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High Anaplastic Lymphoma Kinase Immunohistochemical Staining in Neuroblastoma and Ganglioneuroblastoma Is an Independent Predictor of Poor Outcome

2011; Elsevier BV; Volume: 180; Issue: 3 Linguagem: Inglês

10.1016/j.ajpath.2011.12.003

ISSN

1525-2191

Autores

Floor A.M. Duijkers, José Gaal, Jules P.P. Meijerink, Pieter Admiraal, Rob Pieters, Ronald R. de Krijger, Max M. van Noesel,

Tópico(s)

Cancer, Hypoxia, and Metabolism

Resumo

Anaplastic lymphoma kinase (ALK) mutations occur in 3% to 11% of neuroblastoma (NBL) cases and are associated with high ALK levels. However, high ALK levels appear to be a mutation-independent hallmark of NBL. Evidence about the prognostic relevance of ALK mutations and ALK tumor positivity in patients with NBL has been inconclusive. In this study, we investigated the prognostic relevance of ALK positivity by IHC and ALK mutation status by PCR sequencing in 71 NBL, 12 ganglioneuroblastoma (GNBL), and 20 ganglioneuroma samples in a multivariate model. ALK mutations were present in 2 of 72 NBL and 2 of 12 GNBL samples, which all contained many ALK-positive cells (>50%). In addition, half of all NBL samples showed ALK positivity in most (>50%) of tumor cells, whereas half of the GNBL showed staining in 50%). In addition, half of all NBL samples showed ALK positivity in most (>50%) of tumor cells, whereas half of the GNBL showed staining in <20% of the tumor cells. In most ganglioneuroma samples, a low percentage of tumor cells stained positive for ALK, which mainly involved ganglion cells. Higher percentages of ALK-positive cells in NBL and GNBL patient samples correlated with inferior survival in univariate and multivariate analyses with established prognostic factors, such as stage, age, and MYCN status. In conclusion, ALK positivity by IHC is an independent, poor prognostic factor in patients with GNBL and NBL. ALK IHC is an easy test suitable for future risk stratification in patients with NBL and GNBL. Neuroblastomas (NBLs) are pediatric tumors that arise from the neural crest. These tumors are often aneuploid and possess highly recurrent copy number changes, including gain of 17q and loss of heterozygosity of 1p, 11q, and 14q.1Deyell R.J. Attiyeh E.F. Advances in the understanding of constitutional and somatic genomic alterations in neuroblastoma.Cancer Genet. 2011; 204: 113-121Abstract Full Text Full Text PDF PubMed Scopus (47) Google Scholar, 2Michels E. Vandesompele J. De Preter K. Hoebeeck J. Vermeulen J. Schramm A. Molenaar J.J. Menten B. Marques B. Stallings R.L. Combaret V. Devalck C. De Paepe A. Versteeg R. Eggert A. Laureys G. Van Roy N. Speleman F. ArrayCGH-based classification of neuroblastoma into genomic subgroups.Genes Chromosomes Cancer. 2007; 46: 1098-1108Crossref PubMed Scopus (62) Google Scholar, 3Brodeur G.M. Neuroblastoma: biological insights into a clinical enigma.Nat Rev Cancer. 2003; 3: 203-216Crossref PubMed Scopus (1688) Google Scholar, 4Maris J.M. The biologic basis for neuroblastoma heterogeneity and risk stratification.Curr Opin Pediatr. 2005; 17: 7-13Crossref PubMed Scopus (165) Google Scholar However, few recurrent gene mutations have been discovered thus far. The most common recurrent mutations are found in MYCN (amplified in 20% to 25%),5Brodeur G.M. Seeger R.C. Schwab M. Varmus H.E. Bishop J.M. Amplification of N-myc in untreated human neuroblastomas correlates with advanced disease stage.Science. 1984; 224: 1121-1124Crossref PubMed Scopus (1819) Google Scholar CCND2 (amplified in 2.4%),6Molenaar J.J. van Sluis P. Boon K. Versteeg R. Caron H.N. Rearrangements and increased expression of cyclin D1 (CCND1) in neuroblastoma.Genes Chromosomes Cancer. 2003; 36: 242-249Crossref PubMed Scopus (68) Google Scholar and the more recently discovered anaplastic lymphoma kinase (ALK) gene.7Caren H. Abel F. Kogner P. Martinsson T. High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours.Biochem J. 2008; 416: 153-159Crossref PubMed Scopus (217) Google Scholar, 8Chen 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. Oncogenic mutations of ALK kinase in neuroblastoma.Nature. 2008; 455: 971-974Crossref PubMed Scopus (716) Google Scholar, 9George R.E. Sanda T. Hanna M. Frohling S. Luther 2nd, W. Zhang J. Ahn Y. Zhou W. London W.B. McGrady P. Xue L. Zozulya S. Gregor V.E. Webb T.R. Gray N.S. Gilliland D.G. Diller L. Greulich H. Morris S.W. Meyerson M. Look A.T. Activating mutations in ALK provide a therapeutic target in neuroblastoma.Nature. 2008; 455: 975-978Crossref PubMed Scopus (677) Google Scholar, 10Janoueix-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. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.Nature. 2008; 455: 967-970Crossref PubMed Scopus (687) Google Scholar, 11Mosse 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. Kim C. Hou C. Hakonarson H. Torkamani A. Schork N.J. Brodeur G.M. Tonini G.P. Rappaport E. Devoto M. Maris J.M. Identification of ALK as a major familial neuroblastoma predisposition gene.Nature. 2008; 455: 930-935Crossref PubMed Scopus (1016) Google Scholar, 12Osajima-Hakomori Y. Miyake I. Ohira M. Nakagawara A. Nakagawa A. Sakai R. Biological role of anaplastic lymphoma kinase in neuroblastoma.Am J Pathol. 2005; 167: 213-222Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Many familial or syndromatic NBL diseases are explained by ALK or PHOX2B mutations.10Janoueix-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. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.Nature. 2008; 455: 967-970Crossref PubMed Scopus (687) Google Scholar, 11Mosse 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. Kim C. Hou C. Hakonarson H. Torkamani A. Schork N.J. Brodeur G.M. Tonini G.P. Rappaport E. Devoto M. Maris J.M. Identification of ALK as a major familial neuroblastoma predisposition gene.Nature. 2008; 455: 930-935Crossref PubMed Scopus (1016) Google Scholar ALK mutations are the second most common genetic mutation in NBL, with point mutations in 3% to 11% and amplifications in 1% to 4% of the patients.7Caren H. Abel F. Kogner P. Martinsson T. High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours.Biochem J. 2008; 416: 153-159Crossref PubMed Scopus (217) Google Scholar, 8Chen 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. Oncogenic mutations of ALK kinase in neuroblastoma.Nature. 2008; 455: 971-974Crossref PubMed Scopus (716) Google Scholar, 9George R.E. Sanda T. Hanna M. Frohling S. Luther 2nd, W. Zhang J. Ahn Y. Zhou W. London W.B. McGrady P. Xue L. Zozulya S. Gregor V.E. Webb T.R. Gray N.S. Gilliland D.G. Diller L. Greulich H. Morris S.W. Meyerson M. Look A.T. Activating mutations in ALK provide a therapeutic target in neuroblastoma.Nature. 2008; 455: 975-978Crossref PubMed Scopus (677) Google Scholar, 10Janoueix-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. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.Nature. 2008; 455: 967-970Crossref PubMed Scopus (687) Google Scholar, 11Mosse 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. Kim C. Hou C. Hakonarson H. Torkamani A. Schork N.J. Brodeur G.M. Tonini G.P. Rappaport E. Devoto M. Maris J.M. Identification of ALK as a major familial neuroblastoma predisposition gene.Nature. 2008; 455: 930-935Crossref PubMed Scopus (1016) Google Scholar, 12Osajima-Hakomori Y. Miyake I. Ohira M. Nakagawara A. Nakagawa A. Sakai R. Biological role of anaplastic lymphoma kinase in neuroblastoma.Am J Pathol. 2005; 167: 213-222Abstract Full Text Full Text PDF PubMed Scopus (126) Google Scholar Mutations of the ALK gene have also been described as the most common cause of hereditary NBL.10Janoueix-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. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.Nature. 2008; 455: 967-970Crossref PubMed Scopus (687) Google Scholar, 11Mosse 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. Kim C. Hou C. Hakonarson H. Torkamani A. Schork N.J. Brodeur G.M. Tonini G.P. Rappaport E. Devoto M. Maris J.M. Identification of ALK as a major familial neuroblastoma predisposition gene.Nature. 2008; 455: 930-935Crossref PubMed Scopus (1016) Google Scholar The point mutations in NBL are located in the tyrosine kinase domain of ALK and activate kinase activity,8Chen 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. Oncogenic mutations of ALK kinase in neuroblastoma.Nature. 2008; 455: 971-974Crossref PubMed Scopus (716) Google Scholar, 10Janoueix-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. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.Nature. 2008; 455: 967-970Crossref PubMed Scopus (687) Google Scholar, 13Passoni L. Longo L. Collini P. Coluccia A.M. Bozzi F. Podda M. Gregorio A. Gambini C. Garaventa A. Pistoia V. Del Grosso F. Tonini G.P. Cheng M. Gambacorti-Passerini C. Anichini A. Fossati-Bellani F. Di Nicola M. Luksch R. Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients.Cancer Res. 2009; 69: 7338-7346Crossref PubMed Scopus (142) Google Scholar resulting in phosphorylation of downstream targets.8Chen 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. Oncogenic mutations of ALK kinase in neuroblastoma.Nature. 2008; 455: 971-974Crossref PubMed Scopus (716) Google Scholar, 9George R.E. Sanda T. Hanna M. Frohling S. Luther 2nd, W. Zhang J. Ahn Y. Zhou W. London W.B. McGrady P. Xue L. Zozulya S. Gregor V.E. Webb T.R. Gray N.S. Gilliland D.G. Diller L. Greulich H. Morris S.W. Meyerson M. Look A.T. Activating mutations in ALK provide a therapeutic target in neuroblastoma.Nature. 2008; 455: 975-978Crossref PubMed Scopus (677) Google Scholar, 10Janoueix-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. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma.Nature. 2008; 455: 967-970Crossref PubMed Scopus (687) Google Scholar, 14Motegi A. Fujimoto J. Kotani M. Sakuraba H. Yamamoto T. ALK receptor tyrosine kinase promotes cell growth and neurite outgrowth.J Cell Sci. 2004; 117: 3319-3329Crossref PubMed Scopus (127) Google Scholar, 15Schonherr C. Yang H.L. Vigny M. Palmer R.H. Hallberg B. Anaplastic lymphoma kinase activates the small GTPase Rap1 via the Rap1-specific GEF C3G in both neuroblastoma and PC12 cells.Oncogene. 2010; 29: 2817-2830Crossref PubMed Scopus (39) Google Scholar Mutant ALK acts as a bona fide oncogene because NIH3T3 transfectants that express mutant ALK F1174L or K1062M molecules enforce malignant engraftment in mice.8Chen 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. Oncogenic mutations of ALK kinase in neuroblastoma.Nature. 2008; 455: 971-974Crossref PubMed Scopus (716) Google Scholar The normal function of the ALK protein is not yet fully elucidated, but ALK is especially expressed during the early differentiation of neuronal tissues.16Iwahara T. Fujimoto J. Wen D. Cupples R. Bucay N. Arakawa T. Mori S. Ratzkin B. Yamamoto T. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system.Oncogene. 1997; 14: 439-449Crossref PubMed Scopus (553) Google Scholar, 17Degoutin J. Brunet-de Carvalho N. Cifuentes-Diaz C. Vigny M. ALK (anaplastic lymphoma kinase) expression in DRG neurons and its involvement in neuron-Schwann cells interaction.Eur J Neurosci. 2009; 29: 275-286Crossref PubMed Scopus (43) Google Scholar, 18Morris S.W. Naeve C. Mathew P. James P.L. Kirstein M.N. Cui X. Witte D.P. ALK, the chromosome 2 gene locus altered by the t(2;5) in non-Hodgkin's lymphoma, encodes a novel neural receptor tyrosine kinase that is highly related to leukocyte tyrosine kinase (LTK).Oncogene. 1997; 14: 2175-2188Crossref PubMed Scopus (414) Google Scholar, 19Vernersson E. Khoo N.K. Henriksson M.L. Roos G. Palmer R.H. Hallberg B. Characterization of the expression of the ALK receptor tyrosine kinase in mice.Gene Expr Patterns. 2006; 6: 448-461Crossref PubMed Scopus (113) Google Scholar, 20Li R. Morris S.W. Development of anaplastic lymphoma kinase (ALK) small-molecule inhibitors for cancer therapy.Med Res Rev. 2008; 28: 372-412Crossref PubMed Scopus (112) Google Scholar High levels of ALK have been measured in fetal neuroblasts.16Iwahara T. Fujimoto J. Wen D. Cupples R. Bucay N. Arakawa T. Mori S. Ratzkin B. Yamamoto T. Molecular characterization of ALK, a receptor tyrosine kinase expressed specifically in the nervous system.Oncogene. 1997; 14: 439-449Crossref PubMed Scopus (553) Google Scholar, 21Pulford K. Lamant L. Morris S.W. Butler L.H. Wood K.M. Stroud D. Delsol G. Mason D.Y. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1.Blood. 1997; 89: 1394-1404Crossref PubMed Google Scholar Many NBLs show ALK positivity by immunohistochemistry (IHC), although a wide range of positivity levels in NBL patient cohorts has been described.13Passoni L. Longo L. Collini P. Coluccia A.M. Bozzi F. Podda M. Gregorio A. Gambini C. Garaventa A. Pistoia V. Del Grosso F. Tonini G.P. Cheng M. Gambacorti-Passerini C. Anichini A. Fossati-Bellani F. Di Nicola M. Luksch R. Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients.Cancer Res. 2009; 69: 7338-7346Crossref PubMed Scopus (142) Google Scholar, 21Pulford K. Lamant L. Morris S.W. Butler L.H. Wood K.M. Stroud D. Delsol G. Mason D.Y. Detection of anaplastic lymphoma kinase (ALK) and nucleolar protein nucleophosmin (NPM)-ALK proteins in normal and neoplastic cells with the monoclonal antibody ALK1.Blood. 1997; 89: 1394-1404Crossref PubMed Google Scholar, 22De Brouwer S. De Preter K. Kumps C. Zabrocki P. Porcu M. Westerhout E.M. Lakeman A. Vandesompele J. Hoebeeck J. Van Maerken T. De Paepe A. Laureys G. Schulte J.H. Schramm A. Van Den Broecke C. Vermeulen J. Van Roy N. Beiske K. Renard M. Noguera R. Delattre O. Janoueix-Lerosey I. Kogner P. Martinsson T. Nakagawara A. Ohira M. Caron H. Eggert A. Cools J. Versteeg R. Speleman F. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.Clin Cancer Res. 2010; 16: 4353-4362Crossref PubMed Scopus (205) Google Scholar, 23Lamant L. Pulford K. Bischof D. Morris S.W. Mason D.Y. Delsol G. Mariame B. Expression of the ALK tyrosine kinase gene in neuroblastoma.Am J Pathol. 2000; 156: 1711-1721Abstract Full Text Full Text PDF PubMed Scopus (175) Google Scholar, 24Willoughby V. Sonawala A. Werlang-Perurena A. Donner L.R. A comparative immunohistochemical analysis of small round cell tumors of childhood: utility of peripherin and alpha-internexin as markers for neuroblastomas.Appl Immunohistochem Mol Morphol. 2008; 16: 344-348Crossref PubMed Scopus (12) Google Scholar The relevance of high ALK expression for the pathogenesis of this disease is unclear. The expression of ALK in the more benign ganglioneuroblastoma (GNBL) and ganglioneuroma (GN) has not been investigated yet and is included in this study. ALK aberrations and high ALK expression have been linked to NBL patient prognosis. Results from these studies are reviewed in Table 1.7Caren H. Abel F. Kogner P. Martinsson T. High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours.Biochem J. 2008; 416: 153-159Crossref PubMed Scopus (217) Google Scholar, 8Chen 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. Oncogenic mutations of ALK kinase in neuroblastoma.Nature. 2008; 455: 971-974Crossref PubMed Scopus (716) Google Scholar, 11Mosse 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. Kim C. Hou C. Hakonarson H. Torkamani A. Schork N.J. Brodeur G.M. Tonini G.P. Rappaport E. Devoto M. Maris J.M. Identification of ALK as a major familial neuroblastoma predisposition gene.Nature. 2008; 455: 930-935Crossref PubMed Scopus (1016) Google Scholar, 13Passoni L. Longo L. Collini P. Coluccia A.M. Bozzi F. Podda M. Gregorio A. Gambini C. Garaventa A. Pistoia V. Del Grosso F. Tonini G.P. Cheng M. Gambacorti-Passerini C. Anichini A. Fossati-Bellani F. Di Nicola M. Luksch R. Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients.Cancer Res. 2009; 69: 7338-7346Crossref PubMed Scopus (142) Google Scholar, 22De Brouwer S. De Preter K. Kumps C. Zabrocki P. Porcu M. Westerhout E.M. Lakeman A. Vandesompele J. Hoebeeck J. Van Maerken T. De Paepe A. Laureys G. Schulte J.H. Schramm A. Van Den Broecke C. Vermeulen J. Van Roy N. Beiske K. Renard M. Noguera R. Delattre O. Janoueix-Lerosey I. Kogner P. Martinsson T. Nakagawara A. Ohira M. Caron H. Eggert A. Cools J. Versteeg R. Speleman F. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.Clin Cancer Res. 2010; 16: 4353-4362Crossref PubMed Scopus (205) Google Scholar, 25Schulte J.H. Bachmann H.S. Brockmeyer B. Depreter K. Oberthür A. Ackermann S. Kahlert Y. Pajtler K. Theissen J. Westermann F. Vandesompele J. Speleman F. Berthold F. Eggert A. Brors B. Hero B. Schramm A. Fischer M. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma.Clin Cancer Res. 2011; 17: 5082-5092Crossref PubMed Scopus (83) Google Scholar ALK point mutations and copy number gains are associated with high ALK levels and with inferior prognosis of patients with NBL in univariate analyses.7Caren H. Abel F. Kogner P. Martinsson T. High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours.Biochem J. 2008; 416: 153-159Crossref PubMed Scopus (217) Google Scholar, 8Chen 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. Oncogenic mutations of ALK kinase in neuroblastoma.Nature. 2008; 455: 971-974Crossref PubMed Scopus (716) Google Scholar, 9George R.E. Sanda T. Hanna M. Frohling S. Luther 2nd, W. Zhang J. Ahn Y. Zhou W. London W.B. McGrady P. Xue L. Zozulya S. Gregor V.E. Webb T.R. Gray N.S. Gilliland D.G. Diller L. Greulich H. Morris S.W. Meyerson M. Look A.T. Activating mutations in ALK provide a therapeutic target in neuroblastoma.Nature. 2008; 455: 975-978Crossref PubMed Scopus (677) Google Scholar, 11Mosse 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. Kim C. Hou C. Hakonarson H. Torkamani A. Schork N.J. Brodeur G.M. Tonini G.P. Rappaport E. Devoto M. Maris J.M. Identification of ALK as a major familial neuroblastoma predisposition gene.Nature. 2008; 455: 930-935Crossref PubMed Scopus (1016) Google Scholar, 26Stock C. Bozsaky E. Watzinger F. Poetschger U. Orel L. Lion T. Kowalska A. Ambros P.F. Genes proximal and distal to MYCN are highly expressed in human neuroblastoma as visualized by comparative expressed sequence hybridization.Am J Pathol. 2008; 172: 203-214Abstract Full Text Full Text PDF PubMed Scopus (19) Google Scholar, 27McDermott U. Iafrate A.J. Gray N.S. Shioda T. Classon M. Maheswaran S. Zhou W. Choi H.G. Smith S.L. Dowell L. Ulkus L.E. Kuhlmann G. Greninger P. Christensen J.G. Haber D.A. Settleman J. Genomic alterations of anaplastic lymphoma kinase may sensitize tumors to anaplastic lymphoma kinase inhibitors.Cancer Res. 2008; 68: 3389-3395Crossref PubMed Scopus (367) Google Scholar However, ALK mutation status has not been identified as an independent prognostic factor in multivariate analyses.8Chen 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. Oncogenic mutations of ALK kinase in neuroblastoma.Nature. 2008; 455: 971-974Crossref PubMed Scopus (716) Google Scholar, 22De Brouwer S. De Preter K. Kumps C. Zabrocki P. Porcu M. Westerhout E.M. Lakeman A. Vandesompele J. Hoebeeck J. Van Maerken T. De Paepe A. Laureys G. Schulte J.H. Schramm A. Van Den Broecke C. Vermeulen J. Van Roy N. Beiske K. Renard M. Noguera R. Delattre O. Janoueix-Lerosey I. Kogner P. Martinsson T. Nakagawara A. Ohira M. Caron H. Eggert A. Cools J. Versteeg R. Speleman F. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.Clin Cancer Res. 2010; 16: 4353-4362Crossref PubMed Scopus (205) Google Scholar, 25Schulte J.H. Bachmann H.S. Brockmeyer B. Depreter K. Oberthür A. Ackermann S. Kahlert Y. Pajtler K. Theissen J. Westermann F. Vandesompele J. Speleman F. Berthold F. Eggert A. Brors B. Hero B. Schramm A. Fischer M. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma.Clin Cancer Res. 2011; 17: 5082-5092Crossref PubMed Scopus (83) Google Scholar Two studies22De Brouwer S. De Preter K. Kumps C. Zabrocki P. Porcu M. Westerhout E.M. Lakeman A. Vandesompele J. Hoebeeck J. Van Maerken T. De Paepe A. Laureys G. Schulte J.H. Schramm A. Van Den Broecke C. Vermeulen J. Van Roy N. Beiske K. Renard M. Noguera R. Delattre O. Janoueix-Lerosey I. Kogner P. Martinsson T. Nakagawara A. Ohira M. Caron H. Eggert A. Cools J. Versteeg R. Speleman F. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.Clin Cancer Res. 2010; 16: 4353-4362Crossref PubMed Scopus (205) Google Scholar, 25Schulte J.H. Bachmann H.S. Brockmeyer B. Depreter K. Oberthür A. Ackermann S. Kahlert Y. Pajtler K. Theissen J. Westermann F. Vandesompele J. Speleman F. Berthold F. Eggert A. Brors B. Hero B. Schramm A. Fischer M. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma.Clin Cancer Res. 2011; 17: 5082-5092Crossref PubMed Scopus (83) Google Scholar showed a correlation between ALK mRNA levels in NBL samples and inferior survival univariately, whereas in multivariate analysis, only one of four cohorts remained significant.22De Brouwer S. De Preter K. Kumps C. Zabrocki P. Porcu M. Westerhout E.M. Lakeman A. Vandesompele J. Hoebeeck J. Van Maerken T. De Paepe A. Laureys G. Schulte J.H. Schramm A. Van Den Broecke C. Vermeulen J. Van Roy N. Beiske K. Renard M. Noguera R. Delattre O. Janoueix-Lerosey I. Kogner P. Martinsson T. Nakagawara A. Ohira M. Caron H. Eggert A. Cools J. Versteeg R. Speleman F. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.Clin Cancer Res. 2010; 16: 4353-4362Crossref PubMed Scopus (205) Google Scholar High percentages of ALK-positive cells by IHC were correlated with inferior survival in 2009,13Passoni L. Longo L. Collini P. Coluccia A.M. Bozzi F. Podda M. Gregorio A. Gambini C. Garaventa A. Pistoia V. Del Grosso F. Tonini G.P. Cheng M. Gambacorti-Passerini C. Anichini A. Fossati-Bellani F. Di Nicola M. Luksch R. Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients.Cancer Res. 2009; 69: 7338-7346Crossref PubMed Scopus (142) Google Scholar which was confirmed by others.22De Brouwer S. De Preter K. Kumps C. Zabrocki P. Porcu M. Westerhout E.M. Lakeman A. Vandesompele J. Hoebeeck J. Van Maerken T. De Paepe A. Laureys G. Schulte J.H. Schramm A. Van Den Broecke C. Vermeulen J. Van Roy N. Beiske K. Renard M. Noguera R. Delattre O. Janoueix-Lerosey I. Kogner P. Martinsson T. Nakagawara A. Ohira M. Caron H. Eggert A. Cools J. Versteeg R. Speleman F. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.Clin Cancer Res. 2010; 16: 4353-4362Crossref PubMed Scopus (205) Google Scholar Because ALK IHC is an easily applicable technique for routine diagnostics, this method could also be applied for routine patient risk stratification, particularly in NBL patient trials with ALK inhibitors. Multivariate analysis of ALK protein expression in NBL has not been performed yet.Table 1Summary of Literature on ALK and PrognosisReferenceType of ALK aberration studiedNBL Patients with an aberration [no./total (%)]Univariate analysisMultivariate analysis7Caren H. Abel F. Kogner P. Martinsson T. High incidence of DNA mutations and gene amplifications of the ALK gene in advanced sporadic neuroblastoma tumours.Biochem J. 2008; 416: 153-159Crossref PubMed Scopus (217) Google ScholarALK point mutation10/90 (11.1)33% OS compared with non-ALK aberratedNAALK amplification4/108 (3.7)50% OS compared with non-ALK aberratedNAALK gain20/108 (18.5)52% OS compared with non-ALK aberratedNA8Chen 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. Oncogenic mutations of ALK kinase in neuroblastoma.Nature. 2008; 455: 971-974Crossref PubMed Scopus (716) Google ScholarALK point mutation or13/215 (6.0)NANS (P = 0.58) in model. including MYCN status and stage 4 amplification6/215 (2.8)11Mosse 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. Kim C. Hou C. Hakonarson H. Torkamani A. Schork N.J. Brodeur G.M. Tonini G.P. Rappaport E. Devoto M. Maris J.M. Identification of ALK as a major familial neuroblastoma predisposition gene.Nature. 2008; 455: 930-935Crossref PubMed Scopus (1016) Google ScholarALK gain or112/491 (22.8)Significantly correlated with death from diseaseNA amplification16/491 (3.3)13Passoni L. Longo L. Collini P. Coluccia A.M. Bozzi F. Podda M. Gregorio A. Gambini C. Garaventa A. Pistoia V. Del Grosso F. Tonini G.P. Cheng M. Gambacorti-Passerini C. Anichini A. Fossati-Bellani F. Di Nicola M. Luksch R. Mutation-independent anaplastic lymphoma kinase overexpression in poor prognosis neuroblastoma patients.Cancer Res. 2009; 69: 7338-7346Crossref PubMed Scopus (142) Google ScholarLow ALK IHC staining ( 50% of the cells)45/82 (54.9)22De Brouwer S. De Preter K. Kumps C. Zabrocki P. Porcu M. Westerhout E.M. Lakeman A. Vandesompele J. Hoebeeck J. Van Maerken T. De Paepe A. Laureys G. Schulte J.H. Schramm A. Van Den Broecke C. Vermeulen J. Van Roy N. Beiske K. Renard M. Noguera R. Delattre O. Janoueix-Lerosey I. Kogner P. Martinsson T. Nakagawara A. Ohira M. Caron H. Eggert A. Cools J. Versteeg R. Speleman F. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.Clin Cancer Res. 2010; 16: 4353-4362Crossref PubMed Scopus (205) Google ScholarLow ALK IHC staining (<50% of the cells)17/54 (31.5)High ALK IHC is significantly associated with higher DOD and inferior PFSNAHigh ALK IHC staining (≥50% of the cells)37/54 (68.5)22De Brouwer S. De Preter K. Kumps C. Zabrocki P. Porcu M. Westerhout E.M. Lakeman A. Vandesompele J. Hoebeeck J. Van Maerken T. De Paepe A. Laureys G. Schulte J.H. Schramm A. Van Den Broecke C. Vermeulen J. Van Roy N. Beiske K. Renard M. Noguera R. Delattre O. Janoueix-Lerosey I. Kogner P. Martinsson T. Nakagawara A. Ohira M. Caron H. Eggert A. Cools J. Versteeg R. Speleman F. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification.Clin Cancer Res. 2010; 16: 4353-4362Crossref PubMed Scopus (205) G

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