RESUMEN
Gene fusions are common in high-grade serous ovarian cancer (HGSC). Such genetic lesions may promote tumorigenesis, but the pathogenic mechanisms are currently poorly understood. Here, we investigated the role of a PIK3R1-CCDC178 fusion identified from a patient with advanced HGSC. We show that the fusion induces HGSC cell migration by regulating ERK1/2 and increases resistance to platinum treatment. Platinum resistance was associated with rod and ring-like cellular structure formation. These structures contained, in addition to the fusion protein, CIN85, a key regulator of PI3K-AKT-mTOR signaling. Our data suggest that the fusion-driven structure formation induces a previously unrecognized cell survival and resistance mechanism, which depends on ERK1/2-activation.
Asunto(s)
Fosfatidilinositol 3-Quinasa Clase Ia , Resistencia a Antineoplásicos , Sistema de Señalización de MAP Quinasas , Proteínas de Fusión Oncogénica , Neoplasias Ováricas , Fosfatidilinositol 3-Quinasas , Femenino , Humanos , Fosfatidilinositol 3-Quinasa Clase Ia/genética , Fosfatidilinositol 3-Quinasa Clase Ia/metabolismo , Resistencia a Antineoplásicos/genética , Sistema de Señalización de MAP Quinasas/genética , Neoplasias Ováricas/tratamiento farmacológico , Neoplasias Ováricas/genética , Neoplasias Ováricas/metabolismo , Fosfatidilinositol 3-Quinasas/genética , Fosfatidilinositol 3-Quinasas/metabolismo , Platino (Metal) , Proteínas de Fusión Oncogénica/genética , Proteínas de Fusión Oncogénica/metabolismo , Proteínas del Citoesqueleto/genética , Proteínas del Citoesqueleto/metabolismoRESUMEN
MOTIVATION: Fusion genes are both useful cancer biomarkers and important drug targets. Finding relevant fusion genes is challenging due to genomic instability resulting in a high number of passenger events. To reveal and prioritize relevant gene fusion events we have developed FUsionN Gene Identification toolset (FUNGI) that uses an ensemble of fusion detection algorithms with prioritization and visualization modules. RESULTS: We applied FUNGI to an ovarian cancer dataset of 107 tumor samples from 36 patients. Ten out of 11 detected and prioritized fusion genes were validated. Many of detected fusion genes affect the PI3K-AKT pathway with potential role in treatment resistance. AVAILABILITYAND IMPLEMENTATION: FUNGI and its documentation are available at https://bitbucket.org/alejandra_cervera/fungi as standalone or from Anduril at https://www.anduril.org. SUPPLEMENTARY INFORMATION: Supplementary data are available at Bioinformatics online.
