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<input type="email" aria-label="Sender Email Address" placeholder="email@example.com" id="email-from" class="email-from" pattern="^[a-zA-Z0-9_.+-]+@[a-zA-Z0-9-]+\.[a-zA-Z0-9-.]+$" maxlength="256">
</div>
<div class="action-panel-control-wrap">
<label for="email-citation-format" class="action-panel-label">
Format:
</label>
<select id="email-citation-format" name="citation-format" class="action-panel-selector email-citation-format">
<option selected="selected" value="summary">Summary</option>
<option value="summary-text">Summary (text)</option>
<option value="abstract">Abstract</option>
<option value="abstract-text">Abstract (text)</option>
</select>
</div>
<div class="include-supplemental-container">
<input type="checkbox" aria-label="Include MeSH and other data" name="include-supplemental" id="email-include-supplemental" class="email-include-supplemental">
<label for="email-include-supplemental" class="email-include-supplemental-label">MeSH and other data</label>
</div>
<div class="form-field recaptcha ">
<div class="g-recaptcha" id="id-recaptcha" data-sitekey="6LfsWHMdAAAAAClKbtOpjQ2pMjgsGxvv7NdZW9uI"></div>
</div>
<div id="captcha-error-message" class="usa-input-error-message captcha-validation-message" role="alert"></div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="send">
Send email
</button>
<button class="action-panel-cancel"
aria-label="Close 'Email citations' panel"
ref="linksrc=close_email_panel"
aria-controls="email-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="email"
data-ga-label="cancel">
Cancel
</button>
</div>
<input type="hidden" name="email-search-details" value="" />
<input type="hidden" name="email-search-details-hash" value="0e42663a6c3bd85498fcb88798998fed7bfdc45d457db35281e41afe13cc0524" />
</form>
</div>
</div>
<div id="collections-action-panel"
class="collections-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-collections-open-panel-enabled="false"
data-collections-open-panel-url-hash="#open-collections-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to Collections
</h3>
<form id="collections-action-panel-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-myncbi-max-collection-name-length="100"
data-add-to-collection-max-amount="1000"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/">
<input type="hidden" name="csrfmiddlewaretoken" value="x2BTprgF11ywew9R3TX4ybf5ioWtlHYHOPlY2hJ1BCl08XfHGcA62jLJQsEFeiw1">
<div class="choice-group" role="radiogroup">
<ul class="radio-group-items">
<li>
<input type="radio"
id="collections-action-panel-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_new">
<label for="collections-action-panel-new">Create a new collection</label>
</li>
<li>
<input type="radio"
id="collections-action-panel-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="collections_radio_existing">
<label for="collections-action-panel-existing">Add to an existing collection</label>
</li>
</ul>
</div>
<div class="controls-wrapper">
<div class="action-panel-control-wrap new-collections-controls">
<label for="collections-action-panel-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label>
<input
type="text"
name="add-to-new-collection"
id="collections-action-panel-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="save_share"
data-ga-action="create_collection"
data-ga-label="non_favorties_collection">
<div class="collections-new-name-too-long usa-input-error-message selection-validation-message">
Name must be less than 100 characters
</div>
</div>
<div class="action-panel-control-wrap existing-collections-controls">
<label for="collections-action-panel-add-to-existing" class="action-panel-label">
Choose a collection:
</label>
<select id="collections-action-panel-add-to-existing"
class="action-panel-selector collections-action-add-to-existing"
data-ga-category="save_share"
data-ga-action="select_collection"
data-ga-label="($('#collections-action-add-to-existing').val() === 'Favorites') ? 'Favorites' : 'non_favorites_collection'">
</select>
<div class="collections-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your collection due to an error<br>
<a href="#">Please try again</a>
</div>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="add">
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to Collections' panel"
ref="linksrc=close_collections_panel"
aria-controls="collections-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="collections"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="bibliography-action-panel"
class="bibliography-action-panel action-panel in-progress-dots-panel"
aria-hidden="true"
data-bibliography-open-panel-enabled="false"
data-bibliography-open-panel-url-hash="#open-bibliography-panel">
<div class="inner-wrap">
<h3 class="action-panel-heading">
Add to My Bibliography
</h3>
<form id="bibliography-action-panel-form"
class="bibliography-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-add-to-bibliography-max-amount="100"
data-add-to-bibliography-batch-size="10"
data-bibliography-delegates-url="/list-bibliography-delegates/"
data-add-to-bibliography-url="/add-to-bibliography/"
data-get-article-ids-by-search-url="/get-article-ids-by-search/"
data-mybib-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/mybibliography/">
<input type="hidden" name="csrfmiddlewaretoken" value="x2BTprgF11ywew9R3TX4ybf5ioWtlHYHOPlY2hJ1BCl08XfHGcA62jLJQsEFeiw1">
<div class="action-panel-control-wrap bibliographies-controls">
<div class="choice-group">
<ul class="bibliographies-action-add radio-group-items">
<li>
<input name="bibliography" id="my-bibliography" class="my-bibliography" type="radio" checked/>
<label for="my-bibliography">My Bibliography</label>
</li>
</ul>
</div>
</div>
<div class="bibliographies-retry-load-on-error usa-input-error-message selection-validation-message">
Unable to load your delegates due to an error<br>
<a href="#">Please try again</a>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Adding..."
data-pinger-ignore>
Add
</button>
<button class="action-panel-cancel"
aria-label="Close 'Add to bibliography' panel"
ref="linksrc=close_bibliography_panel"
aria-controls="bibliography-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="mybib"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="saved-search-action-panel" class="saved-search-action-panel action-panel " aria-hidden="true"
data-saved-search-open-panel-enabled="false"
data-saved-search-open-panel-url-hash="#open-saved-search-panel">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your saved search
</h2>
<form id="saved-search-action-panel-form"
class="saved-search-action-panel-form action-panel-content action-form"
data-create-saved-search-url="/create-saved-search/"
data-try-search-terms-url="/try-search-term/"
data-saved-search-root-url="https://www.ncbi.nlm.nih.gov/myncbi/searches/">
<input type="hidden" name="csrfmiddlewaretoken" value="x2BTprgF11ywew9R3TX4ybf5ioWtlHYHOPlY2hJ1BCl08XfHGcA62jLJQsEFeiw1">
<div class="action-panel-control-wrap">
<label for="saved-search-name" class="action-panel-label saved-search-name-label required-field-asterisk">
Name of saved search:
</label>
<input maxlength="200"
type="text"
name="saved-search-name"
id="saved-search-name"
class="saved-search-name"
value=""
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-term" class="action-panel-label required-field-asterisk">
Search terms:
</label>
<textarea name="saved-search-term" id="saved-search-term" class="saved-search-term" required></textarea>
</div>
<div class="test-search-term-wrap">
<a href="#" class="try-search-term">Test search terms</a>
</div>
<div class="choice-group action-panel-extra-margin-top">
<span class="action-panel-label" id="fieldset-label">
Would you like email updates of new search results?
</span>
<fieldset id="saved-search-alert" aria-describedby="fieldset-label">
<legend class="usa-sr-only">Saved Search Alert Radio Buttons</legend>
<ul class="radio-group-items">
<li>
<input type="radio" id="saved-search-alert-yes" class="saved-search-alert-yes" name="saved-search-alert" value="yes" checked>
<label for="saved-search-alert-yes" class="action-panel-label">Yes</label>
</li>
<li>
<input aria-label="No radio input" type="radio" id="saved-search-alert-no" class="saved-search-alert-no" name="saved-search-alert" value="no">
<label for="saved-search-alert-no" class="action-panel-label">No</label>
</li>
</ul>
</fieldset>
</div>
<div class="alert-schedule-wrap">
<div class="action-panel-control-wrap">
<label class="action-panel-label">
Email:
</label>
<span aria-label="Email address" id="saved-search-email" class="action-panel-label"><span class="action-panel-label-bold"></span> (<a class="myncbi-account-settings" href="https://www.ncbi.nlm.nih.gov/account/settings/">change</a>)</span>
</div>
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="saved-search-frequency" class="action-panel-label">
Frequency:
</label>
<select id="saved-search-frequency" class="no-border-panel-selector saved-search-frequency">
<option value="monthly">Monthly</option>
<option value="weekly">Weekly</option>
<option value="daily">Daily</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-monthly-additional">
<label for="saved-search-monthly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-monthly-on-day" class="no-border-panel-selector">
<option value="Sunday">The first Sunday</option>
<option value="Monday">The first Monday</option>
<option value="Tuesday">The first Tuesday</option>
<option value="Wednesday">The first Wednesday</option>
<option value="Thursday">The first Thursday</option>
<option value="Friday">The first Friday</option>
<option value="Saturday">The first Saturday</option>
<option value="day">The first day</option>
<option value="weekday">The first weekday</option>
</select>
</div>
<div class="action-panel-control-wrap saved-search-weekly-additional">
<label for="saved-search-weekly-on-day" class="action-panel-label">
Which day?
</label>
<select id="saved-search-weekly-on-day" class="no-border-panel-selector saved-search-weekly-on-day">
<option value="Sunday">Sunday</option>
<option value="Monday">Monday</option>
<option value="Tuesday">Tuesday</option>
<option value="Wednesday">Wednesday</option>
<option value="Thursday">Thursday</option>
<option value="Friday">Friday</option>
<option value="Saturday">Saturday</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-report" class="action-panel-label">
Report format:
</label>
<select id="saved-search-report" class="no-border-panel-selector saved-search-report">
<option value="DocSum">Summary</option>
<option value="DocSumText">Summary (text)</option>
<option value="Abstract">Abstract</option>
<option value="AbstractText">Abstract (text)</option>
<option value="MEDLINE">PubMed</option>
</select>
</div>
<div class="action-panel-control-wrap">
<label for="saved-search-amount" class="action-panel-label">
Send at most:
</label>
<select id="saved-search-amount" class="no-border-panel-selector saved-search-amount">
<option value="1">1 item</option>
<option value="5" selected>5 items</option>
<option value="10">10 items</option>
<option value="20">20 items</option>
<option value="50">50 items</option>
<option value="100">100 items</option>
<option value="200">200 items</option>
</select>
</div>
<div>
<input type="checkbox" id="saved-search-send-if-no-result" class="saved-search-send-if-no-result" name="saved-search-send-if-no-result">
<label for="saved-search-send-if-no-result" class="action-panel-label smaller-checkbox">
Send even when there aren't any new results
</label>
</div>
<div class="action-panel-control-wrap option-text-in-email-wrap">
<label for="saved-search-email-text" class="action-panel-label">
Optional text in email:
</label>
<textarea name="saved-search-email-text"
id="saved-search-email-text"
class="saved-search-email-text"></textarea>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Saving..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Save
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your saved search' panel"
ref="linksrc=close_saved_search_panel"
aria-controls="saved-search-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="citation-manager-action-panel" class="citation-manager-action-panel action-panel" aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Create a file for external citation management software
</h2>
<form id="citation-manager-action-panel-form"
class="action-panel-content action-form"
action="/results-export-ids/"
data-by-search-action="/results-export-search-data/"
data-by-ids-action="/results-export-ids/"
method="post"
data-by-search-method="post"
data-by-ids-method="post">
<input type="hidden" name="csrfmiddlewaretoken" value="x2BTprgF11ywew9R3TX4ybf5ioWtlHYHOPlY2hJ1BCl08XfHGcA62jLJQsEFeiw1">
<input name="results-format" type="hidden" value="pubmed"/>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Sending..."
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="save">
Create file
</button>
<button class="action-panel-cancel"
aria-label="Close 'Send citations to citation manager' panel"
ref="linksrc=close_citation_manager_panel"
aria-controls="citation-manager-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="citation_manager"
data-ga-label="cancel">
Cancel
</button>
</div>
</form>
</div>
</div>
<div id="rss-action-panel" class="rss-action-panel action-panel " aria-hidden="true">
<div class="inner-wrap">
<h2 class="action-panel-heading">
Your RSS Feed
</h2>
<form id="rss-action-panel-form"
class="rss-action-panel-form action-panel-content action-form"
data-create-rss-feed-url="/create-rss-feed-url/"
data-search-form-term-value="">
<input type="hidden" name="csrfmiddlewaretoken" value="x2BTprgF11ywew9R3TX4ybf5ioWtlHYHOPlY2hJ1BCl08XfHGcA62jLJQsEFeiw1">
<div class="action-panel-control-wrap">
<label for="rss-name" class="action-panel-label required-field-asterisk">
Name of RSS Feed:
</label>
<input maxlength="200"
placeholder="Name"
type="text"
name="rss-name"
id="rss-name"
class="rss-name"
value=''
required
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/">
</div>
<div class="rss-limit-wrap">
<div class="action-panel-control-wrap action-panel-extra-margin-top">
<label for="rss-limit" class="action-panel-label">
Number of items displayed:
</label>
<select id="rss-limit" class="no-border-panel-selector rss-limit">
<option value="5">5</option>
<option value="10">10</option>
<option value="15" selected="selected">15</option>
<option value="20">20</option>
<option value="50">50</option>
<option value="100">100</option>
</select>
</div>
</div>
<div class="action-panel-actions">
<button class="action-panel-submit"
type="submit"
data-loading-label="Creating..."
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="save">
Create RSS
</button>
<button class="action-panel-cancel"
aria-label="Close 'Your RSS' panel"
ref="linksrc=close_rss_panel"
aria-controls="rss-action-panel"
aria-expanded="false"
data-ga-category="save_share"
data-ga-action="alert"
data-ga-label="cancel">
Cancel
</button>
</div>
<div class="action-panel-control-wrap rss-link-copy-wrap">
<label for="rss-link" class="usa-sr-only">RSS Link</label>
<input placeholder="Your RSS Feed Link" type="text" name="rss-link" id="rss-link" class="rss-link" title="RSS Link">
<button
type="button"
disabled
class="rss-link-copy-button disabled"
data-ga-category="save_share"
data-ga-action="rss"
data-ga-label="copy">
Copy
</button>
</div>
</form>
</div>
</div>
</div>
</div>
<div class="article-page" id="article-page" data-article-pmid="26522332">
<aside class="page-sidebar">
<div class="inner-wrap">
<div class="full-text-links">
<div class="full-view">
<h3 class="title">
Full text links
</h3>
<div class="full-text-links-list">
<a class="link-item
dialog-focus"
href="https://linkinghub.elsevier.com/retrieve/pii/S1470-2045(15)00369-1"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=False&amp;PrId=3048&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=26522332&amp;db=pubmed&amp;nlmid=100957246"
title="See full text options at Elsevier Science"
data-ga-category="full_text"
data-ga-action="Elsevier Science"
data-ga-label="26522332"
><img src="https://cdn.ncbi.nlm.nih.gov/corehtml/query/egifs/https:--linkinghub.elsevier.com-ihub-images-14702045-ONC.gif" alt="Elsevier Science full text link"><span class="text">
Elsevier Science
</span></a><a class="link-item
pmc
"
href="https://pmc.ncbi.nlm.nih.gov/articles/pmid/26522332/"
target="_blank"
rel="noopener"
ref="linksrc=fulltextorjournal_fulltext&amp;is_pmc=True&amp;PrId=3494&amp;itool=Abstract-def&amp;log$=linkouticon&amp;uid=26522332&amp;db=pubmed&amp;nlmid=100957246"
title="Free full text at PubMed Central"
data-ga-category="full_text"
data-ga-action="PMC"
data-ga-label="26522332"
><span class="text">
Free PMC article
</span></a>
</div>
</div>
<div class="short-view">
<a href="#" class="full-text-links-button full-text-links-dialog-trigger">
Full text links
</a>
</div>
</div>
<div class="actions-buttons sidebar"><h3 class="title">Actions</h3><div class="inner-wrap"><button class="citation-button citation-dialog-trigger"
aria-label="Open dialog with citation text in different styles"
data-ga-category="save_share"
data-ga-action="cite"
data-ga-label="open"
data-all-citations-url="/26522332/citations/"
data-citation-style="nlm"
data-pubmed-format-link="/26522332/export/"><span class="button-label">Cite</span></button><link type="text/css" href="ncbi-overlay-block/src/overlay-block.css"><div class="collections-button-container" data-article-id="26522332" data-article-db="pubmed"><button class="collections-button collections-dialog-trigger"
aria-label="Save article in MyNCBI collections."
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_button"
data-collections-open-dialog-enabled="false"
data-collections-open-dialog-url="https://account.ncbi.nlm.nih.gov/?back_url=https%3A%2F%2Fpubmed.ncbi.nlm.nih.gov%2F26522332%2F%23open-collections-dialog"
data-in-collections="false"><span class="button-label">Collections</span></button><div class="overlay" role="dialog"><div id="collections-action-dialog"
class="dialog collections-dialog"
aria-hidden="true"><div class="title">Add to Collections</div><div class="collections-action-panel action-panel"><form id="collections-action-dialog-form"
class="collections-action-panel-form action-panel-content action-form action-panel-smaller-selectors"
data-existing-collections-url="/list-existing-collections/"
data-add-to-existing-collection-url="/add-to-existing-collection/"
data-create-and-add-to-new-collection-url="/create-and-add-to-new-collection/"
data-myncbi-max-collection-name-length="100"
data-collections-root-url="https://www.ncbi.nlm.nih.gov/myncbi/collections/"><input type="hidden" name="csrfmiddlewaretoken" value="x2BTprgF11ywew9R3TX4ybf5ioWtlHYHOPlY2hJ1BCl08XfHGcA62jLJQsEFeiw1"><div class="choice-group" role="radiogroup"><ul class="radio-group-items"><li><input type="radio"
id="collections-action-dialog-new"
class="collections-new"
name="collections"
value="new"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_new"><label for="collections-action-dialog-new">Create a new collection</label></li><li><input type="radio"
id="collections-action-dialog-existing"
class="collections-existing"
name="collections"
value="existing"
checked="true"
data-ga-category="collections_button"
data-ga-action="click"
data-ga-label="collections_radio_existing"><label for="collections-action-dialog-existing">Add to an existing collection</label></li></ul></div><div class="controls-wrapper"><div class="action-panel-control-wrap new-collections-controls"><label for="collections-action-dialog-add-to-new" class="action-panel-label required-field-asterisk">
Name your collection:
</label><input
type="text"
name="add-to-new-collection"
id="collections-action-dialog-add-to-new"
class="collections-action-add-to-new"
pattern="[^&quot;&amp;=&lt;&gt;\/]*" title="The following characters are not allowed in the Name field: &quot;&amp;=&lt;&gt;/"
maxlength="100"
data-ga-category="collections_button"
data-ga-action="create_collection"
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<h1 class="heading-title">
Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study
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><sup class="key">1</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.</li>
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><sup class="key">4</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan.</li>
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><sup class="key">5</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
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><sup class="key">6</sup> Department of Biostatistics, College of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL, USA.</li>
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><sup class="key">8</sup> Department of Pathology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
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><sup class="key">9</sup> Department of Pathology and Laboratory Medicine, Nationwide Children&#x27;s Hospital, and Departments of Pathology and Pediatrics, Ohio State University, Columbus, OH, USA.</li>
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><sup class="key">10</sup> Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.</li>
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><sup class="key">11</sup> Maine Children&#x27;s Cancer Program, Scarborough, ME, USA.</li>
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><sup class="key">12</sup> Department of Pediatrics, Duke University, Durham, NC, USA.</li>
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><sup class="key">14</sup> Pediatric Hematology Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.</li>
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><sup class="key">15</sup> Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.</li>
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><sup class="key">16</sup> Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.</li>
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><sup class="key">18</sup> Department of Oncology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Department of Pathology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
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><sup class="key">19</sup> Department of Pathology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
<li data-affiliation-id="full-view-affiliation-20"
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><sup class="key">20</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
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><sup class="key">21</sup> Department of Pediatrics and Center for Childhood Cancer Research, Children&#x27;s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.</li>
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><sup class="key">22</sup> Department of Pediatrics, Benioff Children&#x27;s Hospital and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.</li>
<li data-affiliation-id="full-view-affiliation-23"
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><sup class="key">23</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA. Electronic address: jun.yang@stjude.org.</li>
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Germline genetic variation in ETV6 and risk of childhood acute lymphoblastic leukaemia: a systematic genetic study
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data-ga-label="Julie M Gastier-Foster">Julie M Gastier-Foster</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pathology and Laboratory Medicine, Nationwide Children&#x27;s Hospital, and Departments of Pathology and Pediatrics, Ohio State University, Columbus, OH, USA." href="#short-view-affiliation-9" ref="linksrc=author_aff">
9
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Raetz+E&amp;cauthor_id=26522332"
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data-ga-label="Elizabeth Raetz">Elizabeth Raetz</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA." href="#short-view-affiliation-10" ref="linksrc=author_aff">
10
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Larsen+E&amp;cauthor_id=26522332"
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11
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Martin+PL&amp;cauthor_id=26522332"
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12
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Bowman+WP&amp;cauthor_id=26522332"
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13
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Winick+N&amp;cauthor_id=26522332"
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14
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Komada+Y&amp;cauthor_id=26522332"
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15
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Wang+S&amp;cauthor_id=26522332"
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3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Xu+H&amp;cauthor_id=26522332"
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16
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Mardis+E&amp;cauthor_id=26522332"
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17
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Fulton+R&amp;cauthor_id=26522332"
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17
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Pui+CH&amp;cauthor_id=26522332"
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18
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
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19
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Evans+WE&amp;cauthor_id=26522332"
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20
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Zhang+J&amp;cauthor_id=26522332"
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data-ga-label="Jinghui Zhang">Jinghui Zhang</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Computational Biology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA." href="#short-view-affiliation-3" ref="linksrc=author_aff">
3
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Hunger+SP&amp;cauthor_id=26522332"
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data-ga-label="Stephen P Hunger">Stephen P Hunger</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatrics and Center for Childhood Cancer Research, Children&#x27;s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA." href="#short-view-affiliation-21" ref="linksrc=author_aff">
21
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Relling+MV&amp;cauthor_id=26522332"
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data-ga-label="Mary V Relling">Mary V Relling</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA." href="#short-view-affiliation-20" ref="linksrc=author_aff">
20
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Nichols+KE&amp;cauthor_id=26522332"
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data-ga-label="Kim E Nichols">Kim E Nichols</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Oncology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA." href="#short-view-affiliation-2" ref="linksrc=author_aff">
2
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Loh+ML&amp;cauthor_id=26522332"
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data-ga-label="Mignon L Loh">Mignon L Loh</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pediatrics, Benioff Children&#x27;s Hospital and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA." href="#short-view-affiliation-22" ref="linksrc=author_aff">
22
</a></sup><span class="comma">,&nbsp;</span></span><span class="authors-list-item "><a class="full-name"
href="/?term=Yang+JJ&amp;cauthor_id=26522332"
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data-ga-label="Jun J Yang">Jun J Yang</a><sup class="affiliation-links"><span class="author-sup-separator">&nbsp;</span><a class="affiliation-link" title="Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA. Electronic address: jun.yang@stjude.org." href="#short-view-affiliation-23" ref="linksrc=author_aff">
23
</a></sup></span>
</div>
</div>
<div class="affiliations">
<h3 class="title">
Affiliations
</h3>
<ul class="item-list">
<li data-affiliation-id="short-view-affiliation-1"
id="short-view-affiliation-1"
><sup class="key">1</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.</li>
<li data-affiliation-id="short-view-affiliation-2"
id="short-view-affiliation-2"
><sup class="key">2</sup> Department of Oncology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
<li data-affiliation-id="short-view-affiliation-3"
id="short-view-affiliation-3"
><sup class="key">3</sup> Department of Computational Biology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
<li data-affiliation-id="short-view-affiliation-4"
id="short-view-affiliation-4"
><sup class="key">4</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Department of Pediatrics and Developmental Biology, Tokyo Medical and Dental University Graduate School of Medicine, Tokyo, Japan.</li>
<li data-affiliation-id="short-view-affiliation-5"
id="short-view-affiliation-5"
><sup class="key">5</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
<li data-affiliation-id="short-view-affiliation-6"
id="short-view-affiliation-6"
><sup class="key">6</sup> Department of Biostatistics, College of Medicine, Public Health and Health Professions, University of Florida, Gainesville, FL, USA.</li>
<li data-affiliation-id="short-view-affiliation-7"
id="short-view-affiliation-7"
><sup class="key">7</sup> Department of Biostatistics, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
<li data-affiliation-id="short-view-affiliation-8"
id="short-view-affiliation-8"
><sup class="key">8</sup> Department of Pathology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
<li data-affiliation-id="short-view-affiliation-9"
id="short-view-affiliation-9"
><sup class="key">9</sup> Department of Pathology and Laboratory Medicine, Nationwide Children&#x27;s Hospital, and Departments of Pathology and Pediatrics, Ohio State University, Columbus, OH, USA.</li>
<li data-affiliation-id="short-view-affiliation-10"
id="short-view-affiliation-10"
><sup class="key">10</sup> Huntsman Cancer Institute, University of Utah, Salt Lake City, Utah, USA.</li>
<li data-affiliation-id="short-view-affiliation-11"
id="short-view-affiliation-11"
><sup class="key">11</sup> Maine Children&#x27;s Cancer Program, Scarborough, ME, USA.</li>
<li data-affiliation-id="short-view-affiliation-12"
id="short-view-affiliation-12"
><sup class="key">12</sup> Department of Pediatrics, Duke University, Durham, NC, USA.</li>
<li data-affiliation-id="short-view-affiliation-13"
id="short-view-affiliation-13"
><sup class="key">13</sup> Cook Children&#x27;s Medical Center, Fort Worth, TX, USA.</li>
<li data-affiliation-id="short-view-affiliation-14"
id="short-view-affiliation-14"
><sup class="key">14</sup> Pediatric Hematology Oncology, University of Texas Southwestern Medical Center, Dallas, TX, USA.</li>
<li data-affiliation-id="short-view-affiliation-15"
id="short-view-affiliation-15"
><sup class="key">15</sup> Department of Pediatrics, Mie University Graduate School of Medicine, Mie, Japan.</li>
<li data-affiliation-id="short-view-affiliation-16"
id="short-view-affiliation-16"
><sup class="key">16</sup> Department of Laboratory Medicine, National Key Laboratory of Biotherapy/Collaborative Innovation Center of Biotherapy and Cancer Center, West China Hospital, Sichuan University, Chengdu, China.</li>
<li data-affiliation-id="short-view-affiliation-17"
id="short-view-affiliation-17"
><sup class="key">17</sup> McDonnell Genome Institute, Washington University School of Medicine, St Louis, MO, USA.</li>
<li data-affiliation-id="short-view-affiliation-18"
id="short-view-affiliation-18"
><sup class="key">18</sup> Department of Oncology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Department of Pathology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
<li data-affiliation-id="short-view-affiliation-19"
id="short-view-affiliation-19"
><sup class="key">19</sup> Department of Pathology, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
<li data-affiliation-id="short-view-affiliation-20"
id="short-view-affiliation-20"
><sup class="key">20</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA.</li>
<li data-affiliation-id="short-view-affiliation-21"
id="short-view-affiliation-21"
><sup class="key">21</sup> Department of Pediatrics and Center for Childhood Cancer Research, Children&#x27;s Hospital of Philadelphia and University of Pennsylvania Perelman School of Medicine, Philadelphia, PA, USA.</li>
<li data-affiliation-id="short-view-affiliation-22"
id="short-view-affiliation-22"
><sup class="key">22</sup> Department of Pediatrics, Benioff Children&#x27;s Hospital and Helen Diller Family Comprehensive Cancer Center, University of California, San Francisco, CA, USA.</li>
<li data-affiliation-id="short-view-affiliation-23"
id="short-view-affiliation-23"
><sup class="key">23</sup> Department of Pharmaceutical Sciences, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA; Hematological Malignancies Program, Comprehensive Cancer Center, St Jude Children&#x27;s Research Hospital, Memphis, TN, USA. Electronic address: jun.yang@stjude.org.</li>
</ul>
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<strong class="current-id" title="PubMed ID">26522332</strong>
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<h2 class="title">
Abstract
</h2>
<div class="abstract-content selected"
id="eng-abstract">
<p>
<strong class="sub-title">
Background:
</strong>
Hereditary predisposition is rarely suspected for childhood acute lymphoblastic leukaemia (ALL). Recent reports of germline ETV6 variations associated with substantial familial clustering of haematological malignancies indicated that this gene is a potentially important genetic determinant for ALL susceptibility. Our aims in this study were to comprehensively identify ALL predisposition variants in ETV6 and to determine the extent to which they contributed to the overall risk of childhood ALL.
</p>
<p>
<strong class="sub-title">
Methods:
</strong>
Whole-exome sequencing of an index family with several cases of ALL was done to identify causal variants for ALL predisposition. Targeted sequencing of ETV6 was done in children from the Children's Oncology Group and St Jude Children's Research Hospital front-line ALL trials. Patients were included in this study on the basis of their enrolment in these clinical trials and the availability of germline DNA. ETV6 variant genotypes were compared with non-ALL controls to define ALL-related germline risk variants. ETV6 variant function was characterised bioinformatically and correlated with clinical and demographic features in children with ALL.
</p>
<p>
<strong class="sub-title">
Findings:
</strong>
We identified a novel non-sense ETV6 variant (p.Arg359X) with a high penetrance in an index family. Subsequent targeted sequencing of ETV6 in 4405 childhood ALL cases identified 31 exonic variants (four non-sense, 21 missense, one splice site, and five frameshift variants) that were potentially related to ALL risk in 35 cases (1%). 15 (48%) of 31 ALL-related ETV6 variants clustered in the erythroblast transformation specific domain and were predicted to be highly deleterious. Children with ALL-related ETV6 variants were significantly older at leukaemia diagnosis than those without (10·2 years [IQR 5·3-13·8] vs 4·7 years [3·0-8·7]; p=0·017). The hyperdiploid leukaemia karyotype was highly over-represented in ALL cases harbouring germline ETV6 risk variants compared with the wild-type group (nine [64%] of 14 cases vs 538 [27%] of 2007 cases; p=0·0050).
</p>
<p>
<strong class="sub-title">
Interpretation:
</strong>
Our findings indicated germline ETV6 variations as the basis of a novel genetic syndrome associated with predisposition to childhood ALL. The development of recommendations for clinical interventions and surveillance for individuals harbouring ALL-related ETV6 variants are needed.
</p>
<p>
<strong class="sub-title">
Funding:
</strong>
US National Institutes of Health and American Lebanese Syrian Associated Charities.
</p>
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Conflict of interest statement
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<p xmlns:xlink="http://www.w3.org/1999/xlink" xmlns:mml="http://www.w3.org/1998/Math/MathML" xmlns:p1="http://pubmed.gov/pub-one"><bold>Declaration of interests</bold>: The authors declared no conflicts of interest relevant to this study.</p>
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<p> Figure 1. A novel nonsense germline variant… </p>
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<p> Figure 1. A novel nonsense germline variant in <i> ETV6 </i> (p.R359X) associated with familial ALL </p>
</strong>
<div class="figure-caption-contents"><p> Filled… </p></div>
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<figcaption id="figure-caption-0" class="figure-caption-full figure-caption-text" itemtype="http://schema.org/ImageObject" itemprop="description">
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Figure 1. A novel nonsense germline variant in <i>ETV6</i> (p.R359X) associated with familial ALL
</strong>
<div class="figure-caption-contents">Filled symbols represented individuals with ALL. “WT” and “p.R359X” indicate the wildtype and heterozygous genotype at this <i>ETV6</i> variant, respectively.</div>
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id="article-image-1"
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<p> Figure 2. <i> ETV6 </i> variants identified by targeted… </p>
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<p> Figure 2. <i> ETV6 </i> variants identified by targeted sequencing in 4,405 unselected ALL cases </p>
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<div class="figure-caption-contents"><b> (A) </b> <i> ETV6… </i></div>
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<strong class="figure-label">
Figure 2. <i>ETV6</i> variants identified by targeted sequencing in 4,405 unselected ALL cases
</strong>
<div class="figure-caption-contents"><b>(A)</b>
<i>ETV6</i> was sequenced using Illumina HiSeq platform following capture-based enrichment of this genomic region in 4,405 unselected ALL cases. Variants in non-ALL controls were based on publicly available data from the NHLBI Exome Sequencing Project cohort (N=6,503). Exnoic variants are classified as frameshift, nonsense, missense, and splicing (green, blue, red, or orange solid circles, respectively) for ALL cases (green vertical lines) and non-ALL controls (gray vertical lines). Functional domains are indicated by color based on Pfam annotation. Each circle represents a unique individual carrying the indicated variant (heterozygous or homozygous) except variants recurring in more than 10 individuals for which the number in the circle indicates the exact frequency. <b>(B)</b> ALL-related <i>ETV6</i> variants are highly enriched in the ETS domain which consists of 3 helices (yellow boxes) and 4 β-sheets (yellow arrows). H3 is responsible for direct binding with DNA, which is negatively regulated by the CID domain (H4 and H5, orange boxes) at the C-terminal. Variant function is denoted by the color of each line.</div>
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Why germline variations in ALL can matter.
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<span class="docsum-authors full-authors">Haferlach T.</span>
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<span class="docsum-journal-citation full-journal-citation">Lancet Oncol. 2015 Dec;16(16):1577-8. doi: 10.1016/S1470-2045(15)00440-4. Epub 2015 Oct 28.</span>
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Haematological cancer: ETV6 germline mutation - a risk for ALL.
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Substances
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<div id="related-links" class="related-links">
<h2 class="title">
Related information
</h2>
<ul class="related-links-list"><li><a title="PubMed links associated with Books" href="https://www.ncbi.nlm.nih.gov/books?linkname=pubmed_books_refs&amp;from_uid=26522332"
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Cited in Books
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ClinVar
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Gene
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Gene (GeneRIF)
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MedGen
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MedGen (Bookshelf cited)
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Protein (RefSeq)
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<h2 class="title">
Grants and funding
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<div id="linkout" class="linkout">
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LinkOut - more resources
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