fix columns

+<p>[[<em>TOC</em>]]</p>

+<h2 id="overview">Overview</h2>

+<p>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.<span class="citation"

+data-cites="morinSomaticMutationsAltering2010"><sup><a

+href="#ref-morinSomaticMutationsAltering2010"

+role="doc-biblioref">1</a></sup></span> EZH2 mutations are one of the

+defining features of the EZB genetic subgroup of DLBCL.<span

+class="citation"

+data-cites="wrightProbabilisticClassificationTool2020"><sup><a

+href="#ref-wrightProbabilisticClassificationTool2020"

+role="doc-biblioref">2</a></sup></span> Although mutations in EZH2 have

+been described in some BL patients, they are extremely rare in most BL

+cohorts that have been sequenced.<span class="citation"

+data-cites="loveGeneticLandscapeMutations2012 thomasGeneticSubgroupsInform2023"><sup><a

+href="#ref-loveGeneticLandscapeMutations2012"

+role="doc-biblioref">3</a>,<a

+href="#ref-thomasGeneticSubgroupsInform2023"

+role="doc-biblioref">4</a></sup></span></p>

+<h2 id="experimental-evidence">Experimental Evidence</h2>

+<p>Mutations at the canonical hotspot (Y646) and some less common

+hotspots lead to enhanced histone H3 lysince 27 (H3K27) tri-methylation

+by PRC2.<span class="citation"

+data-cites="yapSomaticMutationsEZH22011"><sup><a

+href="#ref-yapSomaticMutationsEZH22011"

+role="doc-biblioref">5</a></sup></span></p>

+<h2 id="clinical-relevance">Clinical Relevance</h2>

+<p>A number of small molecule/pharmacologic inhibitors of EZH2 activity

+have been described.<span class="citation"

+data-cites="garapaty-raoIdentificationEZH2EZH12013 knutsonSelectiveInhibitionEZH22014"><sup><a

+href="#ref-garapaty-raoIdentificationEZH2EZH12013"

+role="doc-biblioref">6</a>,<a

+href="#ref-knutsonSelectiveInhibitionEZH22014"

+role="doc-biblioref">7</a></sup></span> At least one of these,

+tazemetostat, has shown benefit in FL.<span class="citation"

+data-cites="morinTreatingLymphomaNow2021"><sup><a

+href="#ref-morinTreatingLymphomaNow2021"

+role="doc-biblioref">8</a></sup></span> Tazemetostat (TAZVERIK) has <a

+href="https://www.fda.gov/drugs/fda-granted-accelerated-approval-tazemetostat-follicular-lymphoma">FDA

+approval</a> <em>for adult patients with relapsed or refractory (R/R)

+follicular lymphoma (FL) whose tumors are positive for an EZH2 mutation

+as detected by an FDA-approved test and who have received at least 2

+prior systemic therapies, and for adult patients with R/R FL who have no

+satisfactory alternative treatment options.</em> Combination therapies

+including EZH2 inhibitors are also under exploration for DLBCL patients

+with mutant EZH2.<span class="citation"

+data-cites="scholzeCombinedEZH2Bcl22020"><sup><a

+href="#ref-scholzeCombinedEZH2Bcl22020"

+role="doc-biblioref">9</a></sup></span></p>

+<h2 id="relevance-tier-by-entity">Relevance tier by entity</h2>

+<p>[[include:tables/table1_EZH2]]</p>

+<h2

+id="mutation-incidence-in-large-patient-cohorts-gambl-reanalysis">Mutation

+incidence in large patient cohorts (GAMBL reanalysis)</h2>

+<h3 id="dlbcl">DLBCL</h3>

+<p>[[include:tables/DLBCL_EZH2.md]]</p>

+<h3 id="fl">FL</h3>

+<p>[[include:tables/FL_EZH2.md]]</p>

+<h3 id="bl">BL</h3>

+<p>[[include:tables/BL_EZH2.md]]</p>

+<h2 id="mutation-pattern-and-selective-pressure-estimates">Mutation

+pattern and selective pressure estimates</h2>

+<p>[[include:tables/dnds_EZH2.md]]</p>

+<h2 id="ezh2-hotspots">EZH2 Hotspots</h2>

+<table>

+<thead>

+<tr>

+<th style="text-align: center;">Chromosome</th>

+<th style="text-align: center;">Coordinate (hg19)</th>

+<th style="text-align: center;">ref&gt;alt</th>

+<th style="text-align: center;">HGVSp</th>

+</tr>

+</thead>

+<tbody>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148508745</td>

+<td style="text-align: center;">T&gt;C</td>

+<td style="text-align: center;">N640S</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148508740</td>

+<td style="text-align: center;">A&gt;G</td>

+<td style="text-align: center;">F642L</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148508728</td>

+<td style="text-align: center;">A&gt;T</td>

+<td style="text-align: center;">Y646N</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148508728</td>

+<td style="text-align: center;">A&gt;G</td>

+<td style="text-align: center;">Y646H</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148508727</td>

+<td style="text-align: center;">T&gt;G</td>

+<td style="text-align: center;">Y646S</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148508727</td>

+<td style="text-align: center;">T&gt;C</td>

+<td style="text-align: center;">Y646C</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148508727</td>

+<td style="text-align: center;">T&gt;A</td>

+<td style="text-align: center;">Y646F</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148506466</td>

+<td style="text-align: center;">TG&gt;GC</td>

+<td style="text-align: center;">A682G</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148506467</td>

+<td style="text-align: center;">G&gt;C</td>

+<td style="text-align: center;">A682G</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148506437</td>

+<td style="text-align: center;">GC&gt;AA</td>

+<td style="text-align: center;">A692L</td>

+</tr>

+<tr>

+<td style="text-align: center;">chr7</td>

+<td style="text-align: center;">148506437</td>

+<td style="text-align: center;">G&gt;A</td>

+<td style="text-align: center;">A692V</td>

+</tr>

+</tbody>

+</table>

+<figure>

+<img src="images/hotmaps_3d/EZH2_1.png"

+alt="EZH2 3D structure with HotMAPS hotspots" />

+<figcaption aria-hidden="true">EZH2 3D structure with HotMAPS

+hotspots</figcaption>

+</figure>

+<p>[[include:tables/browser_EZH2.md]]</p>

+<h2 id="expression">Expression</h2>

+<p><img src="images/gene_expression/EZH2_by_pathology.svg" /></p>

+<h2 id="representative-mutations">Representative Mutations</h2>

+<h3 id="bl-1">BL</h3>

+<p><img src="primary/Love_EZH2.svg" /> <strong>Rating</strong> ★ ★ ★ ★

+★</p>

+<h2 id="all-mutations">All Mutations</h2>

+<h3 id="bl-2">BL</h3>

+<p><span class="citation"

+data-cites="loveGeneticLandscapeMutations2012"><sup><a

+href="#ref-loveGeneticLandscapeMutations2012"

+role="doc-biblioref">3</a></sup></span></p>

+<p><a

+href="https://www.bcgsc.ca/downloads/morinlab/GAMBL/Love/1092_reports.html">1092</a>

+<a

+href="https://www.bcgsc.ca/downloads/morinlab/GAMBL/Love/671_reports.html">671</a>

+<a

+href="https://www.bcgsc.ca/downloads/morinlab/GAMBL/Love/672_reports.html">672</a>

+<a

+href="https://www.bcgsc.ca/downloads/morinlab/GAMBL/Love/675_reports.html">675</a></p>

+<!-- ORIGIN: morinSomaticMutationsAltering2010 -->

+<!-- BL: loveGeneticLandscapeMutations2012 -->

+<!-- FL: morinSomaticMutationsAltering2010a -->

+<!-- BL: loveGeneticLandscapeMutations2012 -->

+<!-- DLBCL: morinSomaticMutationsAltering2010 -->

+<!-- PMBL: mottokIntegrativeGenomicAnalysis2019b -->

+<p>[[include:tables/mermaid_EZH2.md]]</p>

+<h2 class="unnumbered" id="references">References</h2>

+<div id="refs" class="references csl-bib-body" role="list">

+<div id="ref-morinSomaticMutationsAltering2010" class="csl-entry"

+role="listitem">

+<div class="csl-left-margin">1. </div><div

+class="csl-right-inline">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 <span>EZH2</span> (<span>Tyr641</span>) in follicular

+and diffuse large <span class="nocase">B-cell</span> lymphomas of

+germinal-center origin. Nat Genet. 2010 Feb;42(2):181–185. PMCID: <a

+href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC2850970">PMC2850970</a></div>

+</div>

+<div id="ref-wrightProbabilisticClassificationTool2020"

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+<div class="csl-left-margin">2. </div><div

+class="csl-right-inline">Wright GW, Huang DW, Phelan JD, Coulibaly ZA,

+Roulland S, Young RM, Wang JQ, Schmitz R, Morin RD, Tang J, Jiang A,

+Bagaev A, Plotnikova O, Kotlov N, Johnson CA, Wilson WH, Scott DW,

+Staudt LM. <a href="https://doi.org/10.1016/j.ccell.2020.03.015">A

+<span>Probabilistic Classification Tool</span> for <span>Genetic

+Subtypes</span> of <span>Diffuse Large B Cell Lymphoma</span> with

+<span>Therapeutic Implications</span></a>. Cancer Cell. 2020 Apr

+13;37(4):551–568.e14. </div>

+</div>

+<div id="ref-loveGeneticLandscapeMutations2012" class="csl-entry"

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+<div class="csl-left-margin">3. </div><div class="csl-right-inline">Love

+C, Sun Z, Jima D, Li G, Zhang J, Miles R, Richards KL, Dunphy CH, Choi

+WWL, Srivastava G, Lugar PL, Rizzieri DA, Lagoo AS, Bernal-Mizrachi L,

+Mann KP, Flowers CR, Naresh KN, Evens AM, Chadburn A, Gordon LI, Czader

+MB, Gill JI, Hsi ED, Greenough A, Moffitt AB, McKinney M, Banerjee A,

+Grubor V, Levy S, Dunson DB, Dave SS. The genetic landscape of mutations

+in <span>Burkitt</span> lymphoma. Nat Genet. 2012 Dec;44(12):1321–1325.

+PMCID: <a

+href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3674561">PMC3674561</a></div>

+</div>

+<div id="ref-thomasGeneticSubgroupsInform2023" class="csl-entry"

+role="listitem">

+<div class="csl-left-margin">4. </div><div

+class="csl-right-inline">Thomas N, Dreval K, Gerhard DS, Hilton LK,

+Abramson JS, Ambinder RF, Barta S, Bartlett NL, Bethony J, Bhatia K,

+Bowen J, Bryan AC, Cesarman E, Casper C, Chadburn A, Cruz M, Dittmer DP,

+Dyer MA, Farinha P, Gastier-Foster JM, Gerrie AS, Grande BM, Greiner T,

+Griner NB, Gross TG, Harris NL, Irvin JD, Jaffe ES, Henry D, Huppi R,

+Leal FE, Lee MS, Martin JP, Martin MR, Mbulaiteye SM, Mitsuyasu R,

+Morris V, Mullighan CG, Mungall AJ, Mungall K, Mutyaba I, Nokta M,

+Namirembe C, Noy A, Ogwang MD, Omoding A, Orem J, Ott G, Petrello H,

+Pittaluga S, Phelan JD, Ramos JC, Ratner L, Reynolds SJ, Rubinstein PG,

+Sissolak G, Slack G, Soudi S, Swerdlow SH, Traverse-Glehen A, Wilson WH,

+Wong J, Yarchoan R, ZenKlusen JC, Marra MA, Staudt LM, Scott DW, Morin

+RD. Genetic subgroups inform on pathobiology in adult and pediatric

+<span>Burkitt</span> lymphoma. Blood. 2023 Feb 23;141(8):904–916. PMCID:

+<a

+href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC10023728">PMC10023728</a></div>

+</div>

+<div id="ref-yapSomaticMutationsEZH22011" class="csl-entry"

+role="listitem">

+<div class="csl-left-margin">5. </div><div class="csl-right-inline">Yap

+DB, Chu J, Berg T, Schapira M, Cheng S-WG, Moradian A, Morin RD, Mungall

+AJ, Meissner B, Boyle M, Marquez VE, Marra MA, Gascoyne RD, Humphries

+RK, Arrowsmith CH, Morin GB, Aparicio SAJR. Somatic mutations at

+<span>EZH2 Y641</span> act dominantly through a mechanism of selectively

+altered <span>PRC2</span> catalytic activity, to increase

+<span>H3K27</span> trimethylation. Blood. 2011 Feb 24;117(8):2451–2459.

+PMCID: <a

+href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3062411">PMC3062411</a></div>

+</div>

+<div id="ref-garapaty-raoIdentificationEZH2EZH12013" class="csl-entry"

+role="listitem">

+<div class="csl-left-margin">6. </div><div

+class="csl-right-inline">Garapaty-Rao S, Nasveschuk C, Gagnon A, Chan

+EY, Sandy P, Busby J, Balasubramanian S, Campbell R, Zhao F, Bergeron L,

+Audia JE, Albrecht BK, Harmange JC, Cummings R, Trojer P. Identification

+of <span>EZH2</span> and <span>EZH1 Small Molecule Inhibitors</span>

+with <span>Selective Impact</span> on <span>Diffuse Large B Cell

+Lymphoma Cell Growth</span>. Chemistry &amp; Biology. 2013

+Nov;20(11):1329–1339. </div>

+</div>

+<div id="ref-knutsonSelectiveInhibitionEZH22014" class="csl-entry"

+role="listitem">

+<div class="csl-left-margin">7. </div><div

+class="csl-right-inline">Knutson SK, Kawano S, Minoshima Y, Warholic NM,

+Huang KC, Xiao Y, Kadowaki T, Uesugi M, Kuznetsov G, Kumar N, Wigle TJ,

+Klaus CR, Allain CJ, Raimondi A, Waters NJ, Smith JJ, Porter-Scott M,

+Chesworth R, Moyer MP, Copeland RA, Richon VM, Uenaka T, Pollock RM,

+Kuntz KW, Yokoi A, Keilhack H. Selective <span>Inhibition</span> of

+<span>EZH2</span> by <span>EPZ-6438 Leads</span> to <span>Potent

+Antitumor Activity</span> in <span>EZH2-Mutant Non-Hodgkin

+Lymphoma</span>. Molecular Cancer Therapeutics [Internet].

+2014;13(4):842–854. Available from: <a

+href="http://dx.doi.org/10.1158/1535-7163.mct-13-0773">http://dx.doi.org/10.1158/1535-7163.mct-13-0773</a></div>

+</div>

+<div id="ref-morinTreatingLymphomaNow2021" class="csl-entry"

+role="listitem">

+<div class="csl-left-margin">8. </div><div

+class="csl-right-inline">Morin RD, Arthur SE, Assouline S. Treating

+lymphoma is now a bit <span class="nocase">EZ-er</span>. Blood Adv. 2021

+Apr 27;5(8):2256–2263. PMCID: <a

+href="https://www.ncbi.nlm.nih.gov/pmc/articles/PMC8095133">PMC8095133</a></div>

+</div>

+<div id="ref-scholzeCombinedEZH2Bcl22020" class="csl-entry"

+role="listitem">

+<div class="csl-left-margin">9. </div><div

+class="csl-right-inline">Scholze H, Stephenson RE, Reynolds R, Shah SB,

+Puri R, Butler SD, Trujillo-Alonso V, Teater M, Besien H van,

+Gibbs-Curtis D, Ueno H, Parvin S, Letai A, Mathew S, Singh A, Cesarman

+E, Melnick A, Giulino‐Roth L. <a

+href="https://doi.org/10.1182/bloodadvances.2020002580">Combined

+<span>EZH2</span> and <span>Bcl-2</span> inhibitors as precision therapy

+for genetically defined <span>DLBCL</span> subtypes.</a> Blood advances.

+2020;4 20:5226–5231. </div>

+</div>

+<div id="ref-mottokIntegrativeGenomicAnalysis2019" class="csl-entry"

+role="listitem">

+<div class="csl-left-margin">10. </div><div

+class="csl-right-inline">Mottok A, Hung SS, Chavez EA, Woolcock B,

+Telenius A, Chong LC, Meissner B, Nakamura H, Rushton C, Viganò E,

+Sarkozy C, Gascoyne RD, Connors JM, Ben-Neriah S, Mungall A, Marra MA,

+Siebert R, Scott DW, Savage KJ, Steidl C. <a

+href="https://doi.org/10.1182/blood.2019001126">Integrative genomic

+analysis identifies key pathogenic mechanisms in primary mediastinal

+large <span class="nocase">B-cell</span> lymphoma</a>. Blood. 2019 Sept

+5;134(10):802–813. </div>

+</div>

+</div>