Genomic ALK alterations in primary and relapsed neuroblastoma.

Child Humans Anaplastic Lymphoma Kinase / genetics Receptor Protein-Tyrosine Kinases / genetics Neoplasm Recurrence, Local / genetics Neuroblastoma / genetics Genomics

Journal

British journal of cancer
ISSN: 1532-1827
Titre abrégé: Br J Cancer
Pays: England
ID NLM: 0370635

Informations de publication

Date de publication:
04 2023
Historique:
received: 04 07 2022
accepted: 08 02 2023
revised: 04 02 2023
medline: 5 4 2023
pubmed: 23 2 2023
entrez: 22 2 2023
Statut: ppublish

Résumé

Genomic alterations of the anaplastic lymphoma kinase gene (ALK) occur recurrently in neuroblastoma, a pediatric malignancy of the sympathetic nervous system. However, information on their development over time has remained sparse. ALK alterations were assessed in neuroblastomas at diagnosis and/or relapse from a total of 943 patients, covering all stages of disease. Longitudinal information on diagnostic and relapsed samples from individual patients was available in 101 and 102 cases for mutation and amplification status, respectively. At diagnosis, ALK point mutations occurred in 10.5% of all cases, with highest frequencies in stage 4 patients <18 months. At relapse, ALK alteration frequency increased by 70%, both in high-risk and non-high-risk cases. The increase was most likely due to de novo mutations, frequently leading to R1275Q substitutions, which are sensitive to pharmacological ALK inhibition. By contrast, the frequency of ALK amplifications did not change over the course of the disease. ALK amplifications, but not mutations, were associated with poor patient outcome. The considerably increased frequency of ALK mutations at relapse and their high prevalence in young stage 4 patients suggest surveying the genomic ALK status regularly in these patient cohorts, and to evaluate ALK-targeted treatment also in intermediate-risk patients.

Sections du résumé

BACKGROUND
Genomic alterations of the anaplastic lymphoma kinase gene (ALK) occur recurrently in neuroblastoma, a pediatric malignancy of the sympathetic nervous system. However, information on their development over time has remained sparse.
METHODS
ALK alterations were assessed in neuroblastomas at diagnosis and/or relapse from a total of 943 patients, covering all stages of disease. Longitudinal information on diagnostic and relapsed samples from individual patients was available in 101 and 102 cases for mutation and amplification status, respectively.
RESULTS
At diagnosis, ALK point mutations occurred in 10.5% of all cases, with highest frequencies in stage 4 patients <18 months. At relapse, ALK alteration frequency increased by 70%, both in high-risk and non-high-risk cases. The increase was most likely due to de novo mutations, frequently leading to R1275Q substitutions, which are sensitive to pharmacological ALK inhibition. By contrast, the frequency of ALK amplifications did not change over the course of the disease. ALK amplifications, but not mutations, were associated with poor patient outcome.
CONCLUSIONS
The considerably increased frequency of ALK mutations at relapse and their high prevalence in young stage 4 patients suggest surveying the genomic ALK status regularly in these patient cohorts, and to evaluate ALK-targeted treatment also in intermediate-risk patients.

Identifiants

DOI: 10.1038/s41416-023-02208-y PMID: 36807339 PMC: PMC10070426
pubmed: 36807339
doi: 10.1038/s41416-023-02208-y
pii: 10.1038/s41416-023-02208-y
pmc: PMC10070426
doi:

Substances chimiques

Anaplastic Lymphoma Kinase EC 2.7.10.1
Receptor Protein-Tyrosine Kinases EC 2.7.10.1

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

1559-1571

Informations de copyright

© 2023. The Author(s).

Références

London WB, Castleberry RP, Matthay KK, Look AT, Seeger RC, Shimada H, et al. Evidence for an age cutoff greater than 365 days for neuroblastoma risk group stratification in the Children’s Oncology Group. J Clin Oncol. 2005;23:6459–65.
pubmed: 16116153 doi: 10.1200/JCO.2005.05.571
Peifer M, Hertwig F, Roels F, Dreidax D, Gartlgruber M, Menon R, et al. Telomerase activation by genomic rearrangements in high-risk neuroblastoma. Nature. 2015;526:700–4.
pubmed: 26466568 pmcid: 4881306 doi: 10.1038/nature14980
Ackermann S, Cartolano M, Hero B, Welte A, Kahlert Y, Roderwieser A, et al. A mechanistic classification of clinical phenotypes in neuroblastoma. Science. 2018;362:1165–70.
pubmed: 30523111 pmcid: 7875194 doi: 10.1126/science.aat6768
Fischer M, Moreno L, Ziegler DS, Marshall LV, Zwaan CM, Irwin MS, et al. Ceritinib in paediatric patients with anaplastic lymphoma kinase-positive malignancies: an open-label, multicentre, phase 1, dose-escalation and dose-expansion study. Lancet Oncol. 2021;22:1764–76.
pubmed: 34780709 doi: 10.1016/S1470-2045(21)00536-2
Janoueix-Lerosey I, Lequin D, Brugieres L, Ribeiro A, de Pontual L, Combaret V, et al. Somatic and germline activating mutations of the ALK kinase receptor in neuroblastoma. Nature. 2008;455:967–70.
pubmed: 18923523 doi: 10.1038/nature07398
Lee CC, Jia Y, Li N, Sun X, Ng K, Ambing E, et al. Crystal structure of the ALK (anaplastic lymphoma kinase) catalytic domain. Biochem J. 2010;430:425–37.
pubmed: 20632993 doi: 10.1042/BJ20100609
Carpenter EL, Mosse YP. Targeting ALK in neuroblastoma-preclinical and clinical advancements. Nat Rev Clin Oncol. 2012;9:391–9.
pubmed: 22585002 pmcid: 3683972 doi: 10.1038/nrclinonc.2012.72
Javanmardi N, Fransson S, Djos A, Sjoberg RM, Nilsson S, Truve K, et al. Low frequency ALK hotspots mutations in neuroblastoma tumours detected by ultra-deep sequencing: implications for ALK inhibitor treatment. Sci Rep. 2019;9:2199.
pubmed: 30778092 pmcid: 6379392 doi: 10.1038/s41598-018-37240-z
Bellini A, Bernard V, Leroy Q, Rio Frio T, Pierron G, Combaret V, et al. Deep sequencing reveals occurrence of subclonal ALK mutations in neuroblastoma at diagnosis. Clin Cancer Res. 2015;21:4913–21.
pubmed: 26059187 doi: 10.1158/1078-0432.CCR-15-0423
Schleiermacher G, Javanmardi N, Bernard V, Leroy Q, Cappo J, Rio Frio T, et al. Emergence of new ALK mutations at relapse of neuroblastoma. J Clin Oncol. 2014;32:2727–34.
pubmed: 25071110 doi: 10.1200/JCO.2013.54.0674
De Brouwer S, De Preter K, Kumps C, Zabrocki P, Porcu M, Westerhout EM, et al. Meta-analysis of neuroblastomas reveals a skewed ALK mutation spectrum in tumors with MYCN amplification. Clin Cancer Res. 2010;16:4353–62.
pubmed: 20719933 doi: 10.1158/1078-0432.CCR-09-2660
Bresler SC, Weiser DA, Huwe PJ, Park JH, Krytska K, Ryles H, et al. ALK mutations confer differential oncogenic activation and sensitivity to ALK inhibition therapy in neuroblastoma. Cancer Cell. 2014;26:682–94.
pubmed: 25517749 pmcid: 4269829 doi: 10.1016/j.ccell.2014.09.019
Schulte JH, Bachmann HS, Brockmeyer B, Depreter K, Oberthur A, Ackermann S, et al. High ALK receptor tyrosine kinase expression supersedes ALK mutation as a determining factor of an unfavorable phenotype in primary neuroblastoma. Clin Cancer Res. 2011;17:5082–92.
pubmed: 21632861 doi: 10.1158/1078-0432.CCR-10-2809
O’Donohue T, Gulati N, Mauguen A, Kushner BH, Shukla N, Rodriguez-Sanchez MI, et al. Differential impact of ALK mutations in neuroblastoma. JCO Precis Oncol. 2021;5:492–500.
doi: 10.1200/PO.20.00181
Bellini A, Potschger U, Bernard V, Lapouble E, Baulande S, Ambros PF, et al. Frequency and prognostic impact of ALK amplifications and mutations in the European Neuroblastoma Study Group (SIOPEN) High-Risk Neuroblastoma Trial (HR-NBL1). J Clin Oncol. 2021;39:3377–90.
pubmed: 34115544 pmcid: 8791815 doi: 10.1200/JCO.21.00086
Trigg RM, Turner SD. ALK in neuroblastoma: biological and therapeutic implications. Cancers. 2018;10:113.
pubmed: 29642598 pmcid: 5923368 doi: 10.3390/cancers10040113
Mosse YP, Laudenslager M, Longo L, Cole KA, Wood A, Attiyeh EF, et al. Identification of ALK as a major familial neuroblastoma predisposition gene. Nature. 2008;455:930–5.
pubmed: 18724359 pmcid: 2672043 doi: 10.1038/nature07261
George RE, Sanda T, Hanna M, Frohling S, Luther W 2nd, Zhang J, et al. Activating mutations in ALK provide a therapeutic target in neuroblastoma. Nature. 2008;455:975–8.
pubmed: 18923525 pmcid: 2587486 doi: 10.1038/nature07397
Chen Y, Takita J, Choi YL, Kato M, Ohira M, Sanada M, et al. Oncogenic mutations of ALK kinase in neuroblastoma. Nature. 2008;455:971–4.
pubmed: 18923524 doi: 10.1038/nature07399
Fransson S, Hansson M, Ruuth K, Djos A, Berbegall A, Javanmardi N, et al. Intragenic anaplastic lymphoma kinase (ALK) rearrangements: translocations as a novel mechanism of ALK activation in neuroblastoma tumors. Genes Chromosomes Cancer. 2015;54:99–109.
pubmed: 25251827 doi: 10.1002/gcc.22223
Cazes A, Louis-Brennetot C, Mazot P, Dingli F, Lombard B, Boeva V, et al. Characterization of rearrangements involving the ALK gene reveals a novel truncated form associated with tumor aggressiveness in neuroblastoma. Cancer Res. 2013;73:195–204.
pubmed: 23139213 doi: 10.1158/0008-5472.CAN-12-1242
Mosse YP, Voss SD, Lim MS, Rolland D, Minard CG, Fox E, et al. Targeting ALK with crizotinib in pediatric anaplastic large cell lymphoma and inflammatory myofibroblastic tumor: a Children’s Oncology Group Study. J Clin Oncol. 2017;35:3215–21.
pubmed: 28787259 pmcid: 5617123 doi: 10.1200/JCO.2017.73.4830
Mosse YP, Lim MS, Voss SD, Wilner K, Ruffner K, Laliberte J, et al. Safety and activity of crizotinib for paediatric patients with refractory solid tumours or anaplastic large-cell lymphoma: a Children’s Oncology Group Phase 1 Consortium Study. Lancet Oncol. 2013;14:472–80.
pubmed: 23598171 pmcid: 3730818 doi: 10.1016/S1470-2045(13)70095-0
Brodeur GM, Pritchard J, Berthold F, Carlsen NL, Castel V, Castelberry RP, et al. Revisions of the international criteria for neuroblastoma diagnosis, staging, and response to treatment. J Clin Oncol. 1993;11:1466–77.
pubmed: 8336186 doi: 10.1200/JCO.1993.11.8.1466
Brodeur GM, Seeger RC, Barrett A, Berthold F, Castleberry RP, D’Angio G, et al. International criteria for diagnosis, staging, and response to treatment in patients with neuroblastoma. J Clin Oncol. 1988;6:1874–81.
pubmed: 3199170 doi: 10.1200/JCO.1988.6.12.1874
Theissen J, Boensch M, Spitz R, Betts D, Stegmaier S, Christiansen H, et al. Heterogeneity of the MYCN oncogene in neuroblastoma. Clin Cancer Res. 2009;15:2085–90.
pubmed: 19276282 doi: 10.1158/1078-0432.CCR-08-1648
Ihle MA, Fassunke J, Konig K, Grunewald I, Schlaak M, Kreuzberg N, et al. Comparison of high resolution melting analysis, pyrosequencing, next generation sequencing and immunohistochemistry to conventional Sanger sequencing for the detection of p.V600E and non-p.V600E BRAF mutations. BMC Cancer. 2014;14:13.
pubmed: 24410877 pmcid: 3893431 doi: 10.1186/1471-2407-14-13
Cun Y, Yang TP, Achter V, Lang U, Peifer M. Copy-number analysis and inference of subclonal populations in cancer genomes using Sclust. Nat Protoc. 2018;13:1488–501.
pubmed: 29844525 doi: 10.1038/nprot.2018.033
Herling CD, Abedpour N, Weiss J, Schmitt A, Jachimowicz RD, Merkel O, et al. Clonal dynamics towards the development of venetoclax resistance in chronic lymphocytic leukemia. Nat Commun. 2018;9:727.
pubmed: 29463802 pmcid: 5820258 doi: 10.1038/s41467-018-03170-7
Worst BC, van Tilburg CM, Balasubramanian GP, Fiesel P, Witt R, Freitag A, et al. Next-generation personalised medicine for high-risk paediatric cancer patients—the INFORM pilot study. Eur J Cancer. 2016;65:91–101.
pubmed: 27479119 doi: 10.1016/j.ejca.2016.06.009
van Tilburg CM, Pfaff E, Pajtler KW, Langenberg KPS, Fiesel P, Jones BC, et al. The pediatric precision oncology INFORM registry: clinical outcome and benefit for patients with very high-evidence targets. Cancer Discov. 2021;11:2764–79.
pubmed: 34373263 pmcid: 9414287 doi: 10.1158/2159-8290.CD-21-0094
Peifer M, Fernandez-Cuesta L, Sos ML, George J, Seidel D, Kasper LH, et al. Integrative genome analyses identify key somatic driver mutations of small-cell lung cancer. Nat Genet. 2012;44:1104–10.
pubmed: 22941188 pmcid: 4915822 doi: 10.1038/ng.2396
R Core Team. R: a language and environment for statistical computing. R Foundation for Statistical Computing, Vienna, Austria; 2021. https://www.R-project.org/ .
Berlak M, Tucker E, Dorel M, Winkler A, McGearey A, Rodriguez-Fos E, et al. Mutations in ALK signaling pathways conferring resistance to ALK inhibitor treatment lead to collateral vulnerabilities in neuroblastoma cells. Mol Cancer. 2022;21:126.
pubmed: 35689207 pmcid: 9185889 doi: 10.1186/s12943-022-01583-z
Sausen M, Leary RJ, Jones S, Wu J, Reynolds CP, Liu X, et al. Integrated genomic analyses identify ARID1A and ARID1B alterations in the childhood cancer neuroblastoma. Nat Genet. 2013;45:12–7.
pubmed: 23202128 doi: 10.1038/ng.2493
Pugh TJ, Morozova O, Attiyeh EF, Asgharzadeh S, Wei JS, Auclair D, et al. The genetic landscape of high-risk neuroblastoma. Nat Genet. 2013;45:279–84.
pubmed: 23334666 pmcid: 3682833 doi: 10.1038/ng.2529
Molenaar JJ, Koster J, Zwijnenburg DA, van Sluis P, Valentijn LJ, van der Ploeg I, et al. Sequencing of neuroblastoma identifies chromothripsis and defects in neuritogenesis genes. Nature. 2012;483:589–93.
pubmed: 22367537 doi: 10.1038/nature10910
Cheung NK, Zhang J, Lu C, Parker M, Bahrami A, Tickoo SK, et al. Association of age at diagnosis and genetic mutations in patients with neuroblastoma. JAMA 2012;307:1062–71.
pubmed: 22416102 pmcid: 3527076 doi: 10.1001/jama.2012.228
Ogawa S, Takita J, Sanada M, Hayashi Y. Oncogenic mutations of ALK in neuroblastoma. Cancer Sci. 2011;102:302–8.
pubmed: 21205076 doi: 10.1111/j.1349-7006.2010.01825.x
Eleveld TF, Oldridge DA, Bernard V, Koster J, Colmet Daage L, Diskin SJ, et al. Relapsed neuroblastomas show frequent RAS-MAPK pathway mutations. Nat Genet. 2015;47:864–71.
pubmed: 26121087 pmcid: 4775079 doi: 10.1038/ng.3333
Padovan-Merhar OM, Raman P, Ostrovnaya I, Kalletla K, Rubnitz KR, Sanford EM, et al. Enrichment of targetable mutations in the relapsed neuroblastoma genome. PLoS Genet. 2016;12:e1006501.
pubmed: 27997549 pmcid: 5172533 doi: 10.1371/journal.pgen.1006501
Foster JH, Voss SD, Hall DC, Minard CG, Balis FM, Wilner K, et al. Activity of crizotinib in patients with ALK-aberrant relapsed/refractory neuroblastoma: a Children’s Oncology Group Study (ADVL0912). Clin Cancer Res. 2021;27:3543–8.
pubmed: 33568345 pmcid: 8254744 doi: 10.1158/1078-0432.CCR-20-4224
Kim C, Choi YB, Lee JW, Yoo KH, Sung KW, Koo HH. Excellent treatment outcomes in children younger than 18 months with stage 4 MYCN nonamplified neuroblastoma. Korean J Pediatr. 2018;61:53–8.
pubmed: 29563945 pmcid: 5854843 doi: 10.3345/kjp.2018.61.2.53
Berthold F, Rosswog C, Christiansen H, Fruhwald M, Hemstedt N, Klingebiel T, et al. Clinical and molecular characterization of patients with stage 4(M) neuroblastoma aged less than 18 months without MYCN amplification. Pediatr Blood Cancer. 2021;68:e29038.
pubmed: 33826231 doi: 10.1002/pbc.29038

Auteurs

Carolina Rosswog (C)

Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.
Else Kröner Forschungskolleg Clonal Evolution in Cancer, University Hospital of Cologne, Cologne, Germany.
Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
ORCID: 0000-0002-8855-6198

Jana Fassunke (J)

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
ORCID: 0000-0002-8391-5577

Angela Ernst (A)

Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.

Birgid Schömig-Markiefka (B)

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

Sabine Merkelbach-Bruse (S)

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

Christoph Bartenhagen (C)

Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.

Maria Cartolano (M)

Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.

Sandra Ackermann (S)

Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.
ORCID: 0000-0002-5869-7344

Jessica Theissen (J)

Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.

Mirjam Blattner-Johnson (M)

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.

Barbara Jones (B)

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.
Department of Pediatric Oncology, Hematology, Immunology and Pulmonology, Heidelberg University Hospital, Heidelberg, Germany.

Kathrin Schramm (K)

Hopp Children's Cancer Center Heidelberg (KiTZ), Heidelberg, Germany.
Division of Pediatric Glioma Research, German Cancer Research Center (DKFZ) and German Cancer Consortium (DKTK), Heidelberg, Germany.

Janine Altmüller (J)

Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.
Berlin Institute of Health at Charité - Universitätsmedizin Berlin, Core Facility Genomics, Berlin, Germany.
Max Delbrück Center for Molecular Medicine in the Helmholtz Association (MDC), Berlin, Germany.

Peter Nürnberg (P)

Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.
Cologne Center for Genomics (CCG), University of Cologne, Faculty of Medicine and University Hospital Cologne, Cologne, Germany.

Monika Ortmann (M)

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.

Frank Berthold (F)

Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.

Martin Peifer (M)

Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany.
Department of Translational Genomics, Medical Faculty, University of Cologne, Cologne, Germany.
ORCID: 0000-0002-5243-5503

Reinhard Büttner (R)

Institute of Pathology, University Hospital of Cologne, Cologne, Germany.
ORCID: 0000-0001-8806-4786

Frank Westermann (F)

Division Neuroblastoma Genomics, B087, German Cancer Research Center and Hopp Children´s Cancer Center at the NCT (KiTZ), Heidelberg, Germany.

Johannes H Schulte (JH)

Department of Paediatric Oncology and Haematology, Charité University Medical Centre Berlin, Berlin, Germany.
ORCID: 0000-0003-0671-1201

Thorsten Simon (T)

Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.
ORCID: 0000-0002-3425-8451

Barbara Hero (B)

Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany.

Matthias Fischer (M)

Department of Experimental Pediatric Oncology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany. matthias.fischer@uk-koeln.de.
Center for Molecular Medicine Cologne (CMMC), Medical Faculty, University of Cologne, Cologne, Germany. matthias.fischer@uk-koeln.de.
Department of Pediatric Oncology and Hematology, University Children's Hospital of Cologne, Medical Faculty, University of Cologne, Cologne, Germany. matthias.fischer@uk-koeln.de.
ORCID: 0000-0003-1363-1242

Articles similaires

[Redispensing of expensive oral anticancer medicines: a practical application].

Lisanne N van Merendonk, Kübra Akgöl, Bastiaan Nuijen
1.00
Humans Antineoplastic Agents Administration, Oral Drug Costs Counterfeit Drugs

Smoking Cessation and Incident Cardiovascular Disease.

Jun Hwan Cho, Seung Yong Shin, Hoseob Kim et al.
1.00
Humans Male Smoking Cessation Cardiovascular Diseases Female

Evaluation of Low-Value Services Across Major Medicare Advantage Insurers and Traditional Medicare.

Ciara Duggan, Adam L Beckman, Ishani Ganguli et al.
1.00
Humans United States Aged Cross-Sectional Studies Medicare Part C

Effectiveness of Virtual Yoga for Chronic Low Back Pain: A Randomized Clinical Trial.

Hallie Tankha, Devyn Gaskins, Amanda Shallcross et al.
1.00
Humans Yoga Low Back Pain Female Male

Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Genomic ALK alterations in primary and...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Genomic ALK alterations in primary and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs à activité tyrosine kinase › Kinase du lymphome anaplasique › Genomic ALK alterations in primary and...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines membranaires › Récepteurs de surface cellulaire › Récepteurs à activité tyrosine kinase › Genomic ALK alterations in primary and...
questionsmedicales.fr › États, signes et symptômes pathologiques › Processus pathologiques › Processus néoplasiques › Récidive tumorale locale › Genomic ALK alterations in primary and...
questionsmedicales.fr › Tumeurs › Tumeurs par type histologique › Tumeurs du tissu nerveux › Tumeurs neuroectodermiques › Tumeurs neuroépitheliales › Tumeurs neuroectodermiques primitives › Tumeurs neuroectodermiques primitives périphériques › Neuroblastome › Genomic ALK alterations in primary and...
questionsmedicales.fr › Disciplines des sciences naturelles › Disciplines des sciences biologiques › Biologie › Génétique › Génomique › Genomic ALK alterations in primary and...