TIAM1 variants improve clinical outcome in neuroblastoma

Autores de IIS La Fe

• Elena Sanmartín García

  Autor

• Yania Yañez Peralta

  Autor

• Victoria Fornés Ferrer

  Autor

• Adela Cañete Nieto

  Autor

• Victoria Castel Sánchez

  Autor

• Jaime Font De Mora Sainz

  Autor

Participantes ajenos a IIS La Fe

• Zugaza, JL

Grupos

• Investigación Clínica y Traslacional en Cáncer

Abstract

Identification of tumor driver mutations is crucial for improving clinical outcome using a personalized approach to the treatment of cancer. Neuroblastoma is a tumor of the peripheral sympathetic nervous system for which only a few driver alterations have been described including MYCN amplification and ALK mutations. We assessed 106 primary neuroblastoma tumors by next generation sequencing using a customized amplicon-based gene panel. Our results reveal that genetic variants in TIAM1 gene associate with better clinical outcome, suggesting a role for these TIAM1 variants in preventing progression of this disease. The detected variants are located within the different domains of TIAM1 that signal to the upstream regulator RAS and downstream effector molecules MYC and RAC, which are all implicated in neuroblastoma etiology and progression. Clinical outcome was improved in tumors where a TIAM1 variant was present concomitantly with either ALK mutation or MYCN amplification. Given the function of these signaling molecules in cell survival, proliferation, differentiation and neurite outgrowth, our data suggest that the TIAM1-mediated network is essential to neuroblastoma and thus, inhibiting TIAM1 reflects a rational strategy for improving therapy efficacy in neuroblastoma.

Keywords

• neuroblastoma; TIAM1; signaling networks; next generation sequencing