Anaplastic lymphoma kinase aberrations correlate with metastatic features in pediatric rhabdomyosarcoma

Patrizia Gasparini, Michela Casanova, R. Villa, Paola Collini, Rita Alaggio, Angelica Zin, P. 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, Maria Grazia DaidoneGabriella Sozzi, Andrea Ferrari

Research output: Contribution to journalArticle

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.

Original languageEnglish
Pages (from-to)58903-58914
Number of pages12
JournalOncotarget
Volume7
Issue number37
DOIs
Publication statusPublished - 2016

Keywords

  • Anaplastic lymphoma kinase
  • Chromosomal rearrangement
  • EML4-ALK
  • Metastasis
  • Rhabdomyosarcoma

ASJC Scopus subject areas

  • Oncology

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    Gasparini, P., Casanova, M., Villa, R., Collini, P., Alaggio, R., Zin, A., Bonvini, P., Antonescu, C. R., Boldrini, R., Caserini, R., Moro, M., Centonze, G., Meazza, C., Massimino, M., Bergamaschi, L., Luksch, R., Chiaravalli, S., Bisogno, G., Zaffaroni, N., ... Ferrari, A. (2016). Anaplastic lymphoma kinase aberrations correlate with metastatic features in pediatric rhabdomyosarcoma. Oncotarget, 7(37), 58903-58914. https://doi.org/10.18632/oncotarget.10368