Oncotarget

Research Papers:

Anaplastic lymphoma kinase aberrations correlate with metastatic features in pediatric rhabdomyosarcoma

Patrizia Gasparini, Michela Casanova, Raffaella Villa, Paola Collini, Rita Alaggio, Angelica Zin, Paolo Bonvini, Cristina R Antonescu, Renata Boldrini, Roberto Caserini, Massimo Moro, Giovanni Centonze, Cristina Meazza, Maura Massimino, Luca Bergamaschi, Roberto Luksch, Stefano Chiaravalli, Gianni Bisogno, Nadia Zaffaroni, MariaGrazia Daidone, Gabriella Sozzi _ and Andrea Ferrari

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Oncotarget. 2016; 7:58903-58914. https://doi.org/10.18632/oncotarget.10368

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Abstract

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

#Co-last authors

Correspondence to:

Gabriella Sozzi, email: gabriella.sozzi@istitutotumori.mi.it

Keywords: anaplastic lymphoma kinase, rhabdomyosarcoma, EML4-ALK, chromosomal rearrangement, metastasis

Received: February 11, 2016     Accepted: June 12, 2016     Published: July 01, 2016

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.


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