title: Anaplastic lymphoma kinase aberrations correlate with metastatic features in pediatric rhabdomyosarcoma.
abstract: Rhabdomyosarcoma (RMS) is the most frequent soft tissue tumor in childhood and arises from immature mesenchymal cells committed to skeletal muscle differentiation. Anaplastic Lymphoma Kinase (ALK) is a receptor tyrosine kinase aberrantly expressed in several cancers. Moreover, ALK full-length receptor protein has been observed in RMS, although its clinical and functional significance is yet controversial. The role of ALK and its clinical relevance were investigated in a selected cohort of 74 FFPE pediatric RMS and a panel of RMS cell lines, evaluating its gene and protein status, utilizing Fluorescent In Situ Hybridization (FISH), immunohistochemistry (IHC) and Western blot approaches. Moreover, to get insight into its possible therapeutic relevance, effects of ALK silencing on cell proliferation, invasion and apoptosis were studied in RMS cells. ALK IHC positivity was significantly correlated with gene copy number gain, the alveolar subtype, PAX3/7-FOXO1 rearrangements, the presence of metastasis at diagnosis and a worse overall outcome. Furthermore, EML4-ALK fusion gene associated with higher protein expression was identified in an embryonal RMS. ALK silencing in RH30 ALK positive cells strongly inhibited invasion capability. Overall, our data suggest a potential role of ALK in pediatric RMS.
authors.affiliation: Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Patrizia
authors.initials: P
authors.lastname: Gasparini
authors.affiliation: Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Michela
authors.initials: M
authors.lastname: Casanova
authors.affiliation: Biomarkers Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Raffaella
authors.initials: R
authors.lastname: Villa
authors.affiliation: Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Paola
authors.initials: P
authors.lastname: Collini
authors.affiliation: Department of Pathology, University Hospital of Padova, Padova, Italy.
authors.forename: Rita
authors.initials: R
authors.lastname: Alaggio
authors.affiliation: Institute of Pediatric Research Città della Speranza, Padova, Italy.
authors.forename: Angelica
authors.initials: A
authors.lastname: Zin
authors.affiliation: Institute of Pediatric Research Città della Speranza, Padova, Italy.
authors.forename: Paolo
authors.initials: P
authors.lastname: Bonvini
authors.affiliation: Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA.
authors.forename: Cristina R
authors.initials: CR
authors.lastname: Antonescu
authors.affiliation: Department of Pathology, Bambino Gesù Children Hospital-Research Institute, Rome, Italy.
authors.forename: Renata
authors.initials: R
authors.lastname: Boldrini
authors.affiliation: Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Caserini
authors.affiliation: Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Massimo
authors.initials: M
authors.lastname: Moro
authors.affiliation: Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Giovanni
authors.initials: G
authors.lastname: Centonze
authors.affiliation: Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Cristina
authors.initials: C
authors.lastname: Meazza
authors.affiliation: Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maura
authors.initials: M
authors.lastname: Massimino
authors.affiliation: Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Luca
authors.initials: L
authors.lastname: Bergamaschi
authors.affiliation: Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Roberto
authors.initials: R
authors.lastname: Luksch
authors.affiliation: Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Stefano
authors.initials: S
authors.lastname: Chiaravalli
authors.affiliation: Hematology Oncology Division, Department of Mother and Child's Health, University Hospital of Padova, Padova, Italy.
authors.forename: Gianni
authors.initials: G
authors.lastname: Bisogno
authors.affiliation: Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Nadia
authors.initials: N
authors.lastname: Zaffaroni
authors.affiliation: Biomarkers Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Maria Grazia
authors.initials: MG
authors.lastname: Daidone
authors.affiliation: Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Gabriella
authors.initials: G
authors.lastname: Sozzi
authors.affiliation: Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy.
authors.forename: Andrea
authors.initials: A
authors.lastname: Ferrari
mesh_terms: D000293:Adolescent; D000328:Adult; D000077548:Anaplastic Lymphoma Kinase; D002454:Cell Differentiation; D045744:Cell Line, Tumor; D002648:Child; D002675:Child, Preschool; D015331:Cohort Studies; D005260:Female; D015321:Gene Rearrangement; D006801:Humans; D007223:Infant; D007231:Infant, Newborn; D008297:Male; D059630:Mesenchymal Stem Cells / Q000502:physiology*; D018482:Muscle, Skeletal / Q000473:pathology*; D009362:Neoplasm Metastasis; D034741:RNA, Small Interfering / Q000235:genetics; D020794:Receptor Protein-Tyrosine Kinases / Q000235:genetics* / Q000378:metabolism; D012208:Rhabdomyosarcoma / Q000175:diagnosis* / Q000235:genetics*; D016896:Treatment Outcome; D055815:Young Adult
chemical_list: D034741:RNA, Small Interfering; C000626173:ALK protein, human; D000077548:Anaplastic Lymphoma Kinase; D020794:Receptor Protein-Tyrosine Kinases
keywords: EML4-ALK; anaplastic lymphoma kinase; chromosomal rearrangement; metastasis; rhabdomyosarcoma