EZH2
Overview
EZH2 encodes a histone methyltransferase that is a component of the polycomb repressive complex 2 (PRC2). This gene is recurrently mutated in both FL and DLBCL and has a common mutation hot spot (Y646) that affects the SET domain.1 Mutations of this residue and some of the less common hotspots lead to enhanced methylation by PRC2.2,3 Pharmacologic inhibitors of this activity such as tazemetostat have shown benefit in FL.3
Relevance tier by entity
| Entity | Tier | Description |
|---|---|---|
| BL | 2 | relevance in BL not firmly established |
| DLBCL | 1 | high-confidence DLBCL gene |
| FL | 1 | high-confidence FL gene |
Mutation incidence in large patient cohorts (GAMBL reanalysis)
| Entity | source | frequency (%) |
|---|---|---|
| BL | GAMBL genomes+capture | 3.46 |
| BL | Thomas cohort | 1.30 |
| BL | Panea cohort | 10.90 |
| DLBCL | GAMBL genomes | 13.77 |
| DLBCL | Schmitz cohort | 9.15 |
| DLBCL | Reddy cohort | 8.91 |
| DLBCL | Chapuy cohort | 5.56 |
| FL | GAMBL genomes | 24.94 |
Mutation pattern and selective pressure estimates
| Entity | aSHM | Significant selection | dN/dS (missense) | dN/dS (nonsense) |
|---|---|---|---|---|
| BL | No | No | 4.992 | 0 |
| DLBCL | No | Yes | 19.753 | 0 |
| FL | No | Yes | 117.987 | 0 |
[!NOTE] First described in BL in 2012 by Love C. First described in DLBCL in 2010 by Morin RD. First described in FL in 2010 by Morin RD
## EZH2 Hotspots
| Chromosome | Coordinate (hg19) | ref>alt | HGVSp |
|---|---|---|---|
| chr7 | 148508745 | T>C | N640S |
| chr7 | 148508740 | A>G | F642L |
| chr7 | 148508728 | A>T | Y646N |
| chr7 | 148508728 | A>G | Y646H |
| chr7 | 148508727 | T>G | Y646S |
| chr7 | 148508727 | T>C | Y646C |
| chr7 | 148508727 | T>A | Y646F |
| chr7 | 148506466 | TG>GC | A682G |
| chr7 | 148506467 | G>C | A682G |
| chr7 | 148506437 | GC>AA | A692L |
| chr7 | 148506437 | G>A | A692V |
View coding variants in ProteinPaint hg19 or hg38
View all variants in GenomePaint hg19 or hg38
References
- Morin RD, Johnson NA, Severson TM, Mungall AJ, An J, Goya R, Paul JE, Boyle M, Woolcock BW, Kuchenbauer F, Yap D, Humphries RK, Griffith OL, Shah S, Zhu H, Kimbara M, Shashkin P, Charlot JF, Tcherpakov M, Corbett R, Tam A, Varhol R, Smailus D, Moksa M, Zhao Y, Delaney A, Qian H, Birol I, Schein J, Moore R, Holt R, Horsman DE, Connors JM, Jones S, Aparicio S, Hirst M, Gascoyne RD, Marra MA. Somatic mutations altering EZH2 (Tyr641) in follicular and diffuse large B-cell lymphomas of germinal-center origin. Nat Genet. 2010 Feb;42(2):181-5. doi: 10.1038/ng.518. Epub 2010 Jan 17. PMID: 20081860; PMCID: PMC2850970.
- Yap DB, Chu J, Berg T, Schapira M, Cheng SW, Moradian A, Morin RD, Mungall AJ, Meissner B, Boyle M, Marquez VE, Marra MA, Gascoyne RD, Humphries RK, Arrowsmith CH, Morin GB, Aparicio SA. Somatic mutations at EZH2 Y641 act dominantly through a mechanism of selectively altered PRC2 catalytic activity, to increase H3K27 trimethylation. Blood. 2011 Feb 24;117(8):2451-9. doi: 10.1182/blood-2010-11-321208. Epub 2010 Dec 29. PMID: 21190999; PMCID: PMC3062411.
- Morin RD, Arthur SE, Assouline S. Treating lymphoma is now a bit EZ-er. Blood Adv. 2021 Apr 27;5(8):2256-2263. doi: 10.1182/bloodadvances.2020002773. PMID: 33904892; PMCID: PMC8095133.
Citing
If you use the information or data from this site, please cite
Krysta Coyle, Kostiantyn Dreval, Daniel Hodson and Ryan D. Morin. Audit of B-cell cancer genes. Blood Adv (2025) 9 (8): 2019–2031.
Disclaimer
The content in these pages has been populated, in part, by an automated process. Although we have scrutinized every page to ensure accuracy, errors will inevitably exist. If you find an error please report it as an issue and we will address it.
License
This work is licensed under a Creative Commons Attribution 4.0 International License.
You are free to:
Share — copy and redistribute the material in any medium or format for any purpose, even commercially.
Adapt — remix, transform, and build upon the material for any purpose, even commercially. The licensor cannot revoke these freedoms as long as you follow the license terms.
