EZH2 codon 641 mutations are common in BCL2-rearranged germinal center B cell lymphomas

• Published in: PloS one Vol. 6; no. 12; p. e28585
• Main Authors: Ryan, Russell J H, Nitta, Mai, Borger, Darrell, Zukerberg, Lawrence R, Ferry, Judith A, Harris, Nancy Lee, Iafrate, A John, Bernstein, Bradley E, Sohani, Aliyah R, Le, Long Phi
• Format: Journal Article
• Language: English
• Published: United States Public Library of Science 14-12-2011; Public Library of Science (PLoS)
• Subjects: Animals; B cells; B-cell lymphoma; Biology; Blotting, Western; Burkitt's lymphoma; Cancer; Cancer therapies; Care and treatment; Chromatin; Clinical trials; Codon; Codon - genetics; Diagnosis; DNA-Binding Proteins - genetics; Drosophila; Enhancer of Zeste Homolog 2 Protein; Enzymatic activity; Enzymes; Epidermal growth factor; Fibroblasts - metabolism; Gene expression; Gene Rearrangement - genetics; Genetic aspects; Genomes; Genomics; Genotype & phenotype; Germinal Center - metabolism; Germinal Center - pathology; Germinal centers; Health aspects; Histone H3; Humans; Insects; Lung cancer; Lymphocytes B; Lymphoma; Lymphoma, B-Cell - genetics; Lymphomas; Lysine; Medical research; Medicine; Melanoma; Metastasis; Methylation; Mice; Mutant Proteins - metabolism; Mutation; Mutation - genetics; Myc protein; NIH 3T3 Cells; Non-Hodgkin's lymphomas; Pathology; Patients; Pharmacology; Polycomb Repressive Complex 2; Polymorphism, Single Nucleotide - genetics; Proto-Oncogene Proteins c-bcl-2 - genetics; Saccharomyces cerevisiae; Screening; Transcription Factors - genetics; United States > US; Massachusetts
• ISSN: 1932-6203; 1932-6203
• DOI: 10.1371/journal.pone.0028585

Mutations at codon 641 of EZH2 are recurrent in germinal center B cell lymphomas, and the most common variants lead to altered EZH2 enzymatic activity and enhanced tri-methylation of histone H3 at lysine 27, a repressive chromatin modification. As an initial step toward screening patients for cancer genotype-directed therapy, we developed a screening assay for EZH2 codon 641 mutations amenable for testing formalin-fixed clinical specimens, based on the sensitive SNaPshot single nucleotide extension technology. We detected EZH2 mutations in 12/55 (22%) follicular lymphomas (FL), 5/35 (14%) diffuse large B cell lymphomas with a germinal center immunophenotype (GCB-DLBCL), and 2/11 (18%) high grade B cell lymphomas with concurrent rearrangements of BCL2 and MYC. No EZH2 mutations were detected in cases of Burkitt lymphoma (0/23). EZH2 mutations were frequently associated with the presence of BCL2 rearrangement (BCL2-R) in both the FL (28% of BCL-R cases versus 0% of BCL2-WT cases, p<0.05) and GCB-DLBCL groups (33% of BCL2-R cases versus 4% of BCL2-WT cases, p<0.04), and across all lymphoma types excluding BL (27% of BCL2-R cases versus 3% of BCL2-WT cases, p<0.003). We confirmed gain-of-function activity for all previously reported EZH2 codon 641 mutation variants. Our findings suggest that EZH2 mutations constitute an additional genetic "hit" in many BCL2-rearranged germinal center B cell lymphomas. Our work may be helpful in the selection of lymphoma patients for future trials of pharmacologic agents targeting EZH2 and EZH2-regulated pathways.