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Frequency and Prognostic Impact of ALK Amplifications and Mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1)
A. Bellini, U. Pötschger, V. Bernard, E. Lapouble, S. Baulande, PF. Ambros, N. Auger, K. Beiske, M. Bernkopf, DR. Betts, J. Bhalshankar, N. Bown, K. de Preter, N. Clément, V. Combaret, J. Font de Mora, SL. George, I. Jiménez, M. Jeison, B....
Jazyk angličtina Země Spojené státy americké
Typ dokumentu časopisecké články, práce podpořená grantem
Grantová podpora
Cancer Research UK - United Kingdom
Department of Health - United Kingdom
NLK
Free Medical Journals
od 2004 do Před 1 rokem
Open Access Digital Library
od 1999-01-01
PubMed
34115544
DOI
10.1200/jco.21.00086
Knihovny.cz E-zdroje
- MeSH
- amplifikace genu * MeSH
- anaplastická lymfomová kináza genetika MeSH
- klinické zkoušky, fáze III jako téma MeSH
- kojenec MeSH
- lidé MeSH
- míra přežití MeSH
- mutační rychlost * MeSH
- následné studie MeSH
- neuroblastom genetika MeSH
- předškolní dítě MeSH
- prognóza MeSH
- protoonkogen n-myc genetika MeSH
- randomizované kontrolované studie jako téma MeSH
- rizikové faktory MeSH
- Check Tag
- kojenec MeSH
- lidé MeSH
- mužské pohlaví MeSH
- předškolní dítě MeSH
- ženské pohlaví MeSH
- Publikační typ
- časopisecké články MeSH
- práce podpořená grantem MeSH
- Geografické názvy
- Evropa MeSH
PURPOSE: In neuroblastoma (NB), the ALK receptor tyrosine kinase can be constitutively activated through activating point mutations or genomic amplification. We studied ALK genetic alterations in high-risk (HR) patients on the HR-NBL1/SIOPEN trial to determine their frequency, correlation with clinical parameters, and prognostic impact. MATERIALS AND METHODS: Diagnostic tumor samples were available from 1,092 HR-NBL1/SIOPEN patients to determine ALK amplification status (n = 330), ALK mutational profile (n = 191), or both (n = 571). RESULTS: Genomic ALK amplification (ALKa) was detected in 4.5% of cases (41 out of 901), all except one with MYCN amplification (MNA). ALKa was associated with a significantly poorer overall survival (OS) (5-year OS: ALKa [n = 41] 28% [95% CI, 15 to 42]; no-ALKa [n = 860] 51% [95% CI, 47 to 54], [P < .001]), particularly in cases with metastatic disease. ALK mutations (ALKm) were detected at a clonal level (> 20% mutated allele fraction) in 10% of cases (76 out of 762) and at a subclonal level (mutated allele fraction 0.1%-20%) in 3.9% of patients (30 out of 762), with a strong correlation between the presence of ALKm and MNA (P < .001). Among 571 cases with known ALKa and ALKm status, a statistically significant difference in OS was observed between cases with ALKa or clonal ALKm versus subclonal ALKm or no ALK alterations (5-year OS: ALKa [n = 19], 26% [95% CI, 10 to 47], clonal ALKm [n = 65] 33% [95% CI, 21 to 44], subclonal ALKm (n = 22) 48% [95% CI, 26 to 67], and no alteration [n = 465], 51% [95% CI, 46 to 55], respectively; P = .001). Importantly, in a multivariate model, involvement of more than one metastatic compartment (hazard ratio [HR], 2.87; P < .001), ALKa (HR, 2.38; P = .004), and clonal ALKm (HR, 1.77; P = .001) were independent predictors of poor outcome. CONCLUSION: Genetic alterations of ALK (clonal mutations and amplifications) in HR-NB are independent predictors of poorer survival. These data provide a rationale for integration of ALK inhibitors in upfront treatment of HR-NB with ALK alterations.
Center for Genomic Medicine Rigshospitalet Copenhagen University Hospital Copenhagen Denmark
Clinical and Translational Oncology Research Group Health Research Institute La Fe Valencia Spain
Departamento de Genética Humana Instituto Nacional de Saúde Doutor Ricardo Jorge Lisbon Portugal
Département d'Oncologie Pédiatrique Gustave Roussy Villejuif France
Department for Studies and Statistics and Integrated Research Vienna Austria
Department of Clinical Genetics Children's Health Ireland at Crumlin Dublin Ireland
Department of Paediatrics Medical University of Vienna Vienna Austria
Department of Pathology IRCCS Istituto Giannina Gaslini Genova Italy
Department of Pathology Oslo University Hospital and Medical Faculty University of Oslo Oslo Norway
Division of Clinical Studies The Institute of Cancer Research London United Kingdom
Equipe SiRIC RTOP Recherche Translationelle en Oncologie Pédiatrique Institut Curie Paris France
Ghent University Ghent Belgium
INSERM U830 Laboratoire de Génétique et Biologie des Cancers Institut Curie Paris France
Institut Curie Genomics of Excellence Platform Research Center Institut Curie Paris France
Institut Gustave Roussy Villejuif France
Instituto de Investigación Sanitaria La Fe Valencia Spain
Karolinska University Hospital Stockholm Sweden
Laboratory of Molecular Biology IRCCS Istituto Giannina Gaslini Genova Italy
Leeds Children's Hospital Leeds General Infirmary Leeds United Kingdom
Paediatric Oncology Fondazione IRCCS Istituto Nazionale dei Tumori Milan Italy
Ruth Rappaport Children's Hospital Rambam Health Care Campus Haifa Israel
Sahlgrenska University Hospital Göteborg Sweden
Schneider Children's Medical Center of Israel Tel Aviv University Tel Aviv Israel
Service de Génétique des tumeurs
St Anna Children's Cancer Research Institute Vienna Austria
Translational Research Laboratory Centre Léon Bérard Lyon France
Unité de Génétique Somatique Service de Génétique Hospital Group Institut Curie Paris France
Citace poskytuje Crossref.org
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