Anaplastic lymphoma kinase aberrations correlate with metastatic features in pediatric rhabdomyosarcoma
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Patrizia Gasparini1,*, Michela Casanova2,*, Raffaella Villa3, Paola Collini4, Rita Alaggio5, Angelica Zin6, Paolo Bonvini6, Cristina R Antonescu8, Renata Boldrini9, Roberto Caserini1, Massimo Moro1, Giovanni Centonze1, Cristina Meazza2, Maura Massimino2, Luca Bergamaschi2, Roberto Luksch2, Stefano Chiaravalli2, Gianni Bisogno10, Nadia Zaffaroni7, MariaGrazia Daidone3, Gabriella Sozzi1,#, Andrea Ferrari2,#
1Tumor Genomics Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
2Department of Pediatric Oncology, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
3Biomarkers Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
4Soft Tissue and Bone Pathology, Histopathology and Pediatric Pathology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
5Department of Pathology, University Hospital of Padova, Padova, Italy
6Institute of Pediatric Research Città della Speranza, Padova, Italy
7Molecular Pharmacology Unit, Fondazione IRCCS Istituto Nazionale dei Tumori, Milan, Italy
8Department of Pathology, Memorial Sloan Kettering Cancer Center, New York, NY, USA
9Department of Pathology, Bambino Gesù Children Hospital-Research Institute, Rome, Italy
10Hematology Oncology Division, Department of Mother and Child’s Health, University Hospital of Padova, Padova, Italy
*These authors contributed equally to this work
Gabriella Sozzi, email: email@example.com
Keywords: anaplastic lymphoma kinase, rhabdomyosarcoma, EML4-ALK, chromosomal rearrangement, metastasis
Received: February 11, 2016 Accepted: June 12, 2016 Published: July 01, 2016
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.
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