TIAM1 variants improve clinical outcome in neuroblastoma.

Elena Sanmartín,Yania Yáñez,Jaime Font De Mora,Victoria Fornés-Ferrer,Adela Cañete,Victoria Castel,José L Zugaza

doi:10.18632/oncotarget.16787

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.

Highlights

TIAM1 is a molecular conduit to a complex network of signaling pathways that control cell-fate decisions
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
We screened primary neuroblastomas by generation sequencing and our results reveal that TIAM1 variants in the domains signaling to MYC, RAS and RAC significantly predict better prognosis in neuroblastoma patients

Summary

INTRODUCTION

TIAM1 is a molecular conduit to a complex network of signaling pathways that control cell-fate decisions. TIAM1 N-terminal region binds to MYC box II, a highly conserved domain among MYC proteins, to inhibit MYCmediated apoptosis [1]. TIAM1 has an additional PH domain closer to the N-terminal region which determines the activation of distinct RAS-mediated signaling pathways such as c-Jun NH2-terminal kinase (JNK) [10]. Cellular and www.impactjournals.com/oncotarget molecular data reveal TIAM1 as a molecular conduit to MYC, RAS and RAC signaling and integrates these three pathways in a network to orchestrate pleiotropic responses in the cell. Cellular polarity in neuroblastoma cells is controlled by TIAM1-dependent RAC activation mediated by the polarity complex PAR-6-PAR-3 [11]. We screened primary neuroblastomas by generation sequencing and our results reveal that TIAM1 variants in the domains signaling to MYC, RAS and RAC significantly predict better prognosis in neuroblastoma patients. These novel observations implicate TIAM1 as a key signaling molecule in neuroblastoma and as a potential target for therapeutic intervention

RESULTS

DISCUSSION

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MATERIALS AND METHODS

Findings

CONFLICTS OF INTEREST