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Frequent mutation of histone-modifying genes in non-Hodgkin lymphoma

2011; Nature Portfolio; Volume: 476; Issue: 7360 Linguagem: Inglês

10.1038/nature10351

1476-4687

Ryan D. Morin, María Méndez-Lago, Andrew J. Mungall, Rodrigo Goya, Karen Mungall, Richard Corbett, Nathalie A. Johnson, Tesa Severson, Readman Chiu, Matthew A. Field, Shaun D. Jackman, Martin Krzywinski, David W. Scott, Diane L. Trinh, Jessica Tamura‐Wells, Sa Li, Marlo Firme, Sanja Rogić, Malachi Griffith, Susanna Chan, Oleksandr Yakovenko, Irmtraud M. Meyer, Eric Y. Stutheit-Zhao, Duane E. Smailus, Michelle Moksa, Suganthi Chittaranjan, Lisa M. Rimsza, Angela Brooks‐Wilson, John J. Spinelli, Susana Ben‐Neriah, Barbara Meissner, Bruce W. Woolcock, Merrill Boyle, Helen McDonald, Angela Tam, Yongjun Zhao, Allen Delaney, Thomas Zeng, Kane Tse, Yaron S.N. Butterfield, İnanç Birol, Robert A. Holt, Jacqueline E. Schein, Douglas E. Horsman, Richard A. Moore, Steven J.M. Jones, Joseph M. Connors, Martin Hirst, Randy D. Gascoyne, Marco A. Marra,

Epigenetics and DNA Methylation

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.