate genes in additional tumours, now show that histone methyltransferases and acetylases are frequently affected by mutations in these tumours. This study suggests a previously unappreciated importance of chromatin biology in lymphomagenesis.
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Follicular lymphomas and diffuse large B-cell lymphomas frequently accumulate mutations in epigenetic regulators, including CREBBP and EP300.
“Follicular lymphomas and diffuse large B-cell lymphomas frequently accumulate mutations in epigenetic regulators, including the HATs CREBBP and EP300 (Morin et al., 2011).”
From HDACs and the epigenetic plasticity of cancer cells: target the complexity (2022) · cites this paper as Morin et al., 2011
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Single-cell transcriptogenomics reveals transcriptional exclusion of ENU-mutated alleles
Li, W., Calder, R. B., Mar, J. C., & Vijg, J. (2015) · Mutation Research - Fundamental and Molecular Mechanisms of Mutagenesis · doi:10.1016/j.mrfmmm.2015.01.002 · Cited by 34 · see citing works
- Authors
- Morin, R. D., Mendez-Lago, M., Mungall, A. J., Goya, R., Mungall, K. L., Corbett, R. D., Johnson, N. A., Severson, T. M., Chiu, R., Field, M., Jackman, S., Krzywinski, M., Scott, D. W., Trinh, D. L., Tamura-Wells, J., Li, S., Firme, M. R., Rogic, S., Griffith, M., Chan, S., Yakovenko, O., Meyer, I. M., Zhao, E. Y., Smailus, D., Moksa, M., Chittaranjan, S., Rimsza, L., Brooks-Wilson, A., Spinelli, J. J., Ben-Neriah, S., Meissner, B., Woolcock, B., Boyle, M., McDonald, H., Tam, A., Zhao, Y., Delaney, A., Zeng, T., Tse, K., Butterfield, Y., Birol, I., Holt, R., Schein, J., Horsman, D. E., Moore, R., Jones, S. J. M., Connors, J. M., Hirst, M., Gascoyne, R. D., & Marra, M. A.
- Affiliations
- BC Cancer Agency (CA)
- University of British Columbia (CA)
- University of Arizona (US)
- Corresponding author
- Marra, Marco A.
- ORCID
- Morin, Ryan D.
- Mungall, Andrew J.
- Mungall, Karen L.
- Johnson, Nathalie A.
- Severson, Tesa M.
- Chiu, Readman
- Field, Matthew
- Jackman, Shaun
- Krzywinski, Martin
- Scott, David W.
- Trinh, Diane L.
- Griffith, Malachi
- Yakovenko, Oleksandr
- Meyer, Irmtraud M.
- Smailus, Duane
- Moksa, Michelle
- Rimsza, Lisa
- Brooks-Wilson, Angela
- Spinelli, John J.
- Meissner, Barbara
- Woolcock, Bruce
- Boyle, Merrill
- Tam, Angela
- Zhao, Yongjun
- Moore, Richard
- Jones, Steven J. M.
- Connors, Joseph M.
- Hirst, Martin
- Gascoyne, Randy D.
- Marra, Marco A.
- Venue
- Nature
- Published
- 2011-07-27
- Volume
- 476
- Issue
- 7360
- Pages
- 298-303
- ISSN
- 0028-0836 (ISSN-L)
- 1476-4687
- PMC
- PMC3210554
- OpenAlex
- W2003262666
- Cited by
- 1,614
- References
- 50
- Citations by year
- 2026: 24 · 2025: 43 · 2024: 77 · 2023: 103 · 2022: 101 · 2021: 113 · 2020: 112 · 2019: 106 · 2018: 103 · 2017: 121 · 2016: 132 · 2015: 134 · 2014: 132 · 2013: 170 · 2012: 118
- FWCI
- 98.11
- Type
- journal article
- Language
- en
- Open access
- hybrid
- doi.org
- Licence
- Locations
- Nature (publishedVersion, cc-by-nc-sa)
- PubMed (publishedVersion)
- Europe PMC (PubMed Central) (acceptedVersion)
- PubMed Central (acceptedVersion)
- ResearchOnline at James Cook University (James Cook University) (submittedVersion)
- RePEc: Research Papers in Economics (submittedVersion)
- MDC Repository (Max-Delbrueck-Center for Molecular Medicine) (submittedVersion)
- ANU Open Research (Australian National University) (submittedVersion)
- Funders
- U.S. Department of Health and Human Services (HHSN261200800001E)
- Leukemia and Lymphoma Society
- Genome Canada
- Canada's Michael Smith Genome Sciences Centre
- Michael Smith Health Research BC
- Genome British Columbia
- Terry Fox Foundation (019001)
- Provincial Health Services Authority
- National Institutes of Health (Contract No. HHSN261200800001E., #HHSN261200800001E, HHSN261200800001C, 5u01ca114778-05)
- Canadian Institutes of Health Research (53912, TGT-53 912)
- National Cancer Institute (No. HHSN261200800001E, U01-CA-114778, Contract No.,HHSN261200800001E, P50CA130805, HHSN261200800001E), 1U01CA114778, U24CA143866)
- Topics
- Health Sciences › Medicine › Pathology and Forensic Medicine › Lymphoma Diagnosis and Treatment
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Genomics and Chromatin Dynamics
- Life Sciences › Biochemistry, Genetics and Molecular Biology › Molecular Biology › Chromatin Remodeling and Cancer
- Keywords
- non-Hodgkin lymphoma, follicular lymphoma, diffuse large B-cell lymphoma, somatic mutations, KMT2D, MEF2B, histone methyltransferase, histone acetyltransferase, CREB-binding protein, EP300, chromatin biology, lymphomagenesis, driver mutations
- MeSH terms
- Histone Methyltransferases, Chromatin, DNA-Binding Proteins, Histones, Humans, Lymphoma, Follicular, Lymphoma, Non-Hodgkin, Mutation, Neoplasm Proteins, Histone-Lysine N-Methyltransferase, Genome, Human, Lymphoma, Large B-Cell, Diffuse, Myogenic Regulatory Factors, Loss of Heterozygosity, MADS Domain Proteins, Histone Acetyltransferases, MEF2 Transcription Factors
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