HPV Associated Head and Neck Cancer
Identifieur interne : 000264 ( Ncbi/Merge ); précédent : 000263; suivant : 000265HPV Associated Head and Neck Cancer
Auteurs : Tara Spence ; Jeff Bruce ; Kenneth W. Yip ; Fei-Fei Liu [Canada]Source :
- Cancers [ 2072-6694 ] ; 2016.
Abstract
Head and neck cancers (HNCs) are a highly heterogeneous group of tumours that are associated with diverse clinical outcomes. Recent evidence has demonstrated that human papillomavirus (HPV) is involved in up to 25% of HNCs; particularly in the oropharyngeal carcinoma (OPC) subtype where it can account for up to 60% of such cases. HPVs are double-stranded DNA viruses that infect epithelial cells; numerous HPV subtypes, including 16, 18, 31, 33, and 35, drive epithelial cell transformation and tumourigenesis. HPV positive (HPV+) HNC represents a distinct molecular and clinical entity from HPV negative (HPV−) disease; the biological basis for which remains to be fully elucidated. HPV positivity is strongly correlated with a significantly superior outcome; indicating that such tumours should have a distinct management approach. This review focuses on the recent scientific and clinical investigation of HPV+ HNC. In particular, we discuss the importance of molecular and clinical evidence for defining the role of HPV in HNC, and the clinical impact of HPV status as a biomarker for HNC.
Url:
DOI: 10.3390/cancers8080075
PubMed: 27527216
PubMed Central: 4999784
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PMC:4999784Le document en format XML
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<affiliation><nlm:aff id="af1-cancers-08-00075">Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada;<email>tara.spence@rmp.uhn.ca</email>
(T.S.);<email>jeffpbruce@gmail.com</email>
(J.B.);<email>ken.yip@utoronto.ca</email>
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<author><name sortKey="Bruce, Jeff" sort="Bruce, Jeff" uniqKey="Bruce J" first="Jeff" last="Bruce">Jeff Bruce</name>
<affiliation><nlm:aff id="af1-cancers-08-00075">Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada;<email>tara.spence@rmp.uhn.ca</email>
(T.S.);<email>jeffpbruce@gmail.com</email>
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<author><name sortKey="Yip, Kenneth W" sort="Yip, Kenneth W" uniqKey="Yip K" first="Kenneth W." last="Yip">Kenneth W. Yip</name>
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(T.S.);<email>jeffpbruce@gmail.com</email>
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<affiliation><nlm:aff id="af1-cancers-08-00075">Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada;<email>tara.spence@rmp.uhn.ca</email>
(T.S.);<email>jeffpbruce@gmail.com</email>
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<sourceDesc><biblStruct><analytic><title xml:lang="en" level="a" type="main">HPV Associated Head and Neck Cancer</title>
<author><name sortKey="Spence, Tara" sort="Spence, Tara" uniqKey="Spence T" first="Tara" last="Spence">Tara Spence</name>
<affiliation><nlm:aff id="af1-cancers-08-00075">Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada;<email>tara.spence@rmp.uhn.ca</email>
(T.S.);<email>jeffpbruce@gmail.com</email>
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<author><name sortKey="Bruce, Jeff" sort="Bruce, Jeff" uniqKey="Bruce J" first="Jeff" last="Bruce">Jeff Bruce</name>
<affiliation><nlm:aff id="af1-cancers-08-00075">Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada;<email>tara.spence@rmp.uhn.ca</email>
(T.S.);<email>jeffpbruce@gmail.com</email>
(J.B.);<email>ken.yip@utoronto.ca</email>
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<author><name sortKey="Yip, Kenneth W" sort="Yip, Kenneth W" uniqKey="Yip K" first="Kenneth W." last="Yip">Kenneth W. Yip</name>
<affiliation><nlm:aff id="af1-cancers-08-00075">Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada;<email>tara.spence@rmp.uhn.ca</email>
(T.S.);<email>jeffpbruce@gmail.com</email>
(J.B.);<email>ken.yip@utoronto.ca</email>
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<author><name sortKey="Liu, Fei Fei" sort="Liu, Fei Fei" uniqKey="Liu F" first="Fei-Fei" last="Liu">Fei-Fei Liu</name>
<affiliation><nlm:aff id="af1-cancers-08-00075">Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada;<email>tara.spence@rmp.uhn.ca</email>
(T.S.);<email>jeffpbruce@gmail.com</email>
(J.B.);<email>ken.yip@utoronto.ca</email>
(K.W.Y.)</nlm:aff>
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<front><div type="abstract" xml:lang="en"><p>Head and neck cancers (HNCs) are a highly heterogeneous group of tumours that are associated with diverse clinical outcomes. Recent evidence has demonstrated that human papillomavirus (HPV) is involved in up to 25% of HNCs; particularly in the oropharyngeal carcinoma (OPC) subtype where it can account for up to 60% of such cases. HPVs are double-stranded DNA viruses that infect epithelial cells; numerous HPV subtypes, including 16, 18, 31, 33, and 35, drive epithelial cell transformation and tumourigenesis. HPV positive (HPV+) HNC represents a distinct molecular and clinical entity from HPV negative (HPV−) disease; the biological basis for which remains to be fully elucidated. HPV positivity is strongly correlated with a significantly superior outcome; indicating that such tumours should have a distinct management approach. This review focuses on the recent scientific and clinical investigation of HPV+ HNC. In particular, we discuss the importance of molecular and clinical evidence for defining the role of HPV in HNC, and the clinical impact of HPV status as a biomarker for HNC.</p>
</div>
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<pmc article-type="review-article"><pmc-dir>properties open_access</pmc-dir>
<front><journal-meta><journal-id journal-id-type="nlm-ta">Cancers (Basel)</journal-id>
<journal-id journal-id-type="iso-abbrev">Cancers (Basel)</journal-id>
<journal-id journal-id-type="publisher-id">cancers</journal-id>
<journal-title-group><journal-title>Cancers</journal-title>
</journal-title-group>
<issn pub-type="epub">2072-6694</issn>
<publisher><publisher-name>MDPI</publisher-name>
</publisher>
</journal-meta>
<article-meta><article-id pub-id-type="pmid">27527216</article-id>
<article-id pub-id-type="pmc">4999784</article-id>
<article-id pub-id-type="doi">10.3390/cancers8080075</article-id>
<article-id pub-id-type="publisher-id">cancers-08-00075</article-id>
<article-categories><subj-group subj-group-type="heading"><subject>Review</subject>
</subj-group>
</article-categories>
<title-group><article-title>HPV Associated Head and Neck Cancer</article-title>
</title-group>
<contrib-group><contrib contrib-type="author"><name><surname>Spence</surname>
<given-names>Tara</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-08-00075">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Bruce</surname>
<given-names>Jeff</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-08-00075">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Yip</surname>
<given-names>Kenneth W.</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-08-00075">1</xref>
</contrib>
<contrib contrib-type="author"><name><surname>Liu</surname>
<given-names>Fei-Fei</given-names>
</name>
<xref ref-type="aff" rid="af1-cancers-08-00075">1</xref>
<xref ref-type="aff" rid="af2-cancers-08-00075">2</xref>
<xref ref-type="aff" rid="af3-cancers-08-00075">3</xref>
<xref rid="c1-cancers-08-00075" ref-type="corresp">*</xref>
</contrib>
</contrib-group>
<contrib-group><contrib contrib-type="editor"><name><surname>Wong</surname>
<given-names>David</given-names>
</name>
<role>Academic Editor</role>
</contrib>
</contrib-group>
<aff id="af1-cancers-08-00075"><label>1</label>
Department of Radiation Oncology, Princess Margaret Cancer Centre, University Health Network, Toronto, ON M5G 2M9, Canada;<email>tara.spence@rmp.uhn.ca</email>
(T.S.);<email>jeffpbruce@gmail.com</email>
(J.B.);<email>ken.yip@utoronto.ca</email>
(K.W.Y.)</aff>
<aff id="af2-cancers-08-00075"><label>2</label>
Department of Medical Biophysics, University of Toronto, Toronto, ON M5G 1L7, Canada</aff>
<aff id="af3-cancers-08-00075"><label>3</label>
Department of Radiation Oncology, University of Toronto, Toronto, ON M5T 1P5, Canada</aff>
<author-notes><corresp id="c1-cancers-08-00075"><label>*</label>
Correspondence: <email>fei-fei.liu@rmp.uhn.on.ca</email>
; Tel.: +1-416-946-4501 (ext. 5620)</corresp>
</author-notes>
<pub-date pub-type="epub"><day>05</day>
<month>8</month>
<year>2016</year>
</pub-date>
<pub-date pub-type="collection"><month>8</month>
<year>2016</year>
</pub-date>
<volume>8</volume>
<issue>8</issue>
<elocation-id>75</elocation-id>
<history><date date-type="received"><day>29</day>
<month>6</month>
<year>2016</year>
</date>
<date date-type="accepted"><day>02</day>
<month>8</month>
<year>2016</year>
</date>
</history>
<permissions><copyright-statement>© 2016 by the authors; licensee MDPI, Basel, Switzerland.</copyright-statement>
<copyright-year>2016</copyright-year>
<license><license-p><pmc-comment>CREATIVE COMMONS</pmc-comment>
This article is an open access article distributed under the terms and conditions of the Creative Commons Attribution (CC-BY) license (<ext-link ext-link-type="uri" xlink:href="http://creativecommons.org/licenses/by/4.0/">http://creativecommons.org/licenses/by/4.0/</ext-link>
).</license-p>
</license>
</permissions>
<abstract><p>Head and neck cancers (HNCs) are a highly heterogeneous group of tumours that are associated with diverse clinical outcomes. Recent evidence has demonstrated that human papillomavirus (HPV) is involved in up to 25% of HNCs; particularly in the oropharyngeal carcinoma (OPC) subtype where it can account for up to 60% of such cases. HPVs are double-stranded DNA viruses that infect epithelial cells; numerous HPV subtypes, including 16, 18, 31, 33, and 35, drive epithelial cell transformation and tumourigenesis. HPV positive (HPV+) HNC represents a distinct molecular and clinical entity from HPV negative (HPV−) disease; the biological basis for which remains to be fully elucidated. HPV positivity is strongly correlated with a significantly superior outcome; indicating that such tumours should have a distinct management approach. This review focuses on the recent scientific and clinical investigation of HPV+ HNC. In particular, we discuss the importance of molecular and clinical evidence for defining the role of HPV in HNC, and the clinical impact of HPV status as a biomarker for HNC.</p>
</abstract>
<kwd-group><kwd>biomarker</kwd>
<kwd>head and neck cancer</kwd>
<kwd>head and neck squamous cell carcinoma</kwd>
<kwd>human papillomavirus</kwd>
<kwd>(HPV+)</kwd>
<kwd>HPV negative (HPV−)</kwd>
<kwd>microRNA</kwd>
<kwd>oropharyngeal carcinoma</kwd>
<kwd>prognosis</kwd>
</kwd-group>
</article-meta>
</front>
<floats-group><fig id="cancers-08-00075-f001" position="float"><label>Figure 1</label>
<caption><p>Structure of the HPV16 Genome (adapted from <uri xlink:type="simple" xlink:href="http://pave.niaid.nih.gov/">http://pave.niaid.nih.gov/</uri>
, [<xref rid="B12-cancers-08-00075" ref-type="bibr">12</xref>
]). Coding regions and spliced transcripts encoded by the HPV16 genome are depicted. The early (E) genes encode the non-structural proteins that are produced early in the infectious cycle, while the late (L) genes encode structural capsid proteins that are produced late during viral infection.</p>
</caption>
<graphic xlink:href="cancers-08-00075-g001"></graphic>
</fig>
<table-wrap id="cancers-08-00075-t001" position="float"><object-id pub-id-type="pii">cancers-08-00075-t001_Table 1</object-id>
<label>Table 1</label>
<caption><p>Methods for determination of HPV status and HPV subtype.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Method</th>
<th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Principle</th>
<th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Advantage</th>
<th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Disadvantage</th>
<th align="center" valign="top" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref</th>
</tr>
</thead>
<tbody><tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>HPV16 E1 PCR</bold>
</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HPV16, the most common HPV subtype implicated in HNC, is quantified by qRT-PCR in DNA extracted from bulk tumour tissue</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Highly sensitive</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">False positives may occur; technically more difficult to perform than IHC/ISH; detects only HPV16</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B10-cancers-08-00075" ref-type="bibr">10</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>p16 IHC</bold>
</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">p16 is upregulated indirectly via repression of pRb by E7; loss of p16 is common in HPV- HNC</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Technically easy to perform and clinically feasible; comparatively low cost</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Indirect method of HPV detection; does not distinguish between HPV subtypes</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B10-cancers-08-00075" ref-type="bibr">10</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>HPV16 ISH</bold>
</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HPV16, the most common HPV subtype implicated in HNC, is quantified and directly visualized in tumour cells</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Technically easier to perform and clinically feasible; comparatively low cost; allows direct visualization of HPV in tumour nuclei</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Detects only HPV16</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B10-cancers-08-00075" ref-type="bibr">10</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>RNA-Seq</bold>
</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Specific HPV viral transcripts can be detected by sequencing RNA transcripts</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Accurate method for detecting HPV positivity and HPV subtype</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">High cost; technically difficult, requiring specialized resources; limited clinical feasibility at present</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B14-cancers-08-00075" ref-type="bibr">14</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>DNA Sequencing</bold>
</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">HPV can be detected by DNA sequencing </td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Accurate method for detecting HPV positivity and HPV subtype</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">High cost; technically difficult, requiring specialized resources; limited clinical feasibility at present</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B48-cancers-08-00075" ref-type="bibr">48</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>Roche Linear Array</bold>
</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Detection of HPV by PCR amplification of DNA using HPV subtype specific primers</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Accurate method for detecting HPV positivity and HPV subtype; most accurate method for resolving the presence of multiple HPV subtypes in one sample</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Requires specialized resources; limited clinical feasibility at present</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B48-cancers-08-00075" ref-type="bibr">48</xref>
]</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>Abbreviations: head and neck cancer (HNC), human papillomavirus (HPV), immunohistochemistry (IHC), in situ hybridization (ISH), polymerase chain reaction (PCR), quantitative real-time polymerase chain reaction (qRT-PCR).</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="cancers-08-00075-t002" position="float"><object-id pub-id-type="pii">cancers-08-00075-t002_Table 2</object-id>
<label>Table 2</label>
<caption><p>MicroRNAs implicated as biomarkers in HPV+ HNC.</p>
</caption>
<table frame="hsides" rules="groups"><thead><tr><th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">MicroRNAs</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">HNC Subtype</th>
<th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Expression in HNC <sup>¥</sup>
</th>
<th align="left" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Role as Biomarkers</th>
<th align="center" valign="middle" style="border-top:solid thin;border-bottom:solid thin" rowspan="1" colspan="1">Ref</th>
</tr>
</thead>
<tbody><tr><td rowspan="2" align="left" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>miR-20b, miR-9, miR-9*</bold>
</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>OPC</bold>
</td>
<td align="left" valign="middle" rowspan="1" colspan="1">miR-9, miR-9* (up)</td>
<td rowspan="2" align="left" valign="middle" style="border-bottom:solid thin" colspan="1">Associated with HPV/p16-status</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">[<xref rid="B53-cancers-08-00075" ref-type="bibr">53</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">miR-20b (down)</td>
</tr>
<tr><td rowspan="2" align="left" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>miR-107, miR-151, miR-492</bold>
</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>OPC</bold>
</td>
<td align="left" valign="middle" rowspan="1" colspan="1">miR-107, miR-151(up) </td>
<td rowspan="2" align="left" valign="middle" style="border-bottom:solid thin" colspan="1">Correlated with overall survival</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">[<xref rid="B53-cancers-08-00075" ref-type="bibr">53</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">miR-492 (down)</td>
</tr>
<tr><td rowspan="2" align="left" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>miR-20b, miR-107, miR-151, miR-182, miR-361</bold>
</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>OPC</bold>
</td>
<td align="left" valign="middle" rowspan="1" colspan="1">miR-107, miR-151, miR-182, miR-361 (up)</td>
<td rowspan="2" align="left" valign="middle" style="border-bottom:solid thin" colspan="1">Correlated with disease free survival</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">[<xref rid="B53-cancers-08-00075" ref-type="bibr">53</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">miR-20b (down)</td>
</tr>
<tr><td rowspan="2" align="left" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>miR-151, miR-152, miR-324-5p, miR-361, miR-492</bold>
</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1"><bold>OPC</bold>
</td>
<td align="left" valign="middle" rowspan="1" colspan="1">miR-151, miR-324-5p, miR-361 (up) </td>
<td rowspan="2" align="left" valign="middle" style="border-bottom:solid thin" colspan="1">Correlated with distant metastases</td>
<td rowspan="2" align="center" valign="middle" style="border-bottom:solid thin" colspan="1">[<xref rid="B53-cancers-08-00075" ref-type="bibr">53</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">miR-152, miR-492 (down)</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>let-7d, miR-205</bold>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>HNSCC</bold>
</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">down</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Associated with disease free and overall survival</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B54-cancers-08-00075" ref-type="bibr">54</xref>
]</td>
</tr>
<tr><td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>miR-210</bold>
</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1"><bold>HNC overall</bold>
</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">down</td>
<td align="left" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">Associated with hypoxia; correlate with reduced overall and disease free survival</td>
<td align="center" valign="middle" style="border-bottom:solid thin" rowspan="1" colspan="1">[<xref rid="B55-cancers-08-00075" ref-type="bibr">55</xref>
]</td>
</tr>
</tbody>
</table>
<table-wrap-foot><fn><p>Abbreviations: head and neck cancer (HNC), head and neck squamous cell carcinoma (HNSCC), human papillomavirus (HPV), microRNA (miR), oropharyngeal carcinoma (OPC). <sup>¥</sup>
Expression normalized relative to normal adjacent tissue [<xref rid="B53-cancers-08-00075" ref-type="bibr">53</xref>
], contralateral healthy mucosa [<xref rid="B54-cancers-08-00075" ref-type="bibr">54</xref>
], or histologically normal tonsil tissue from tonsillectomy patients [<xref rid="B55-cancers-08-00075" ref-type="bibr">55</xref>
].</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-group>
</pmc>
<affiliations><list><country><li>Canada</li>
</country>
<region><li>Ontario</li>
</region>
<settlement><li>Toronto</li>
</settlement>
<orgName><li>Université de Toronto</li>
</orgName>
</list>
<tree><noCountry><name sortKey="Bruce, Jeff" sort="Bruce, Jeff" uniqKey="Bruce J" first="Jeff" last="Bruce">Jeff Bruce</name>
<name sortKey="Spence, Tara" sort="Spence, Tara" uniqKey="Spence T" first="Tara" last="Spence">Tara Spence</name>
<name sortKey="Yip, Kenneth W" sort="Yip, Kenneth W" uniqKey="Yip K" first="Kenneth W." last="Yip">Kenneth W. Yip</name>
</noCountry>
<country name="Canada"><region name="Ontario"><name sortKey="Liu, Fei Fei" sort="Liu, Fei Fei" uniqKey="Liu F" first="Fei-Fei" last="Liu">Fei-Fei Liu</name>
</region>
<name sortKey="Liu, Fei Fei" sort="Liu, Fei Fei" uniqKey="Liu F" first="Fei-Fei" last="Liu">Fei-Fei Liu</name>
</country>
</tree>
</affiliations>
</record>
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