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Entry
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- #613014 - NEUROBLASTOMA, SUSCEPTIBILITY TO, 3; NBLST3
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- OMIM
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<p>
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<span class="h4">#613014</span>
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<br />
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<strong>Table of Contents</strong>
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</p>
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<a href="#title"><strong>Title</strong></a>
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<a href="#phenotypeMap"><strong>Phenotype-Gene Relationships</strong></a>
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<a href="#text"><strong>Text</strong></a>
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<li role="presentation" style="margin-left: 1em">
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<a href="#molecularGenetics">Molecular Genetics</a>
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<a href="#references"><strong>References</strong></a>
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<a href="#contributors"><strong>Contributors</strong></a>
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<a href="#creationDate"><strong>Creation Date</strong></a>
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<a href="#editHistory"><strong>Edit History</strong></a>
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<div style="display: table-cell;">External Links</div>
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<div style="display: table-cell;">Clinical Resources</div>
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<div><a href="https://clinicaltrials.gov/search?cond=NEUROBLASTOMA" class="mim-tip-hint" title="A registry of federally and privately supported clinical trials conducted in the United States and around the world." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Clinical Trials', 'domain': 'clinicaltrials.gov'})">Clinical Trials</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/ClinicalLabs_Search_Simple.php?lng=EN&LnkId=548&Typ=Pat" class="mim-tip-hint" title="A list of European laboratories that offer genetic testing." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'EuroGentest', 'domain': 'orpha.net'})">EuroGentest</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/books/NBK24599/" class="mim-tip-hint" title="Expert-authored, peer-reviewed descriptions of inherited disorders including the uses of genetic testing in diagnosis, management, and genetic counseling." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Gene Reviews', 'domain': 'ncbi.nlm.nih.gov'})">Gene Reviews</a></div>
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<div><a href="https://www.diseaseinfosearch.org/x/8996" class="mim-tip-hint" title="Network of disease-specific advocacy organizations, universities, private companies, government agencies, and public policy organizations." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'Genetic Alliance', 'domain': 'diseaseinfosearch.org'})">Genetic Alliance</a></div>
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<div><a href="https://medlineplus.gov/genetics/condition/neuroblastoma" class="mim-tip-hint" title="Consumer-friendly information about the effects of genetic variation on human health." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'MedlinePlus Genetics', 'domain': 'medlineplus.gov'})">MedlinePlus Genetics</a></div>
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<div><a href="https://www.ncbi.nlm.nih.gov/gtr/all/tests/?term=613014[mim]" class="mim-tip-hint" title="Genetic Testing Registry." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'GTR', 'domain': 'ncbi.nlm.nih.gov'})">GTR</a></div>
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<div><a href="https://www.orpha.net/consor/cgi-bin/OC_Exp.php?lng=EN&Expert=635" class="mim-tip-hint" title="European reference portal for information on rare diseases and orphan drugs." target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'OrphaNet', 'domain': 'orpha.net'})">OrphaNet</a></div>
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<span class="mim-tip-bottom" qtip_title="<strong>Looking for this gene or this phenotype in other resources?</strong>" qtip_text="Select a related resource from the dropdown menu and click for a targeted link to information directly relevant.">
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<a id="number" class="mim-anchor"></a>
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<a href="#" class="mim-tip-icd" qtip_title="<strong>ICD+</strong>" qtip_text="
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<strong>ORPHA:</strong> 635<br />
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">ICD+</a>
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<span class="h3">
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<span class="mim-font mim-tip-hint" title="Phenotype description, molecular basis known">
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<span class="text-danger"><strong>#</strong></span>
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613014
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<a id="preferredTitle" class="mim-anchor"></a>
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NEUROBLASTOMA, SUSCEPTIBILITY TO, 3; NBLST3
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<br />
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<h4>
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<span class="mim-font">
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<strong>Phenotype-Gene Relationships</strong>
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</h4>
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus
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Gene/Locus <br /> MIM number
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<span class="mim-font">
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<a href="/geneMap/2/157?start=-3&limit=10&highlight=157">
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2p23.2-p23.1
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<span class="mim-font">
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{Neuroblastoma, susceptibility to, 3}
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<span class="mim-font">
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<a href="/entry/613014"> 613014 </a>
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<td>
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<span class="mim-font">
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<abbr class="mim-tip-hint" title="3 - The molecular basis of the disorder is known"> 3 </abbr>
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<span class="mim-font">
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ALK
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<span class="mim-font">
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<a href="/entry/105590"> 105590 </a>
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PheneGene Graphics <span class="caret"></span>
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</button>
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<ul class="dropdown-menu" style="width: 17em;">
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<li><a href="/graph/linear/613014" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Linear'})"> Linear </a></li>
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<li><a href="/graph/radial/613014" target="_blank" onclick="gtag('event', 'mim_graph', {'destination': 'Radial'})"> Radial </a></li>
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</div>
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<span class="glyphicon glyphicon-question-sign mim-tip-hint" title="OMIM PheneGene graphics depict relationships between phenotypes, groups of related phenotypes (Phenotypic Series), and genes.<br /><a href='/static/omim/pdf/OMIM_Graphics.pdf' target='_blank'>A quick reference overview and guide (PDF)</a>"></span>
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<span id="mimTextToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<span class="mim-tip-floating" qtip_title="<strong>Looking For More References?</strong>" qtip_text="Click the 'reference plus' icon <span class='glyphicon glyphicon-plus-sign'></span> at the end of each OMIM text paragraph to see more references related to the content of the preceding paragraph.">
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because susceptibility to neuroblastoma-3 (NBLST3) is conferred by germline or somatic mutations in the ALK gene (<a href="/entry/105590">105590</a>) on chromosome 2p23.</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (<a href="/entry/256700">256700</a>).</p>
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<span id="mimMolecularGeneticsToggleTriangle" class="small mimTextToggleTriangle">▼</span>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p><a href="#6" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a> identified 3 separate germline missense mutations in the tyrosine kinase domain of the ALK gene that segregated with the disease in 8 separate families with neuroblastoma. There was incomplete penetrance. Resequencing in 194 high-risk neuroblastoma the samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the 10 mutations mapped to critical regions of the kinase domain and were predicted with high probability to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK mRNA resulted in profound inhibition of growth in all cell lines harboring mutant or amplified ALK, as well as in 2 of 6 wildtype cell lines for ALK. <a href="#6" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a> concluded that heritable mutations of ALK are the main cause of susceptibility to the development of neuroblastoma within families. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18724359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#5" class="mim-tip-reference" title="Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O. <strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong> Nature 455: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>] [<a href="https://doi.org/10.1038/nature07398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923523">Janoueix-Lerosey et al. (2008)</a> conducted a genomewide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the ALK tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumor DNAs, they identified somatic mutations of the ALK kinase domain that mainly clustered in 2 hotspots. Germline mutations were observed in 2 neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated, and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wildtype ALK, led to a marked decrease of cell proliferation. Altogether, <a href="#5" class="mim-tip-reference" title="Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O. <strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong> Nature 455: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>] [<a href="https://doi.org/10.1038/nature07398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923523">Janoueix-Lerosey et al. (2008)</a> concluded that their data identified ALK as critical player in neuroblastoma development that may represent a therapeutic target. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a genomewide scan of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, <a href="#2" class="mim-tip-reference" title="Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S. <strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong> Nature 455: 971-974, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923524</a>] [<a href="https://doi.org/10.1038/nature07399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923524">Chen et al. (2008)</a> identified the ALK locus as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed 8 novel missense mutations in 13 of 215 (6.1%) fresh tumors and 8 of 24 (33%) neuroblastoma-derived cell lines. All but 1 mutation in the primary samples (12 of 13) were found in stage 3 or 4 of the disease and were harbored in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wildtype kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumors in nude mice. Furthermore, <a href="#2" class="mim-tip-reference" title="Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S. <strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong> Nature 455: 971-974, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923524</a>] [<a href="https://doi.org/10.1038/nature07399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923524">Chen et al. (2008)</a> demonstrated that downregulation of ALK through RNA interference suppressed proliferation of neuroblastoma cells harboring mutated ALK. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#4" class="mim-tip-reference" title="George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others. <strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong> Nature 455: 975-978, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923525">George et al. (2008)</a> reported the detection of mutations in the ALK gene in 8% of primary neuroblastomas. Five were identified in the kinase domain of ALK, of which 3 were somatic and 2 were germline. The most frequent mutation, F1174L, was identified in 3 different neuroblastoma cell lines as well as in several tumor samples. It was not identified in any germline cases, consistent with it being a somatic mutation. ALK cDNAs encoding the F1174L and R1275Q (<a href="/entry/105590#0001">105590.0001</a>) variants, but not wildtype ALK cDNA, transformed interleukin-3 (IL3; <a href="/entry/147740">147740</a>)-dependent murine hematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to a small-molecule inhibitor of ALK. Furthermore, 2 human neuroblastoma cell lines harboring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis. Short hairpin RNA-mediated knockdown of ALK expression also resulted in apoptosis and impaired cell proliferation. Thus, <a href="#4" class="mim-tip-reference" title="George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others. <strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong> Nature 455: 975-978, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923525">George et al. (2008)</a> concluded that activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumors and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibitors. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p><a href="#6" class="mim-tip-reference" title="Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others. <strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong> Nature 455: 930-935, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07261" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18724359">Mosse et al. (2008)</a>, <a href="#5" class="mim-tip-reference" title="Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O. <strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong> Nature 455: 967-970, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>] [<a href="https://doi.org/10.1038/nature07398" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923523">Janoueix-Lerosey et al. (2008)</a>, <a href="#2" class="mim-tip-reference" title="Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S. <strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong> Nature 455: 971-974, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923524</a>] [<a href="https://doi.org/10.1038/nature07399" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923524">Chen et al. (2008)</a>, and <a href="#4" class="mim-tip-reference" title="George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others. <strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong> Nature 455: 975-978, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/nature07397" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923525">George et al. (2008)</a> all found somatic missense mutations in ALK at codon F1174, within the kinase domain. These studies reported that 59 of 617 (9.6%) sporadic neuroblastoma cases investigated had somatic single-nucleotide mutations in ALK (<a href="#3" class="mim-tip-reference" title="Eng, C. <strong>A ringleader identified.</strong> Nature 455: 883-884, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923503</a>] [<a href="https://doi.org/10.1038/455883a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923503">Eng, 2008</a>). Somatic mutations were associated with more aggressive tumors and lethal cases of this cancer. <a href="https://pubmed.ncbi.nlm.nih.gov/?term=18923503+18923523+18923524+18724359+18923525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>In a commentary, <a href="#3" class="mim-tip-reference" title="Eng, C. <strong>A ringleader identified.</strong> Nature 455: 883-884, 2008.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923503</a>] [<a href="https://doi.org/10.1038/455883a" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="18923503">Eng (2008)</a> noted that among the familial studies, the weighted mean proportion of individuals carrying the germline mutations who actually developed neuroblastoma (penetrance) seemed to be around 57% across all families. One of the germline mutations had a lower penetrance of about 40% compared with the other 3 mutations, whose weighted-average penetrance was 61%. These penetrance percentages are relatively low compared with those of other established cancer predisposition genes such as RET (<a href="/entry/164761">164761</a>) and PTEN (<a href="/entry/601728">601728</a>). <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p><p>To determine the frequency of ALK mutations in neuroblastic tumors, <a href="#1" class="mim-tip-reference" title="Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others. <strong>ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.</strong> Europ. J. Hum. Genet. 20: 291-297, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22071890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22071890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22071890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22071890">Bourdeaut et al. (2012)</a> sequenced the ALK gene in 26 patients with perinatal onset of neuroblastoma, 16 patients with multifocal postnatal onset of neuroblastoma, and 8 children or young adults with multiple malignancies, including a neuroblastic tumor. A de novo heterozygous germline mutation (R1275Q; <a href="/entry/105590#0001">105590.0001</a>) was found in 1 patient with perinatal onset, and 2 different heterozygous mutations (see, e.g., <a href="/entry/105590#0003">105590.0003</a>) were found in 2 unrelated patients with postnatal multifocal onset. However, each of the latter 2 mutations were found in several unaffected relatives, indicating incomplete penetrance. Tumor tissue from all 3 patients also carried the corresponding mutation. Considering the whole cohort, younger age at onset did not seem to offer selection criteria for ALK analysis, but all mutation carriers had multifocal tumors. <a href="#1" class="mim-tip-reference" title="Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others. <strong>ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.</strong> Europ. J. Hum. Genet. 20: 291-297, 2012.[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22071890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22071890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22071890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>] [<a href="https://doi.org/10.1038/ejhg.2011.195" target="_blank" onclick="gtag('event', 'mim_outbound', {'destination': 'Publisher'})">Full Text</a>]" pmid="22071890">Bourdeaut et al. (2012)</a> concluded that ALK mutations are rare events in patients with a high probability of predisposition to neuroblastoma. <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22071890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})"><span class="glyphicon glyphicon-plus-sign mim-tip-hint" title="Click this 'reference-plus' icon to see articles related to this paragraph in PubMed."></span></a></p>
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/22071890/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">22071890</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=22071890[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=22071890" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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<strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong>
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Nature 455: 971-974, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923524/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923524</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923524" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature07399" target="_blank">Full Text</a>]
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<a id="Eng2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Eng, C.
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<strong>A ringleader identified.</strong>
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Nature 455: 883-884, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923503/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923503</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923503" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/455883a" target="_blank">Full Text</a>]
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<a id="George2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others.
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<strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong>
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Nature 455: 975-978, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923525/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923525</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18923525[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923525" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature07397" target="_blank">Full Text</a>]
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<a id="Janoueix-Lerosey2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O.
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<strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong>
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Nature 455: 967-970, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18923523/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18923523</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18923523" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature07398" target="_blank">Full Text</a>]
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<a id="Mosse2008" class="mim-anchor"></a>
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<div class="">
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<p class="mim-text-font">
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Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others.
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<strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong>
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Nature 455: 930-935, 2008.
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[PubMed: <a href="https://pubmed.ncbi.nlm.nih.gov/18724359/" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">18724359</a>, <a href="https://www.ncbi.nlm.nih.gov/pmc/?term=18724359[PMID]&report=imagesdocsum" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Image', 'domain': 'ncbi.nlm.nih.gov'})">images</a>, <a href="https://pubmed.ncbi.nlm.nih.gov/?cmd=link&linkname=pubmed_pubmed&from_uid=18724359" target="_blank" onclick="gtag('event', 'mim_outbound', {'name': 'PubMed Related', 'domain': 'pubmed.ncbi.nlm.nih.gov'})">related citations</a>]
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[<a href="https://doi.org/10.1038/nature07261" target="_blank">Full Text</a>]
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<span class="mim-text-font">
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Cassandra L. Kniffin - updated : 11/5/2012
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Creation Date:
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Cassandra L. Kniffin : 9/16/2009
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carol : 11/08/2012
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ckniffin : 11/5/2012<br>carol : 9/21/2009<br>ckniffin : 9/18/2009
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<strong>#</strong> 613014
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NEUROBLASTOMA, SUSCEPTIBILITY TO, 3; NBLST3
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<strong>ORPHA:</strong> 635;
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Location
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Phenotype
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Phenotype <br /> MIM number
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Inheritance
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Phenotype <br /> mapping key
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Gene/Locus <br /> MIM number
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2p23.2-p23.1
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{Neuroblastoma, susceptibility to, 3}
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<span class="mim-font">
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613014
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3
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ALK
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<span class="mim-font">
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105590
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<strong>TEXT</strong>
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<p>A number sign (#) is used with this entry because susceptibility to neuroblastoma-3 (NBLST3) is conferred by germline or somatic mutations in the ALK gene (105590) on chromosome 2p23.</p><p>For a general phenotypic description and a discussion of genetic heterogeneity of neuroblastoma, see NBLST1 (256700).</p>
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<span class="mim-font">
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<strong>Molecular Genetics</strong>
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<p>Mosse et al. (2008) identified 3 separate germline missense mutations in the tyrosine kinase domain of the ALK gene that segregated with the disease in 8 separate families with neuroblastoma. There was incomplete penetrance. Resequencing in 194 high-risk neuroblastoma the samples showed somatically acquired mutations in the tyrosine kinase domain in 12.4% of samples. Nine of the 10 mutations mapped to critical regions of the kinase domain and were predicted with high probability to be oncogenic drivers. Mutations resulted in constitutive phosphorylation, and targeted knockdown of ALK mRNA resulted in profound inhibition of growth in all cell lines harboring mutant or amplified ALK, as well as in 2 of 6 wildtype cell lines for ALK. Mosse et al. (2008) concluded that heritable mutations of ALK are the main cause of susceptibility to the development of neuroblastoma within families. </p><p>Janoueix-Lerosey et al. (2008) conducted a genomewide comparative genomic hybridization analysis on a large series of neuroblastomas. Copy number increase at the locus encoding the ALK tyrosine kinase receptor was observed recurrently. One particularly informative case presented a high-level gene amplification that was strictly limited to ALK, indicating that this gene may contribute on its own to neuroblastoma development. Through subsequent direct sequencing of cell lines and primary tumor DNAs, they identified somatic mutations of the ALK kinase domain that mainly clustered in 2 hotspots. Germline mutations were observed in 2 neuroblastoma families, indicating that ALK is a neuroblastoma predisposition gene. Mutated ALK proteins were overexpressed, hyperphosphorylated, and showed constitutive kinase activity. The knockdown of ALK expression in ALK-mutated cells, but also in cell lines overexpressing a wildtype ALK, led to a marked decrease of cell proliferation. Altogether, Janoueix-Lerosey et al. (2008) concluded that their data identified ALK as critical player in neuroblastoma development that may represent a therapeutic target. </p><p>In a genomewide scan of genetic lesions in 215 primary neuroblastoma samples using high-density single-nucleotide polymorphism genotyping microarrays, Chen et al. (2008) identified the ALK locus as a recurrent target of copy number gain and gene amplification. Furthermore, DNA sequencing of ALK revealed 8 novel missense mutations in 13 of 215 (6.1%) fresh tumors and 8 of 24 (33%) neuroblastoma-derived cell lines. All but 1 mutation in the primary samples (12 of 13) were found in stage 3 or 4 of the disease and were harbored in the kinase domain. The mutated kinases were autophosphorylated and displayed increased kinase activity compared with the wildtype kinase. They were able to transform NIH3T3 fibroblasts as shown by their colony formation ability in soft agar and their capacity to form tumors in nude mice. Furthermore, Chen et al. (2008) demonstrated that downregulation of ALK through RNA interference suppressed proliferation of neuroblastoma cells harboring mutated ALK. </p><p>George et al. (2008) reported the detection of mutations in the ALK gene in 8% of primary neuroblastomas. Five were identified in the kinase domain of ALK, of which 3 were somatic and 2 were germline. The most frequent mutation, F1174L, was identified in 3 different neuroblastoma cell lines as well as in several tumor samples. It was not identified in any germline cases, consistent with it being a somatic mutation. ALK cDNAs encoding the F1174L and R1275Q (105590.0001) variants, but not wildtype ALK cDNA, transformed interleukin-3 (IL3; 147740)-dependent murine hematopoietic Ba/F3 cells to cytokine-independent growth. Ba/F3 cells expressing these mutations were sensitive to a small-molecule inhibitor of ALK. Furthermore, 2 human neuroblastoma cell lines harboring the F1174L mutation were also sensitive to the inhibitor. Cytotoxicity was associated with increased amounts of apoptosis. Short hairpin RNA-mediated knockdown of ALK expression also resulted in apoptosis and impaired cell proliferation. Thus, George et al. (2008) concluded that activating alleles of the ALK receptor tyrosine kinase are present in primary neuroblastoma tumors and in established neuroblastoma cell lines, and confer sensitivity to ALK inhibitors. </p><p>Mosse et al. (2008), Janoueix-Lerosey et al. (2008), Chen et al. (2008), and George et al. (2008) all found somatic missense mutations in ALK at codon F1174, within the kinase domain. These studies reported that 59 of 617 (9.6%) sporadic neuroblastoma cases investigated had somatic single-nucleotide mutations in ALK (Eng, 2008). Somatic mutations were associated with more aggressive tumors and lethal cases of this cancer. </p><p>In a commentary, Eng (2008) noted that among the familial studies, the weighted mean proportion of individuals carrying the germline mutations who actually developed neuroblastoma (penetrance) seemed to be around 57% across all families. One of the germline mutations had a lower penetrance of about 40% compared with the other 3 mutations, whose weighted-average penetrance was 61%. These penetrance percentages are relatively low compared with those of other established cancer predisposition genes such as RET (164761) and PTEN (601728). </p><p>To determine the frequency of ALK mutations in neuroblastic tumors, Bourdeaut et al. (2012) sequenced the ALK gene in 26 patients with perinatal onset of neuroblastoma, 16 patients with multifocal postnatal onset of neuroblastoma, and 8 children or young adults with multiple malignancies, including a neuroblastic tumor. A de novo heterozygous germline mutation (R1275Q; 105590.0001) was found in 1 patient with perinatal onset, and 2 different heterozygous mutations (see, e.g., 105590.0003) were found in 2 unrelated patients with postnatal multifocal onset. However, each of the latter 2 mutations were found in several unaffected relatives, indicating incomplete penetrance. Tumor tissue from all 3 patients also carried the corresponding mutation. Considering the whole cohort, younger age at onset did not seem to offer selection criteria for ALK analysis, but all mutation carriers had multifocal tumors. Bourdeaut et al. (2012) concluded that ALK mutations are rare events in patients with a high probability of predisposition to neuroblastoma. </p>
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<h4>
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<span class="mim-font">
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<strong>REFERENCES</strong>
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</span>
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</h4>
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<div>
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<p />
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Bourdeaut, F., Ferrand, S., Brugieres, L., Hilbert, M., Ribeiro, A., Lacroix, L., Benard, J., Combaret, V., Michon, J., Valteau-Couanet, D., Isidor, B., Rialland, X., and 8 others.
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<strong>ALK germline mutations in patients with neuroblastoma: a rare and weakly penetrant syndrome.</strong>
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Europ. J. Hum. Genet. 20: 291-297, 2012.
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[PubMed: 22071890]
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[Full Text: https://doi.org/10.1038/ejhg.2011.195]
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Chen, Y., Takita, J., Choi, Y. L., Kato, M., Ohira, M., Sanada, M., Wang, L., Soda, M., Kikuchi, A., Igarashi, T., Nakagawara, A., Hayashi, Y., Mano, H., Ogawa, S.
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<strong>Oncogenic mutations of ALK kinase in neuroblastoma.</strong>
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Nature 455: 971-974, 2008.
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[PubMed: 18923524]
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[Full Text: https://doi.org/10.1038/nature07399]
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<p class="mim-text-font">
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Eng, C.
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<strong>A ringleader identified.</strong>
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Nature 455: 883-884, 2008.
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[PubMed: 18923503]
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[Full Text: https://doi.org/10.1038/455883a]
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George, R. E., Sanda, T., Hanna, M., Frohling, S., Luther, W., II, Zhang, J., Ahn, Y., Zhou, W., London, W. B., McGrady, P., Xue, L., Zozulya, S., and 9 others.
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<strong>Activating mutations in ALK provide a therapeutic target in neuroblastoma.</strong>
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Nature 455: 975-978, 2008.
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[PubMed: 18923525]
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[Full Text: https://doi.org/10.1038/nature07397]
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Janoueix-Lerosey, I., Lequin, D., Brugieres, L., Ribeiro, A., de Pontual, L., Combaret, V., Raynal, V., Puisieux, A., Schleiermacher, G., Pierron, G., Valteau-Couanet, D., Frebourg, T., Michon, J., Lyonnet, S., Amiel, J., Delattre, O.
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<strong>Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.</strong>
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Nature 455: 967-970, 2008.
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[PubMed: 18923523]
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[Full Text: https://doi.org/10.1038/nature07398]
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Mosse, Y. P., Laudenslager, M., Longo, L., Cole, K. A., Wood, A., Attiyeh, E. F., Laquaglia, M. J., Sennett, R., Lynch, J. E., Perri, P., Laureys, G., Speleman, F., and 10 others.
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<strong>Identification of ALK as a major familial neuroblastoma predisposition gene.</strong>
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Nature 455: 930-935, 2008.
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[PubMed: 18724359]
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[Full Text: https://doi.org/10.1038/nature07261]
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Cassandra L. Kniffin - updated : 11/5/2012
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Cassandra L. Kniffin : 9/16/2009
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carol : 11/08/2012<br>ckniffin : 11/5/2012<br>carol : 9/21/2009<br>ckniffin : 9/18/2009
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