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

Abstract

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.

• Authors: Russell J H Ryan, Mai Nitta, Darrell Borger, Lawrence R Zukerberg, Judith A Ferry, Nancy Lee Harris, A John Iafrate, Bradley E Bernstein, Aliyah R Sohani, Long Phi Le
• Journal: PloS one (PLoS One) Vol. 6 Issue 12 Pg. e28585 ( 2011) ISSN: 1932-6203 [Electronic] United States
• PMID: 22194861 (Publication Type: Journal Article, Research Support, Non-U.S. Gov't)

Chemical References

• Codon
• DNA-Binding Proteins
• Mutant Proteins
• Proto-Oncogene Proteins c-bcl-2
• Transcription Factors
• EZH2 protein, human
• Enhancer of Zeste Homolog 2 Protein
• Polycomb Repressive Complex 2

Topics

• Animals
• Blotting, Western
• Codon (genetics)
• DNA-Binding Proteins (genetics)
• Enhancer of Zeste Homolog 2 Protein
• Fibroblasts (metabolism)
• Gene Rearrangement (genetics)
• Germinal Center (metabolism, pathology)
• Humans
• Lymphoma, B-Cell (genetics)
• Mice
• Mutant Proteins (metabolism)
• Mutation (genetics)
• NIH 3T3 Cells
• Polycomb Repressive Complex 2
• Polymorphism, Single Nucleotide (genetics)
• Proto-Oncogene Proteins c-bcl-2 (genetics)
• Transcription Factors (genetics)