TIAM1 variants improve clinical outcome in neuroblastoma
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Elena Sanmartín1, Yania Yáñez2,3, Victoria Fornés-Ferrer4, José L. Zugaza5,6,7, Adela Cañete2,3, Victoria Castel2,3 and Jaime Font de Mora1,3
1Laboratory of Cellular and Molecular Biology, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
2Pediatric Oncology Unit, Hospital Universitario y Politécnico La Fe, València, Spain
3Precision Oncology Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
4Biostatistics Unit, Instituto de Investigación Sanitaria La Fe, Valencia, Spain
5Department of Genetics, Physical Anthropology and Animal Physiology, University of the Basque Country, Leioa, Spain
6Achucarro Basque Center for Neuroscience, Bizkaia Science and Technology Park, Zamudio, Spain
7IKERBASQUE, Basque Foundation for Science, Bilbao, Spain
Jaime Font de Mora, email: [email protected]
Keywords: neuroblastoma, TIAM1, signaling networks, next generation sequencing
Received: June 04, 2016 Accepted: March 17, 2017 Published: April 03, 2017
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.
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