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genes/EZH2.md
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| 1 | +--- |
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| 2 | +bibliography: 'morinlab.bib' |
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| 3 | +csl: 'NLM.csl' |
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| 4 | +link-citations: true |
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| 5 | +nocite: | |
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| 6 | + @mottokIntegrativeGenomicAnalysis2019, @morinSomaticMutationsAltering2010, @loveGeneticLandscapeMutations2012 |
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| 7 | +--- |
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| 8 | +[[_TOC_]] |
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| 9 | + |
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| 10 | +## Overview |
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| 11 | +EZH2 encodes a histone methyltransferase that is a component of the polycomb repressive complex 2 (PRC2). |
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| 12 | +This gene is recurrently mutated in both FL and DLBCL and has a common mutation hot spot (Y646) that affects the SET domain.[@morinSomaticMutationsAltering2010] |
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| 13 | +EZH2 mutations are one of the defining features of the EZB genetic subgroup of DLBCL.[@wrightProbabilisticClassificationTool2020] |
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| 14 | +Although mutations in EZH2 have been described in some BL patients, they are extremely rare in most BL cohorts that have been sequenced.[@loveGeneticLandscapeMutations2012; @thomasGeneticSubgroupsInform2023] |
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| 15 | + |
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| 16 | + |
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| 17 | +## Experimental Evidence |
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| 18 | + |
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| 19 | +Mutations at the main hotspot and some less common hotspots lead to enhanced methylation by PRC2.[@yapSomaticMutationsEZH22011] |
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| 20 | +A number of small molecule/pharmacologic inhibitors of EZH2 activity have been described.[@garapaty-raoIdentificationEZH2EZH12013; @knutsonSelectiveInhibitionEZH22014] At least one of these, tazemetostat, has shown benefit in FL.[@morinTreatingLymphomaNow2021] |
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| 21 | +Combination therapies including EZH2 inhibitors are also under exploration for DLBCL patients with mutant EZH2.[@scholzeCombinedEZH2Bcl22020] |
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| 22 | + |
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| 23 | + |
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| 24 | +## Relevance tier by entity |
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| 25 | + |
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| 26 | +[[include:tables/table1_EZH2]] |
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| 27 | + |
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| 28 | +## Mutation incidence in large patient cohorts (GAMBL reanalysis) |
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| 29 | + |
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| 30 | + |
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| 31 | +### DLBCL |
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| 32 | +[[include:tables/DLBCL_EZH2.md]] |
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| 33 | + |
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| 34 | +### FL |
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| 35 | +[[include:tables/FL_EZH2.md]] |
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| 36 | + |
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| 37 | +### BL |
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| 38 | +[[include:tables/BL_EZH2.md]] |
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| 39 | + |
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| 40 | + |
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| 41 | +## Mutation pattern and selective pressure estimates |
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| 42 | + |
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| 43 | +[[include:tables/dnds_EZH2.md]] |
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| 44 | + |
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| 45 | +## EZH2 Hotspots |
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| 46 | + |
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| 47 | +| Chromosome |Coordinate (hg19) | ref>alt | HGVSp | |
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| 48 | + | :---:| :---: | :--: | :---: | |
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| 49 | +| chr7 | 148508745 | T>C | N640S | |
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| 50 | +|chr7|148508740|A>G|F642L| |
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| 51 | +| chr7 | 148508728 | A>T | Y646N | |
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| 52 | +| chr7 | 148508728 | A>G | Y646H | |
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| 53 | +| chr7 | 148508727 | T>G | Y646S | |
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| 54 | +| chr7 | 148508727 | T>C | Y646C | |
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| 55 | +| chr7 | 148508727 | T>A | Y646F | |
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| 56 | +|chr7|148506466|TG>GC|A682G| |
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| 57 | +|chr7|148506467|G>C|A682G| |
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| 58 | +|chr7|148506437|GC>AA|A692L| |
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| 59 | +|chr7|148506437|G>A|A692V| |
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| 60 | + |
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| 61 | +[[include:tables/browser_EZH2.md]] |
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| 62 | + |
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| 63 | +## Expression |
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| 64 | + |
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| 65 | + |
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| 66 | +## Representative Mutations |
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| 67 | + |
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| 68 | +### BL |
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| 69 | + |
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| 70 | + |
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| 71 | +**Rating** |
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| 72 | +★ ★ ★ ★ ★ |
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| 73 | + |
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| 74 | +## All Mutations |
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| 75 | + |
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| 76 | +### BL |
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| 77 | + |
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| 78 | +[@loveGeneticLandscapeMutations2012] |
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| 79 | + |
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| 80 | +[1092](https://www.bcgsc.ca/downloads/morinlab/GAMBL/Love/1092_reports.html) |
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| 81 | +[671](https://www.bcgsc.ca/downloads/morinlab/GAMBL/Love/671_reports.html) |
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| 82 | +[672](https://www.bcgsc.ca/downloads/morinlab/GAMBL/Love/672_reports.html) |
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| 83 | +[675](https://www.bcgsc.ca/downloads/morinlab/GAMBL/Love/675_reports.html) |
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| 84 | + |
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| 85 | +<!-- ORIGIN: morinSomaticMutationsAltering2010 --> |
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| 86 | +<!-- BL: loveGeneticLandscapeMutations2012 --> |
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| 87 | +<!-- FL: morinSomaticMutationsAltering2010a --> |
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| 88 | +<!-- BL: loveGeneticLandscapeMutations2012 --> |
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| 89 | +<!-- DLBCL: morinSomaticMutationsAltering2010 --> |
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| 90 | +<!-- PMBL: mottokIntegrativeGenomicAnalysis2019b --> |
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| 91 | + |
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| 92 | +[[include:tables/mermaid_EZH2.md]] |
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| 93 | + |
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| 94 | +## References |
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| 95 | + |