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International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee

Identifieur interne : 002778 ( Pmc/Checkpoint ); précédent : 002777; suivant : 002779

International consensus for neuroblastoma molecular diagnostics: report from the International Neuroblastoma Risk Group (INRG) Biology Committee

Auteurs : P F Ambros [Autriche] ; I M Ambros [Autriche] ; G M Brodeur [États-Unis] ; M. Haber [Australie] ; J. Khan [États-Unis] ; A. Nakagawara [Japon] ; G. Schleiermacher [France] ; F. Speleman [Belgique] ; R. Spitz [Allemagne] ; W B London [États-Unis] ; S L Cohn [États-Unis] ; A D J. Pearson [Royaume-Uni] ; J M Maris [États-Unis]

Source :

RBID : PMC:2694415

Abstract

Neuroblastoma serves as a paradigm for utilising tumour genomic data for determining patient prognosis and treatment allocation. However, before the establishment of the International Neuroblastoma Risk Group (INRG) Task Force in 2004, international consensus on markers, methodology, and data interpretation did not exist, compromising the reliability of decisive genetic markers and inhibiting translational research efforts. The objectives of the INRG Biology Committee were to identify highly prognostic genetic aberrations to be included in the new INRG risk classification schema and to develop precise definitions, decisive biomarkers, and technique standardisation. The review of the INRG database (n=8800 patients) by the INRG Task Force finally enabled the identification of the most significant neuroblastoma biomarkers. In addition, the Biology Committee compared the standard operating procedures of different cooperative groups to arrive at international consensus for methodology, nomenclature, and future directions. Consensus was reached to include MYCN status, 11q23 allelic status, and ploidy in the INRG classification system on the basis of an evidence-based review of the INRG database. Standardised operating procedures for analysing these genetic factors were adopted, and criteria for proper nomenclature were developed. Neuroblastoma treatment planning is highly dependant on tumour cell genomic features, and it is likely that a comprehensive panel of DNA-based biomarkers will be used in future risk assignment algorithms applying genome-wide techniques. Consensus on methodology and interpretation is essential for uniform INRG classification and will greatly facilitate international and cooperative clinical and translational research studies.


Url:
DOI: 10.1038/sj.bjc.6605014
PubMed: 19401703
PubMed Central: 2694415


Affiliations:


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PMC:2694415

Le document en format XML

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<p>Neuroblastoma serves as a paradigm for utilising tumour genomic data for determining patient prognosis and treatment allocation. However, before the establishment of the International Neuroblastoma Risk Group (INRG) Task Force in 2004, international consensus on markers, methodology, and data interpretation did not exist, compromising the reliability of decisive genetic markers and inhibiting translational research efforts. The objectives of the INRG Biology Committee were to identify highly prognostic genetic aberrations to be included in the new INRG risk classification schema and to develop precise definitions, decisive biomarkers, and technique standardisation. The review of the INRG database (
<italic>n</italic>
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<italic>MYCN</italic>
status, 11q23 allelic status, and ploidy in the INRG classification system on the basis of an evidence-based review of the INRG database. Standardised operating procedures for analysing these genetic factors were adopted, and criteria for proper nomenclature were developed. Neuroblastoma treatment planning is highly dependant on tumour cell genomic features, and it is likely that a comprehensive panel of DNA-based biomarkers will be used in future risk assignment algorithms applying genome-wide techniques. Consensus on methodology and interpretation is essential for uniform INRG classification and will greatly facilitate international and cooperative clinical and translational research studies.</p>
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<name>
<surname>Ambros</surname>
<given-names>P F</given-names>
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<xref ref-type="corresp" rid="caf1">*</xref>
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<name>
<surname>Ambros</surname>
<given-names>I M</given-names>
</name>
<xref ref-type="aff" rid="aff1">1</xref>
<xref ref-type="corresp" rid="caf1">*</xref>
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<surname>Brodeur</surname>
<given-names>G M</given-names>
</name>
<xref ref-type="aff" rid="aff2">2</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Haber</surname>
<given-names>M</given-names>
</name>
<xref ref-type="aff" rid="aff3">3</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Khan</surname>
<given-names>J</given-names>
</name>
<xref ref-type="aff" rid="aff4">4</xref>
</contrib>
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<name>
<surname>Nakagawara</surname>
<given-names>A</given-names>
</name>
<xref ref-type="aff" rid="aff5">5</xref>
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<name>
<surname>Schleiermacher</surname>
<given-names>G</given-names>
</name>
<xref ref-type="aff" rid="aff6">6</xref>
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<name>
<surname>Speleman</surname>
<given-names>F</given-names>
</name>
<xref ref-type="aff" rid="aff7">7</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Spitz</surname>
<given-names>R</given-names>
</name>
<xref ref-type="aff" rid="aff8">8</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>London</surname>
<given-names>W B</given-names>
</name>
<xref ref-type="aff" rid="aff9">9</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Cohn</surname>
<given-names>S L</given-names>
</name>
<xref ref-type="aff" rid="aff10">10</xref>
</contrib>
<contrib contrib-type="author">
<name>
<surname>Pearson</surname>
<given-names>A D J</given-names>
</name>
<xref ref-type="aff" rid="aff11">11</xref>
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<contrib contrib-type="author">
<name>
<surname>Maris</surname>
<given-names>J M</given-names>
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<xref ref-type="aff" rid="aff2">2</xref>
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<aff id="aff1">
<label>1</label>
<institution>CCRI, Children's Cancer Research Institute</institution>
Vienna,
<country>Austria</country>
</aff>
<aff id="aff2">
<label>2</label>
<institution>Center for Childhood Cancer Research, Children's Hospital of Philadelphia, University of Pennsylvania School of Medicine</institution>
PA,
<country>USA</country>
</aff>
<aff id="aff3">
<label>3</label>
<institution>Children's Cancer Institute Australia</institution>
Sydney,
<country>Australia</country>
</aff>
<aff id="aff4">
<label>4</label>
<institution>National Cancer Institute</institution>
Bethesda, MD,
<country>USA</country>
</aff>
<aff id="aff5">
<label>5</label>
<institution>Chiba Cancer Center Research Institute</institution>
<country>Japan</country>
</aff>
<aff id="aff6">
<label>6</label>
<institution>Institut Curie</institution>
Paris,
<country>France</country>
</aff>
<aff id="aff7">
<label>7</label>
<institution>Centre for Medical Genetics</institution>
Ghent,
<country>Belgium</country>
</aff>
<aff id="aff8">
<label>8</label>
<institution>University of Cologne</institution>
<country>Germany</country>
</aff>
<aff id="aff9">
<label>9</label>
<institution>Children's Oncology Group Statistics and Data Center, University of Florida</institution>
Gainesville, FL,
<country>USA</country>
</aff>
<aff id="aff10">
<label>10</label>
<institution>The University of Chicago</institution>
Chicago, IL,
<country>USA</country>
</aff>
<aff id="aff11">
<label>11</label>
<institution>Section of Paediatrics, Institute of Cancer Research and Royal Marsden Hospital</institution>
Surrey,
<country>UK</country>
</aff>
<author-notes>
<corresp id="caf1">
<label>*</label>
Author for correspondence:
<email xlink:href="mailto:ambros@ccri.at">ambros@ccri.at</email>
</corresp>
<corresp id="caf2">
<label>*</label>
Author for correspondence:
<email xlink:href="mailto:maris@chop.edu">maris@chop.edu</email>
</corresp>
</author-notes>
<pub-date pub-type="epub">
<day>28</day>
<month>04</month>
<year>2009</year>
</pub-date>
<pub-date pub-type="ppub">
<day>05</day>
<month>05</month>
<year>2009</year>
</pub-date>
<volume>100</volume>
<issue>9</issue>
<fpage>1471</fpage>
<lpage>1482</lpage>
<history>
<date date-type="received">
<day>30</day>
<month>09</month>
<year>2008</year>
</date>
<date date-type="rev-recd">
<day>26</day>
<month>02</month>
<year>2009</year>
</date>
<date date-type="accepted">
<day>06</day>
<month>03</month>
<year>2009</year>
</date>
</history>
<copyright-statement>Copyright 2009, Cancer Research UK</copyright-statement>
<copyright-year>2009</copyright-year>
<permissions>
<copyright-holder>Cancer Research UK</copyright-holder>
</permissions>
<abstract>
<p>Neuroblastoma serves as a paradigm for utilising tumour genomic data for determining patient prognosis and treatment allocation. However, before the establishment of the International Neuroblastoma Risk Group (INRG) Task Force in 2004, international consensus on markers, methodology, and data interpretation did not exist, compromising the reliability of decisive genetic markers and inhibiting translational research efforts. The objectives of the INRG Biology Committee were to identify highly prognostic genetic aberrations to be included in the new INRG risk classification schema and to develop precise definitions, decisive biomarkers, and technique standardisation. The review of the INRG database (
<italic>n</italic>
=8800 patients) by the INRG Task Force finally enabled the identification of the most significant neuroblastoma biomarkers. In addition, the Biology Committee compared the standard operating procedures of different cooperative groups to arrive at international consensus for methodology, nomenclature, and future directions. Consensus was reached to include
<italic>MYCN</italic>
status, 11q23 allelic status, and ploidy in the INRG classification system on the basis of an evidence-based review of the INRG database. Standardised operating procedures for analysing these genetic factors were adopted, and criteria for proper nomenclature were developed. Neuroblastoma treatment planning is highly dependant on tumour cell genomic features, and it is likely that a comprehensive panel of DNA-based biomarkers will be used in future risk assignment algorithms applying genome-wide techniques. Consensus on methodology and interpretation is essential for uniform INRG classification and will greatly facilitate international and cooperative clinical and translational research studies.</p>
</abstract>
<kwd-group>
<kwd>neuroblastoma</kwd>
<kwd>treatment planning</kwd>
<kwd>genomic</kwd>
<kwd>translational</kwd>
<kwd>international consensus</kwd>
<kwd>INRG</kwd>
<kwd>genetic risk factors</kwd>
</kwd-group>
</article-meta>
</front>
<floats-wrap>
<fig id="fig1">
<label>Figure 1</label>
<caption>
<p>Biological pathways and genetic features in neuroblastic tumours. Tumour cell ploidy (grey columns) can be used to subdivide neuroblastoma tumours into two broad groups (separated by the long punctuated line). Although the ploidy subgroups roughly correspond to the biologic subgroups (aggressive neuroblastomas marked by a red background – either with
<italic>MYCN</italic>
amplification in dark red and separated by a short punctuated line from neuroblastomas without
<italic>MYCN</italic>
amplification
<italic>vs</italic>
less aggressive behaving neuroblastomas indicated by a green background), they do not totally match. Although aggressive near-triploid neuroblastomas (in red below the long punctuated line) have been observed, it is less clear if ‘benign' diploid neuroblastomas without any structural aberrations (in green above the long punctuated line) occur. ‘Benign' clinical behaviour refers either to spontaneous regression/maturation without any therapy or with surgery only (no cytotoxic therapy).</p>
</caption>
<graphic mime-subtype="eps" xlink:href="6605014f1"></graphic>
</fig>
<fig id="fig2">
<label>Figure 2</label>
<caption>
<p>Recommendations concerning the splitting of the tumour material for resected tumours or surgical biopsies. All specimens should be transported to the pathology laboratory as quickly as possible. From there, the snap frozen and/or OCT embedded material should then be transported immediately to the biology lab (can be used for any type of DNA, RNA or protein work). Normal reference cells (e.g., peripheral blood) should be sent to the reference laboratories.</p>
</caption>
<graphic mime-subtype="eps" xlink:href="6605014f2"></graphic>
</fig>
<fig id="fig3">
<label>Figure 3</label>
<caption>
<p>Heterogeneous
<italic>MYCN</italic>
amplification and recommended procedure for the clarification of the underlying genetic pattern.</p>
</caption>
<graphic mime-subtype="eps" xlink:href="6605014f3"></graphic>
</fig>
<table-wrap id="tbl1" position="float">
<label>Table 1</label>
<caption>
<p content-type="table-title">Tests of association of genetic factors</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>MYCN</italic>
amplification</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>1p aberration</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>11q aberration</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>17q gain</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Diploidy</td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
<0.0001</td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
<0.0001</td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
=0.1242</td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
=0.3613</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>MNA</italic>
</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
<0.0001</td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
=0.0006
<sup>*</sup>
</td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
=0.0096</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">1p aberration</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
=0.0613</td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
<0.0001</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">11q aberration</td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50"> </td>
<td align="center" valign="top" charoff="50">
<italic>P</italic>
<0.0001</td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t1-fn1">
<label></label>
<p>
<sup>*</sup>
Inversely associated. MNA
<italic>MYCN</italic>
amplification</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl2a" position="float">
<label>Table 2a</label>
<caption>
<p content-type="table-title">Event-free and overall survival (EFS and OS) of genetic factors by INSS stage</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>INSS stage 1</bold>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>INSS stage 2</bold>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>INSS stage 3</bold>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>INSS stage 4s</bold>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>INSS Stage 1,2,3,4s</bold>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>INSS Stage 4</bold>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Hyper diploid (
<italic>n</italic>
=2611)</td>
<td align="center" valign="top" charoff="50">719 (28)</td>
<td align="center" valign="top" charoff="50">93±2</td>
<td align="center" valign="top" charoff="50">99±1</td>
<td align="center" valign="top" charoff="50">415 (16)</td>
<td align="center" valign="top" charoff="50">88±3</td>
<td align="center" valign="top" charoff="50">96±2</td>
<td align="center" valign="top" charoff="50">452 (17)</td>
<td align="center" valign="top" charoff="50">82±3</td>
<td align="center" valign="top" charoff="50">86±3</td>
<td align="center" valign="top" charoff="50">232 (9)</td>
<td align="center" valign="top" charoff="50">86±3</td>
<td align="center" valign="top" charoff="50">92±3</td>
<td align="center" valign="top" charoff="50">1818 (70)</td>
<td align="center" valign="top" charoff="50">88±1</td>
<td align="center" valign="top" charoff="50">94±1</td>
<td align="center" valign="top" charoff="50">728 (28)</td>
<td align="center" valign="top" charoff="50">47±3</td>
<td align="center" valign="top" charoff="50">53±3</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Diploid
<italic>n</italic>
=1086)</td>
<td align="center" valign="top" charoff="50">196 (18)</td>
<td align="center" valign="top" charoff="50">90±4</td>
<td align="center" valign="top" charoff="50">96±2</td>
<td align="center" valign="top" charoff="50">119 (11)</td>
<td align="center" valign="top" charoff="50">84±5</td>
<td align="center" valign="top" charoff="50">90±5</td>
<td align="center" valign="top" charoff="50">152 (14)</td>
<td align="center" valign="top" charoff="50">65±6</td>
<td align="center" valign="top" charoff="50">66±6</td>
<td align="center" valign="top" charoff="50">62 (6)</td>
<td align="center" valign="top" charoff="50">77±9</td>
<td align="center" valign="top" charoff="50">77±9</td>
<td align="center" valign="top" charoff="50">529 (49)</td>
<td align="center" valign="top" charoff="50">80±3</td>
<td align="center" valign="top" charoff="50">84±3</td>
<td align="center" valign="top" charoff="50">527 (50)</td>
<td align="center" valign="top" charoff="50">31±3</td>
<td align="center" valign="top" charoff="50">36±3</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>MYCN,</italic>
not amplified (
<italic>n</italic>
=5947)</td>
<td align="center" valign="top" charoff="50">1626 (27)</td>
<td align="center" valign="top" charoff="50">93±1</td>
<td align="center" valign="top" charoff="50">98±1</td>
<td align="center" valign="top" charoff="50">947 (16)</td>
<td align="center" valign="top" charoff="50">85±2</td>
<td align="center" valign="top" charoff="50">97±1</td>
<td align="center" valign="top" charoff="50">1013 (17)</td>
<td align="center" valign="top" charoff="50">81±2</td>
<td align="center" valign="top" charoff="50">89±1</td>
<td align="center" valign="top" charoff="50">481 (8)</td>
<td align="center" valign="top" charoff="50">82±2</td>
<td align="center" valign="top" charoff="50">91±2</td>
<td align="center" valign="top" charoff="50">4067 (68)</td>
<td align="center" valign="top" charoff="50">87±1</td>
<td align="center" valign="top" charoff="50">95±1</td>
<td align="center" valign="top" charoff="50">1798 (31)</td>
<td align="center" valign="top" charoff="50">45±2</td>
<td align="center" valign="top" charoff="50">54±2</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>MYCN,</italic>
amplified (
<italic>n</italic>
=1155)</td>
<td align="center" valign="top" charoff="50">48 (4)</td>
<td align="center" valign="top" charoff="50">50±12</td>
<td align="center" valign="top" charoff="50">76±9</td>
<td align="center" valign="top" charoff="50">39 (3)</td>
<td align="center" valign="top" charoff="50">57±12</td>
<td align="center" valign="top" charoff="50">67±11</td>
<td align="center" valign="top" charoff="50">217 (19)</td>
<td align="center" valign="top" charoff="50">45±4</td>
<td align="center" valign="top" charoff="50">48±4</td>
<td align="center" valign="top" charoff="50">47 (4)</td>
<td align="center" valign="top" charoff="50">41±9</td>
<td align="center" valign="top" charoff="50">45±9</td>
<td align="center" valign="top" charoff="50">351 (30)</td>
<td align="center" valign="top" charoff="50">46±4</td>
<td align="center" valign="top" charoff="50">53±4</td>
<td align="center" valign="top" charoff="50">787 (69)</td>
<td align="center" valign="top" charoff="50">21±2</td>
<td align="center" valign="top" charoff="50">25±2</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">1p normal (
<italic>n</italic>
=1659)</td>
<td align="center" valign="top" charoff="50">489 (29)</td>
<td align="center" valign="top" charoff="50">93±2</td>
<td align="center" valign="top" charoff="50">98±1</td>
<td align="center" valign="top" charoff="50">264 (16)</td>
<td align="center" valign="top" charoff="50">83±3</td>
<td align="center" valign="top" charoff="50">98±1</td>
<td align="center" valign="top" charoff="50">313 (19)</td>
<td align="center" valign="top" charoff="50">77±3</td>
<td align="center" valign="top" charoff="50">88±3</td>
<td align="center" valign="top" charoff="50">152 (9)</td>
<td align="center" valign="top" charoff="50">86±4</td>
<td align="center" valign="top" charoff="50">95±3</td>
<td align="center" valign="top" charoff="50">1218 (73)</td>
<td align="center" valign="top" charoff="50">86±1</td>
<td align="center" valign="top" charoff="50">95±1</td>
<td align="center" valign="top" charoff="50">430 (26)</td>
<td align="center" valign="top" charoff="50">42±3</td>
<td align="center" valign="top" charoff="50">50±3</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">1p aberration (
<italic>n</italic>
=493)</td>
<td align="center" valign="top" charoff="50">48 (10)</td>
<td align="center" valign="top" charoff="50">76±9</td>
<td align="center" valign="top" charoff="50">100</td>
<td align="center" valign="top" charoff="50">29 (6)</td>
<td align="center" valign="top" charoff="50">63±11</td>
<td align="center" valign="top" charoff="50">81±9</td>
<td align="center" valign="top" charoff="50">90 (18)</td>
<td align="center" valign="top" charoff="50">52±7</td>
<td align="center" valign="top" charoff="50">61±7</td>
<td align="center" valign="top" charoff="50">29 (6)</td>
<td align="center" valign="top" charoff="50">60±13</td>
<td align="center" valign="top" charoff="50">67±12</td>
<td align="center" valign="top" charoff="50">196 (40)</td>
<td align="center" valign="top" charoff="50">60±5</td>
<td align="center" valign="top" charoff="50">74±4</td>
<td align="center" valign="top" charoff="50">280 (57)</td>
<td align="center" valign="top" charoff="50">24±4</td>
<td align="center" valign="top" charoff="50">32±4</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">11q normal (
<italic>n</italic>
=844)</td>
<td align="center" valign="top" charoff="50">227 (27)</td>
<td align="center" valign="top" charoff="50">90±3</td>
<td align="center" valign="top" charoff="50">99±1</td>
<td align="center" valign="top" charoff="50">141 (17)</td>
<td align="center" valign="top" charoff="50">71±7</td>
<td align="center" valign="top" charoff="50">95±3</td>
<td align="center" valign="top" charoff="50">152 (18)</td>
<td align="center" valign="top" charoff="50">77±5</td>
<td align="center" valign="top" charoff="50">85±4</td>
<td align="center" valign="top" charoff="50">69 (8)</td>
<td align="center" valign="top" charoff="50">86±7</td>
<td align="center" valign="top" charoff="50">95±5</td>
<td align="center" valign="top" charoff="50">589 (70)</td>
<td align="center" valign="top" charoff="50">82±3</td>
<td align="center" valign="top" charoff="50">94±2</td>
<td align="center" valign="top" charoff="50">233 (28)</td>
<td align="center" valign="top" charoff="50">42±5</td>
<td align="center" valign="top" charoff="50">50±5</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">11q aberration (
<italic>n</italic>
=220)</td>
<td align="center" valign="top" charoff="50">11 (5)</td>
<td align="center" valign="top" charoff="50">73±22</td>
<td align="center" valign="top" charoff="50">91±14</td>
<td align="center" valign="top" charoff="50">11 (5)</td>
<td align="center" valign="top" charoff="50">45±34</td>
<td align="center" valign="top" charoff="50">91±16</td>
<td align="center" valign="top" charoff="50">35 (16)</td>
<td align="center" valign="top" charoff="50">51±11</td>
<td align="center" valign="top" charoff="50">75±11</td>
<td align="center" valign="top" charoff="50">8 (4)</td>
<td align="center" valign="top" charoff="50">38±30</td>
<td align="center" valign="top" charoff="50">63±38</td>
<td align="center" valign="top" charoff="50">65 (30)</td>
<td align="center" valign="top" charoff="50">51±10</td>
<td align="center" valign="top" charoff="50">79±8</td>
<td align="center" valign="top" charoff="50">153 (70)</td>
<td align="center" valign="top" charoff="50">28±6</td>
<td align="center" valign="top" charoff="50">47±7</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">17q normal (
<italic>n</italic>
=187)</td>
<td align="center" valign="top" charoff="50">36 (19)</td>
<td align="center" valign="top" charoff="50">78±9</td>
<td align="center" valign="top" charoff="50">97±4</td>
<td align="center" valign="top" charoff="50">22 (12)</td>
<td align="center" valign="top" charoff="50">77±12</td>
<td align="center" valign="top" charoff="50">100</td>
<td align="center" valign="top" charoff="50">47 (25)</td>
<td align="center" valign="top" charoff="50">74±7</td>
<td align="center" valign="top" charoff="50">85±6</td>
<td align="center" valign="top" charoff="50">15 (8)</td>
<td align="center" valign="top" charoff="50">92±11</td>
<td align="center" valign="top" charoff="50">92±11</td>
<td align="center" valign="top" charoff="50">120 (64)</td>
<td align="center" valign="top" charoff="50">78±5</td>
<td align="center" valign="top" charoff="50">92±3</td>
<td align="center" valign="top" charoff="50">60 (32)</td>
<td align="center" valign="top" charoff="50">40±7</td>
<td align="center" valign="top" charoff="50">46±7</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">17q gain (
<italic>n</italic>
=175)</td>
<td align="center" valign="top" charoff="50">20 (11)</td>
<td align="center" valign="top" charoff="50">95±9</td>
<td align="center" valign="top" charoff="50">100</td>
<td align="center" valign="top" charoff="50">19 (11)</td>
<td align="center" valign="top" charoff="50">51±18</td>
<td align="center" valign="top" charoff="50">84±14</td>
<td align="center" valign="top" charoff="50">16 (9)</td>
<td align="center" valign="top" charoff="50">75±13</td>
<td align="center" valign="top" charoff="50">94±7</td>
<td align="center" valign="top" charoff="50">4 (2)</td>
<td align="center" valign="top" charoff="50">100</td>
<td align="center" valign="top" charoff="50">100</td>
<td align="center" valign="top" charoff="50">59 (34)</td>
<td align="center" valign="top" charoff="50">76±8</td>
<td align="center" valign="top" charoff="50">93±5</td>
<td align="center" valign="top" charoff="50">104 (59)</td>
<td align="center" valign="top" charoff="50">24±6</td>
<td align="center" valign="top" charoff="50">38±7</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tbl2b" position="float">
<label>Table 2b</label>
<caption>
<p content-type="table-title">Event-free and overall survival (EFS and OS) of genetic factors, by age and primary tumour site at diagnosis</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
<col align="center"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>Age <547 days</bold>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>Age > 547 days</bold>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>Adrenal primary tumour site</bold>
</th>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>Non-adrenal primary tumour site</bold>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50"> </th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>
<italic>n</italic>
(%)</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year EFS±s.e.</bold>
</th>
<th align="center" valign="top" charoff="50">
<bold>5-year OS±s.e.</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Hyper diploid (
<italic>n</italic>
=2611)</td>
<td align="center" valign="top" charoff="50">1816 (70)</td>
<td align="center" valign="top" charoff="50">88±1</td>
<td align="center" valign="top" charoff="50">95±1</td>
<td align="center" valign="top" charoff="50">795 (30)</td>
<td align="center" valign="top" charoff="50">48±3</td>
<td align="center" valign="top" charoff="50">54±3</td>
<td align="center" valign="top" charoff="50">1023 (39)</td>
<td align="center" valign="top" charoff="50">73±2</td>
<td align="center" valign="top" charoff="50">78±2</td>
<td align="center" valign="top" charoff="50">1473 (56)</td>
<td align="center" valign="top" charoff="50">78±2</td>
<td align="center" valign="top" charoff="50">85±1</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Diploid (
<italic>n</italic>
=1086)</td>
<td align="center" valign="top" charoff="50">425 (39)</td>
<td align="center" valign="top" charoff="50">70±4</td>
<td align="center" valign="top" charoff="50">75±4</td>
<td align="center" valign="top" charoff="50">661 (61)</td>
<td align="center" valign="top" charoff="50">46±3</td>
<td align="center" valign="top" charoff="50">50±3</td>
<td align="center" valign="top" charoff="50">489 (45)</td>
<td align="center" valign="top" charoff="50">49±4</td>
<td align="center" valign="top" charoff="50">54±3</td>
<td align="center" valign="top" charoff="50">556 (51)</td>
<td align="center" valign="top" charoff="50">60±3</td>
<td align="center" valign="top" charoff="50">64±3</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>MYCN,</italic>
not amplified (
<italic>n</italic>
=5947)</td>
<td align="center" valign="top" charoff="50">3657 (61)</td>
<td align="center" valign="top" charoff="50">88±1</td>
<td align="center" valign="top" charoff="50">95±1</td>
<td align="center" valign="top" charoff="50">2290 (39)</td>
<td align="center" valign="top" charoff="50">51±1</td>
<td align="center" valign="top" charoff="50">60±1</td>
<td align="center" valign="top" charoff="50">2439 (41)</td>
<td align="center" valign="top" charoff="50">69±1</td>
<td align="center" valign="top" charoff="50">76±1</td>
<td align="center" valign="top" charoff="50">3265 (55)</td>
<td align="center" valign="top" charoff="50">77±1</td>
<td align="center" valign="top" charoff="50">86±1</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>MYCN,</italic>
amplified (
<italic>n</italic>
=1155)</td>
<td align="center" valign="top" charoff="50">404 (35)</td>
<td align="center" valign="top" charoff="50">36±3</td>
<td align="center" valign="top" charoff="50">41±3</td>
<td align="center" valign="top" charoff="50">751 (65)</td>
<td align="center" valign="top" charoff="50">26±2</td>
<td align="center" valign="top" charoff="50">30±2</td>
<td align="center" valign="top" charoff="50">732 (63)</td>
<td align="center" valign="top" charoff="50">27±2</td>
<td align="center" valign="top" charoff="50">33±2</td>
<td align="center" valign="top" charoff="50">384 (33)</td>
<td align="center" valign="top" charoff="50">33±4</td>
<td align="center" valign="top" charoff="50">37±4</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">1p normal (
<italic>n</italic>
=1659)</td>
<td align="center" valign="top" charoff="50">1095 (66)</td>
<td align="center" valign="top" charoff="50">88±1</td>
<td align="center" valign="top" charoff="50">96±1</td>
<td align="center" valign="top" charoff="50">564 (34)</td>
<td align="center" valign="top" charoff="50">49±3</td>
<td align="center" valign="top" charoff="50">59±3</td>
<td align="center" valign="top" charoff="50">751 (45)</td>
<td align="center" valign="top" charoff="50">71±2</td>
<td align="center" valign="top" charoff="50">78±2</td>
<td align="center" valign="top" charoff="50">881 (53)</td>
<td align="center" valign="top" charoff="50">77±2</td>
<td align="center" valign="top" charoff="50">88±2</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">1p aberration (
<italic>n</italic>
=493)</td>
<td align="center" valign="top" charoff="50">185 (38)</td>
<td align="center" valign="top" charoff="50">57±5</td>
<td align="center" valign="top" charoff="50">65±5</td>
<td align="center" valign="top" charoff="50">308 (62)</td>
<td align="center" valign="top" charoff="50">26±3</td>
<td align="center" valign="top" charoff="50">38±4</td>
<td align="center" valign="top" charoff="50">323 (66)</td>
<td align="center" valign="top" charoff="50">33±4</td>
<td align="center" valign="top" charoff="50">44±4</td>
<td align="center" valign="top" charoff="50">157 (32)</td>
<td align="center" valign="top" charoff="50">48±5</td>
<td align="center" valign="top" charoff="50">58±5</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">11q normal (
<italic>n</italic>
=844)</td>
<td align="center" valign="top" charoff="50">510 (60)</td>
<td align="center" valign="top" charoff="50">83±3</td>
<td align="center" valign="top" charoff="50">93±2</td>
<td align="center" valign="top" charoff="50">334 (40)</td>
<td align="center" valign="top" charoff="50">46±4</td>
<td align="center" valign="top" charoff="50">57±4</td>
<td align="center" valign="top" charoff="50">359 (43)</td>
<td align="center" valign="top" charoff="50">64±4</td>
<td align="center" valign="top" charoff="50">72±4</td>
<td align="center" valign="top" charoff="50">451 (53)</td>
<td align="center" valign="top" charoff="50">73±3</td>
<td align="center" valign="top" charoff="50">85±3</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">11q aberration (
<italic>n</italic>
=220)</td>
<td align="center" valign="top" charoff="50">63 (29)</td>
<td align="center" valign="top" charoff="50">61±11</td>
<td align="center" valign="top" charoff="50">85±8</td>
<td align="center" valign="top" charoff="50">157 (71)</td>
<td align="center" valign="top" charoff="50">26±5</td>
<td align="center" valign="top" charoff="50">47±6</td>
<td align="center" valign="top" charoff="50">126 (57)</td>
<td align="center" valign="top" charoff="50">34±6</td>
<td align="center" valign="top" charoff="50">52±7</td>
<td align="center" valign="top" charoff="50">93 (42)</td>
<td align="center" valign="top" charoff="50">35±9</td>
<td align="center" valign="top" charoff="50">63±9</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">17q normal (
<italic>n</italic>
=187)</td>
<td align="center" valign="top" charoff="50">104 (56)</td>
<td align="center" valign="top" charoff="50">80±5</td>
<td align="center" valign="top" charoff="50">92±3</td>
<td align="center" valign="top" charoff="50">83 (44)</td>
<td align="center" valign="top" charoff="50">44±6</td>
<td align="center" valign="top" charoff="50">53±6</td>
<td align="center" valign="top" charoff="50">74 (40)</td>
<td align="center" valign="top" charoff="50">60±7</td>
<td align="center" valign="top" charoff="50">65±7</td>
<td align="center" valign="top" charoff="50">105 (56)</td>
<td align="center" valign="top" charoff="50">67±6</td>
<td align="center" valign="top" charoff="50">82±5</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">17q gain (
<italic>n</italic>
=175)</td>
<td align="center" valign="top" charoff="50">65 (37)</td>
<td align="center" valign="top" charoff="50">68±9</td>
<td align="center" valign="top" charoff="50">83±7</td>
<td align="center" valign="top" charoff="50">110 (63)</td>
<td align="center" valign="top" charoff="50">27±5</td>
<td align="center" valign="top" charoff="50">41±6</td>
<td align="center" valign="top" charoff="50">116 (66)</td>
<td align="center" valign="top" charoff="50">37±7</td>
<td align="center" valign="top" charoff="50">51±7</td>
<td align="center" valign="top" charoff="50">53 (30)</td>
<td align="center" valign="top" charoff="50">53±9</td>
<td align="center" valign="top" charoff="50">67±9</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tbl3" position="float">
<label>Table 3</label>
<caption>
<p content-type="table-title">Consensus of genetic markers currently used for therapy stratification and proposed for future analyses</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50">
<bold>Genetic INRG risk classification markers</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Techniques recommended/accepted</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>DNA probes recommended and comments</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">
<bold>Obligatory markers</bold>
</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>MYCN</italic>
</td>
<td align="left" valign="top" charoff="50">I-FISH
<break></break>
PCR, aCGH, MLPA</td>
<td align="left" valign="top" charoff="50">Two colour I-FISH: BAC or other large DNA-insert clone for the
<italic>MYCN</italic>
gene and a clone of similar size for a gene/locus on the long arm of chromosome 2 (e.g., LAF at 2q11); commercially available probes should be used whenever possible</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">11q23</td>
<td align="left" valign="top" charoff="50">I-FISH, PCR; pan-/multigenomic techniques: aCGH (oligo, clone or SNP based); MLPA</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Ploidy</td>
<td align="left" valign="top" charoff="50">Flow or static cytometry</td>
<td align="left" valign="top" charoff="50">Normal cells from the same patient should be used as a diploid standard</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<bold>Genetic markers to be analysed prospectively</bold>
</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">1p</td>
<td align="left" valign="top" charoff="50">aCGH, SNP arrays, MLPA etc.</td>
<td align="left" valign="top" charoff="50">Commercially available platform preferred</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">2p</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>DDX1</italic>
</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>NAG</italic>
</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>ALK</italic>
</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">3p</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">4p</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">7q</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">9p</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">12p</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">14q</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">17q</td>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Others</td>
<td align="left" valign="top" charoff="50">aCGH, SNP arrays</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t3-fn1">
<label></label>
<p>aCGH=array-based comparative genomic hybridisation; BAC=bacterial artificial chromosomes; I-FISH=interphase fluorescence
<italic>in situ</italic>
hybridisation; INRG=International Neuroblastoma Risk Group; MLPA=multiplex ligation-dependent probe amplification; PCR=polymerase chain reaction; SNP=single nucleotide polymorphism.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl4" position="float">
<label>Table 4</label>
<caption>
<p content-type="table-title">Laboratories responsible for Neuroblastom Genetics</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th align="left" valign="top" charoff="50">
<bold>National Group</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Name</bold>
</th>
<th align="left" valign="top" charoff="50"> </th>
<th align="left" valign="top" charoff="50">
<bold>Institution</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Town</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Country</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Australia</td>
<td align="left" valign="top" charoff="50">Michelle</td>
<td align="left" valign="top" charoff="50">Haber, PhD</td>
<td align="left" valign="top" charoff="50">Children's Cancer Institute Australia and COG</td>
<td align="left" valign="top" charoff="50">Sydney, NSW</td>
<td align="left" valign="top" charoff="50">Australia</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">COG</td>
<td align="left" valign="top" charoff="50">Julie</td>
<td align="left" valign="top" charoff="50">Gastier-Foster, PhD</td>
<td align="left" valign="top" charoff="50">Nationwide Children's Hospital</td>
<td align="left" valign="top" charoff="50">Columbus, OH</td>
<td align="left" valign="top" charoff="50">USA</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Michael</td>
<td align="left" valign="top" charoff="50">Hogarty, MD</td>
<td align="left" valign="top" charoff="50">Children's Hospital of Philadelphia</td>
<td align="left" valign="top" charoff="50">Philadelphia, PA</td>
<td align="left" valign="top" charoff="50">USA</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Rochelle</td>
<td align="left" valign="top" charoff="50">Bagatell, MD</td>
<td align="left" valign="top" charoff="50">Children's Hospital of Philadelphia</td>
<td align="left" valign="top" charoff="50">Philadelphia, PA</td>
<td align="left" valign="top" charoff="50">USA</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Germany</td>
<td align="left" valign="top" charoff="50">Frank</td>
<td align="left" valign="top" charoff="50">Berthold, MD</td>
<td align="left" valign="top" charoff="50">Department of Pediatric Hematology and Oncology, University of Cologne</td>
<td align="left" valign="top" charoff="50">Cologne</td>
<td align="left" valign="top" charoff="50">Germany</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Jessica</td>
<td align="left" valign="top" charoff="50">Theißen, PhD</td>
<td align="left" valign="top" charoff="50">Department of Pediatric Hematology and Oncology, University of Cologne</td>
<td align="left" valign="top" charoff="50">Cologne</td>
<td align="left" valign="top" charoff="50">Germany</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Manfred</td>
<td align="left" valign="top" charoff="50">Schwab, PhD</td>
<td align="left" valign="top" charoff="50">Division of Cytogenetics, German Cancer Research Center</td>
<td align="left" valign="top" charoff="50">Heidelberg</td>
<td align="left" valign="top" charoff="50">Germany</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Frank</td>
<td align="left" valign="top" charoff="50">Westermann, MD</td>
<td align="left" valign="top" charoff="50">Division of Cytogenetics, German Cancer Research Center</td>
<td align="left" valign="top" charoff="50">Heidelberg</td>
<td align="left" valign="top" charoff="50">Germany</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Freimut H</td>
<td align="left" valign="top" charoff="50">Schilling, MD</td>
<td align="left" valign="top" charoff="50">Department of Pediatric Oncology and Hematology, Olgahospital</td>
<td align="left" valign="top" charoff="50">Stuttgart</td>
<td align="left" valign="top" charoff="50">Germany</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Sabine</td>
<td align="left" valign="top" charoff="50">Stegmaier, PhD</td>
<td align="left" valign="top" charoff="50">Department of Pediatric Oncology and Hematology, Olgahospital</td>
<td align="left" valign="top" charoff="50">Stuttgart</td>
<td align="left" valign="top" charoff="50">Germany</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Niggli</td>
<td align="left" valign="top" charoff="50">Felix, MD</td>
<td align="left" valign="top" charoff="50">Department of Pediatric Oncology and Hematology</td>
<td align="left" valign="top" charoff="50">Zurich</td>
<td align="left" valign="top" charoff="50">Switzerland</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Japan</td>
<td align="left" valign="top" charoff="50">Akira</td>
<td align="left" valign="top" charoff="50">Nakagawara, MD</td>
<td align="left" valign="top" charoff="50">Chiba Cancer Center Research Institute</td>
<td align="left" valign="top" charoff="50">Chiba</td>
<td align="left" valign="top" charoff="50">Japan</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Miki</td>
<td align="left" valign="top" charoff="50">Ohira, MD</td>
<td align="left" valign="top" charoff="50">Chiba Cancer Center Research Institute</td>
<td align="left" valign="top" charoff="50">Chiba</td>
<td align="left" valign="top" charoff="50">Japan</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Yasuhiko</td>
<td align="left" valign="top" charoff="50">Kaneko, MD</td>
<td align="left" valign="top" charoff="50">Saitama Cancer Center Research Institute</td>
<td align="left" valign="top" charoff="50">Saitama</td>
<td align="left" valign="top" charoff="50">Japan</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Junko</td>
<td align="left" valign="top" charoff="50">Takita, MD</td>
<td align="left" valign="top" charoff="50">Department of Pediatrics, University of Tokyo</td>
<td align="left" valign="top" charoff="50">Tokyo</td>
<td align="left" valign="top" charoff="50">Japan</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Hajime</td>
<td align="left" valign="top" charoff="50">Ohkita, MD</td>
<td align="left" valign="top" charoff="50">National Center for Child Health and Development</td>
<td align="left" valign="top" charoff="50">Tokyo</td>
<td align="left" valign="top" charoff="50">Japan</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">SIOPEN Biology</td>
<td align="left" valign="top" charoff="50">Peter F</td>
<td align="left" valign="top" charoff="50">Ambros, PhD</td>
<td align="left" valign="top" charoff="50">CCRI, Children's Cancer Research Institute</td>
<td align="left" valign="top" charoff="50">Vienna</td>
<td align="left" valign="top" charoff="50">Austria</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Inge M</td>
<td align="left" valign="top" charoff="50">Ambros, MD</td>
<td align="left" valign="top" charoff="50">CCRI, Children's Cancer Research Institute</td>
<td align="left" valign="top" charoff="50">Vienna</td>
<td align="left" valign="top" charoff="50">Austria</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Frank</td>
<td align="left" valign="top" charoff="50">Spelemann, PhD</td>
<td align="left" valign="top" charoff="50">Center for Medical Genetics-OK5, University of Ghent</td>
<td align="left" valign="top" charoff="50">Ghent</td>
<td align="left" valign="top" charoff="50">Belgium</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Nadine</td>
<td align="left" valign="top" charoff="50">Van Roy, PhD</td>
<td align="left" valign="top" charoff="50">Center for Medical Genetics-OK5, University of Ghent</td>
<td align="left" valign="top" charoff="50">Ghent</td>
<td align="left" valign="top" charoff="50">Belgium</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Ales</td>
<td align="left" valign="top" charoff="50">Vicha, MD</td>
<td align="left" valign="top" charoff="50">Department of Pediatric Hematology and Oncology, Motol</td>
<td align="left" valign="top" charoff="50">Prague</td>
<td align="left" valign="top" charoff="50">Czech Republic</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Jean</td>
<td align="left" valign="top" charoff="50">Bénard, MD</td>
<td align="left" valign="top" charoff="50">Lab De Pharmacologie Clinique et Moleculaire, Instiut Gustav Roussy</td>
<td align="left" valign="top" charoff="50">Villejuife-Cedex</td>
<td align="left" valign="top" charoff="50">France</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Alexander</td>
<td align="left" valign="top" charoff="50">Valent, PhD</td>
<td align="left" valign="top" charoff="50">Lab De Pharmacologie Clinique et Moleculaire, Instiut Gustav Roussy</td>
<td align="left" valign="top" charoff="50">Villejuife-Cedex</td>
<td align="left" valign="top" charoff="50">France</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Jérome</td>
<td align="left" valign="top" charoff="50">Couturier, MD</td>
<td align="left" valign="top" charoff="50">Unité de Cytogénétique oncologique, Institut Curie – Section Médicale</td>
<td align="left" valign="top" charoff="50">Paris</td>
<td align="left" valign="top" charoff="50">France</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Olivier</td>
<td align="left" valign="top" charoff="50">Delattre, PhD</td>
<td align="left" valign="top" charoff="50">Unité de Cytogénétique oncologique, Institut Curie – Section Médicale</td>
<td align="left" valign="top" charoff="50">Paris</td>
<td align="left" valign="top" charoff="50">France</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Gudrun</td>
<td align="left" valign="top" charoff="50">Schleiermacher, MD</td>
<td align="left" valign="top" charoff="50">Unité de Cytogénétique oncologique, Institut Curie, Section Médicale</td>
<td align="left" valign="top" charoff="50">Paris</td>
<td align="left" valign="top" charoff="50">France</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Marta</td>
<td align="left" valign="top" charoff="50">Jeison, PhD</td>
<td align="left" valign="top" charoff="50">Pediatric Hematology Oncology Department, Schneider Children's Medical Center of Israel</td>
<td align="left" valign="top" charoff="50">Petah Tikva</td>
<td align="left" valign="top" charoff="50">Israel</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Gian Paolo</td>
<td align="left" valign="top" charoff="50">Tonini, PhD</td>
<td align="left" valign="top" charoff="50">Translational Paediatric Oncology, National Cancer Research Institute (IST)</td>
<td align="left" valign="top" charoff="50">Genoa</td>
<td align="left" valign="top" charoff="50">Italy</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Raffaella</td>
<td align="left" valign="top" charoff="50">Defferrari, PhD</td>
<td align="left" valign="top" charoff="50">Translational Paediatric Oncology, National Cancer Research Institute (IST)</td>
<td align="left" valign="top" charoff="50">Genoa</td>
<td align="left" valign="top" charoff="50">Italy</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Katia</td>
<td align="left" valign="top" charoff="50">Mazzocco, PhD</td>
<td align="left" valign="top" charoff="50">Translational Paediatric Oncology, National Cancer Research Institute (IST)</td>
<td align="left" valign="top" charoff="50">Genoa</td>
<td align="left" valign="top" charoff="50">Italy</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Klaus</td>
<td align="left" valign="top" charoff="50">Beiske, MD</td>
<td align="left" valign="top" charoff="50">Department of Pathology, Rikshospitalet</td>
<td align="left" valign="top" charoff="50">Oslo</td>
<td align="left" valign="top" charoff="50">Norway</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Barbara</td>
<td align="left" valign="top" charoff="50">Marques, PhD</td>
<td align="left" valign="top" charoff="50">Centro de Genética Humana, Instituto Nacinal de Saúde</td>
<td align="left" valign="top" charoff="50">Lisbon</td>
<td align="left" valign="top" charoff="50">Portugal</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Nicole</td>
<td align="left" valign="top" charoff="50">Gross Ph.D.</td>
<td align="left" valign="top" charoff="50">Recherche en Oncologie Pédiatrique</td>
<td align="left" valign="top" charoff="50">Lausanne</td>
<td align="left" valign="top" charoff="50">Switzerland</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Rosa</td>
<td align="left" valign="top" charoff="50">Noguera, MD</td>
<td align="left" valign="top" charoff="50">Facultad de Medicina</td>
<td align="left" valign="top" charoff="50">Valencia</td>
<td align="left" valign="top" charoff="50">Spain</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Tommy</td>
<td align="left" valign="top" charoff="50">Martinsson, PhD</td>
<td align="left" valign="top" charoff="50">Gahlgrenska Univ. Hospital/East, Gothenburg University</td>
<td align="left" valign="top" charoff="50">Gothenburg</td>
<td align="left" valign="top" charoff="50">Sweden</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Deborah A.</td>
<td align="left" valign="top" charoff="50">Tweddle, MD</td>
<td align="left" valign="top" charoff="50">Department of Health</td>
<td align="left" valign="top" charoff="50">Newcastle</td>
<td align="left" valign="top" charoff="50">UK</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">John</td>
<td align="left" valign="top" charoff="50">Lunec, PhD</td>
<td align="left" valign="top" charoff="50">Northern Institute for Cancer Research</td>
<td align="left" valign="top" charoff="50">Newcastle</td>
<td align="left" valign="top" charoff="50">UK</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">Nick</td>
<td align="left" valign="top" charoff="50">Bown, PhD</td>
<td align="left" valign="top" charoff="50">Institute of Human Genetics</td>
<td align="left" valign="top" charoff="50">Newcastle</td>
<td align="left" valign="top" charoff="50">UK</td>
</tr>
</tbody>
</table>
</table-wrap>
<table-wrap id="tbl5" position="float">
<label>Table 5</label>
<caption>
<p content-type="table-title">
<italic>MYCN</italic>
terms and definitions of I-FISH results</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>
<italic>MYCN</italic>
status analysed by I-FISH</bold>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50">
<bold>Terms</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Description</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Comments</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">
<italic>MYCN</italic>
not amplified (normal
<italic>MYCN</italic>
status)</td>
<td align="left" valign="top" charoff="50">A balanced ratio between the
<italic>MYCN</italic>
-specific signals and the signal number of the reference probe on the chromosome 2q arm</td>
<td align="left" valign="top" charoff="50">Neuroblastic tumours have a propensity to polyploidisation, especially but not exclusively after therapy with the occurrence of giant polyploid nuclei. The number of
<italic>MYCN</italic>
signals must not exceed the number of reference signals on 2q (caveat: the centromeric probe is unqualified as reference probe because of frequent centromeric associations in such tumours). The number of other chromosomes or the DNA index should be checked as well.</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">2p24 gain:</td>
<td align="left" valign="top" charoff="50">The term 2p24 gain is suggested as a descriptive generic term for
<italic>MYCN</italic>
signal numbers exceeding up to 4-fold the number of reference signals on chromosomal arm 2q. This pattern could reflect either:</td>
<td align="left" valign="top" charoff="50">The use of a 2p specific probe in addition to 2q (optionally a centromeric probe) is recommended to clarify the presence of a chromosome 2p gain
<italic>vs</italic>
a restricted
<italic>MYCN</italic>
gain. The discrimination could be important since a
<italic>MYCN</italic>
gain could indicate an ‘incipient'
<italic>MYCN</italic>
amplification.</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> (a) 2p gain</td>
<td align="left" valign="top" charoff="50">(a) a gain of short arms of chromosome 2, for example, from unbalanced translocations involving 2p; or</td>
<td align="left" valign="top" charoff="50">Equal number of
<italic>MYCN</italic>
and 2p signals, exceeding 2q signals (mostly a consistent excess of one or two
<italic>MYCN</italic>
and 2p signals).</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> (b)
<italic>MYCN</italic>
gain</td>
<td align="left" valign="top" charoff="50">(b) a gain of the
<italic>MYCN</italic>
gene either chromosomally integrated (such as duplications) or extrachromosomally</td>
<td align="left" valign="top" charoff="50">An inconsistent
<italic>MYCN</italic>
excess with a varying number of excess signals is much more likely in line with
<italic>MYCN</italic>
gain as extrachromosomally elements. The latter can also be found in tumours with heterogeneous
<italic>MYCN</italic>
amplification.</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>MYCN</italic>
amplification, ‘homogeneous'</td>
<td align="left" valign="top" charoff="50">More than 4-fold increase in the
<italic>MYCN</italic>
signal number compared with the reference probe located on the chromosome 2q</td>
<td align="left" valign="top" charoff="50">Details on the amplification grade (a) >4–10 times; (b) >10 times; (c) >30 times amplification, and also on the type of amplification either double minutes (dmin) or homogeneously staining regions (hsr) should be given in the report.
<break></break>
Besides tumour cells with amplification defined as such, a proportion of tumour cells can also show ‘
<italic>MYCN</italic>
gain'. However, tumour cells without
<italic>MYCN</italic>
gain or amplification are extremely rare.</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">
<italic>MYCN</italic>
amplification, ‘heterogeneous'</td>
<td align="left" valign="top" charoff="50">Generic term for the coexistence of amplified as well as non-amplified tumour cells in the same tumour</td>
<td align="left" valign="top" charoff="50">Single cells (at least two) or cell clusters or a multitude of cells with MNA besides proven tumour cells without MNA. The terms ‘focal' and ‘diffuse MNA' are specifications, which, however, can only be attributed after evaluation of the tissue sections. In case amplified tumour cells are found in addition to non-amplified cells, a very meticulous procedure is strongly recommended to exclude false-positive or false negative results (see
<xref ref-type="fig" rid="fig3">Figure 3</xref>
).</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> (a) Focal heterogeneous
<italic>MYCN</italic>
amplification</td>
<td align="left" valign="top" charoff="50">Defined as the more or less focal (one focus or several foci – multifocal) occurrence of
<italic>MYCN</italic>
-amplified cells surrounded by non-amplified tumour cells.</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> (b) Diffuse heterogeneous
<italic>MYCN</italic>
amplification</td>
<td align="left" valign="top" charoff="50">Designates a tumour, which contains the
<italic>MYCN</italic>
amplified cells in a scattered pattern besides non-
<italic>MYCN</italic>
amplified tumour cells.</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">No result</td>
<td align="left" valign="top" charoff="50">Should be specified: unclear or not interpretable;</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">inadequate tumour cell content; no tumour; not carried out</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t5-fn1">
<label></label>
<p>I-FISH=interphase fluorescence
<italic>in situ</italic>
hybridisation.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl6" position="float">
<label>Table 6</label>
<caption>
<p content-type="table-title">Terms and definitions for segmental chromosome aberrations of I-FISH results</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>Segmental chromosome aberrations analysed by I-FISH</bold>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50">
<bold>Terms</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Description</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Comments</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Normal status</td>
<td align="left" valign="top" charoff="50">Balanced ratio between the signal numbers of the chromosomal region of interest and the reference signals on the opposite arm of the chromosome</td>
<td align="left" valign="top" charoff="50">In the case of a 2/2 ratio, an isodisomy with a complete LOH of all loci located on the investigated chromosome cannot be excluded. However, uniparental isodisomies are extremely rare in NB tumours.</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">I-FISH imbalance (inconclusive with regard to LOH)</td>
<td align="left" valign="top" charoff="50">Unbalanced ratio between the signal numbers of the chromosomal region of interest and the reference signals with more than one signals of the chromosomal region of interest</td>
<td align="left" valign="top" charoff="50">Does not necessarily correspond to an LOH, and is therefore called inconclusive. PCR should be performed to clarify this result. In NB tumours, imbalances frequently, but not always, reflect LOH. Fluorescence
<italic>in situ</italic>
hybridisation imbalances can also occur focally. Interphase fluorescence
<italic>in situ</italic>
hybridisation imbalances should only be diagnosed if hybridisation failure can be excluded. At least 200 cells should be evaluated.</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Deletion</td>
<td align="left" valign="top" charoff="50">Unbalanced ratio between the signal numbers of the chromosomal region of interest and the reference signals with only one signal of the chromosomal region of interest</td>
<td align="left" valign="top" charoff="50">This hybridisation pattern corresponds to an LOH. Deletions can also occur focally. Interphase fluorescence
<italic>in situ</italic>
hybridisation deletion should only be diagnosed if hybridisation failure can be excluded. At least 200 cells should be evaluated.</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Gain</td>
<td align="left" valign="top" charoff="50">Up to 4-fold excess of signal numbers of the chromosomal region of interest compared with the reference signals</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">No result</td>
<td align="left" valign="top" charoff="50">Should be specified: unclear or not interpretable; inadequate tumour cell content; no tumour; Not carried out</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t6-fn1">
<label></label>
<p>I-FISH=interphase fluorescence
<italic>in situ</italic>
hybridisation.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl7" position="float">
<label>Table 7</label>
<caption>
<p content-type="table-title">Terms and definitions of segmental chromosome aberrations analysed by PCR</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>Losses of chromosomal parts analysed by PCR</bold>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50">
<bold>Terms</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Description</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Comments</bold>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50">
<bold>Normal status</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Similar band intensities</bold>
</th>
<th align="left" valign="top" charoff="50"> </th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Allelic imbalance (inconclusive)</td>
<td align="left" valign="top" charoff="50">Different band intensities; The result can mean either allele disequilibrium or LOH</td>
<td align="left" valign="top" charoff="50">One band is relatively weaker, when compared with the ratio of constitutional DNA controls. Needs further clarification by FISH (copy number of the respective chromosome has to be known) and re-evaluation of the tumour cell content (an LOH could be masked by a high number of normal cells). Alternatively, different PCR probes, located on both arms (p and q) can circumvent the need for the use of another technique.
<break></break>
Allele disequilibrium means an imbalance between the number of maternal and paternal alleles (in the case of odd numbers of the respective chromosome), but not a physical loss of alleles</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Allelic loss</td>
<td align="left" valign="top" charoff="50">Loss of one band</td>
<td align="left" valign="top" charoff="50">One band has completely, or almost completely disappeared</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">No result</td>
<td align="left" valign="top" charoff="50">Should be specified: unclear or not interpretable; inadequate tumour cell content (<60%); constitutional homozygosity; no DNA; no tumour; not carried out</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t7-fn1">
<label></label>
<p>FISH=fluorescence
<italic>in situ</italic>
hybridisation.</p>
</fn>
</table-wrap-foot>
</table-wrap>
<table-wrap id="tbl8" position="float">
<label>Table 8</label>
<caption>
<p content-type="table-title">Terms and definitions of chromosome aberrations analysed by MLPA</p>
</caption>
<table frame="hsides" rules="groups" border="1" width="85%">
<colgroup>
<col align="left"></col>
<col align="left"></col>
<col align="left"></col>
</colgroup>
<thead valign="bottom">
<tr>
<th colspan="3" align="center" valign="top" charoff="50">
<bold>Chromosome and gene status analysed by MLPA</bold>
</th>
</tr>
<tr>
<th align="left" valign="top" charoff="50">
<bold>Terms</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Description</bold>
</th>
<th align="left" valign="top" charoff="50">
<bold>Comments</bold>
</th>
</tr>
</thead>
<tbody valign="top">
<tr>
<td align="left" valign="top" charoff="50">Normal status</td>
<td align="left" valign="top" charoff="50">Balanced ratio between the majority of signals (signal intensity is visualised in the graphic representation of the MLPA results as height of the bars) of both chromosomal arms</td>
<td align="left" valign="top" charoff="50">In the case of a balanced ratio, a uniparental isodisomy (a uniparental isodisomy means that both chromosomes are derived from one parent. Thus, the two chromosomes are not homologous but identical. However, uniparental isodisomies are rare in NB tumours) with a complete LOH of all loci located on the investigated chromosome cannot be excluded</td>
</tr>
<tr>
<td colspan="3" align="left" valign="top" charoff="50">
<italic>Segmental chromosome aberration</italic>
</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> Loss</td>
<td align="left" valign="top" charoff="50">Unbalanced ratio between the signals of the chromosomal region of interest (at least two adjacent probes) and the reference signals (at least two probes) signals</td>
<td align="left" valign="top" charoff="50">This result could correspond to a FISH deletion that reflects an LOH, or a FISH imbalance, which does not necessarily indicate an LOH.</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> Gain</td>
<td align="left" valign="top" charoff="50">Unbalanced ratio (low signal excess) between the signals of the chromosomal region of interest (at least two adjacent probes) and the reference signals (at least two) of the chromosomal region of interest</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50"> </td>
<td align="left" valign="top" charoff="50">The threshold between gain and amplification needs to be determined for the experimental system with the help of other techniques,for example, I-FISH</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">Amplification</td>
<td align="left" valign="top" charoff="50">Unbalanced ratio (high signal excess) between the signals of a gene and all other probes located on the same chromosome</td>
<td align="left" valign="top" charoff="50">The threshold between gain and amplification needs to be determined for the experimental system with the help of other techniques, for example, I-FISH</td>
</tr>
<tr>
<td align="left" valign="top" charoff="50">No result</td>
<td align="left" valign="top" charoff="50">Should be specified: unclear or not interpretable; inadequate tumour cell content; no tumour; not carried out</td>
<td align="left" valign="top" charoff="50"> </td>
</tr>
</tbody>
</table>
<table-wrap-foot>
<fn id="t8-fn1">
<label></label>
<p>FISH=fluorescence
<italic>in situ</italic>
hybridisation; MLPA=multiplex ligation-dependent probe amplification; I-FISH=interphase fluorescence
<italic>in situ</italic>
hybridisation.</p>
</fn>
</table-wrap-foot>
</table-wrap>
</floats-wrap>
</pmc>
<affiliations>
<list>
<country>
<li>Allemagne</li>
<li>Australie</li>
<li>Autriche</li>
<li>Belgique</li>
<li>France</li>
<li>Japon</li>
<li>Royaume-Uni</li>
<li>États-Unis</li>
</country>
</list>
<tree>
<country name="Autriche">
<noRegion>
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</noRegion>
<name sortKey="Ambros, I M" sort="Ambros, I M" uniqKey="Ambros I" first="I M" last="Ambros">I M Ambros</name>
</country>
<country name="États-Unis">
<noRegion>
<name sortKey="Brodeur, G M" sort="Brodeur, G M" uniqKey="Brodeur G" first="G M" last="Brodeur">G M Brodeur</name>
</noRegion>
<name sortKey="Cohn, S L" sort="Cohn, S L" uniqKey="Cohn S" first="S L" last="Cohn">S L Cohn</name>
<name sortKey="Khan, J" sort="Khan, J" uniqKey="Khan J" first="J" last="Khan">J. Khan</name>
<name sortKey="London, W B" sort="London, W B" uniqKey="London W" first="W B" last="London">W B London</name>
<name sortKey="Maris, J M" sort="Maris, J M" uniqKey="Maris J" first="J M" last="Maris">J M Maris</name>
</country>
<country name="Australie">
<noRegion>
<name sortKey="Haber, M" sort="Haber, M" uniqKey="Haber M" first="M" last="Haber">M. Haber</name>
</noRegion>
</country>
<country name="Japon">
<noRegion>
<name sortKey="Nakagawara, A" sort="Nakagawara, A" uniqKey="Nakagawara A" first="A" last="Nakagawara">A. Nakagawara</name>
</noRegion>
</country>
<country name="France">
<noRegion>
<name sortKey="Schleiermacher, G" sort="Schleiermacher, G" uniqKey="Schleiermacher G" first="G" last="Schleiermacher">G. Schleiermacher</name>
</noRegion>
</country>
<country name="Belgique">
<noRegion>
<name sortKey="Speleman, F" sort="Speleman, F" uniqKey="Speleman F" first="F" last="Speleman">F. Speleman</name>
</noRegion>
</country>
<country name="Allemagne">
<noRegion>
<name sortKey="Spitz, R" sort="Spitz, R" uniqKey="Spitz R" first="R" last="Spitz">R. Spitz</name>
</noRegion>
</country>
<country name="Royaume-Uni">
<noRegion>
<name sortKey="Pearson, A D J" sort="Pearson, A D J" uniqKey="Pearson A" first="A D J" last="Pearson">A D J. Pearson</name>
</noRegion>
</country>
</tree>
</affiliations>
</record>

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