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Clinical and Molecular features of Long-term Survivors with glioblastoma

Manuel Amosa, Neurosurgery Hospital Virgen de la Salud; Elena Capilla, Radiology Hospital Virgen de la Salud; Ángel Rodríguez de Lope Neurosurgery Hospital Virgen de la Salud; Jesús González-García, Pathology Hospital General Universitario de Ciudad Real; Isabel Herrera, Radiology Hospital Virgen de la Salud; David Albadalejo, Molecular Pathology Research Unit; Jorge Javier Villaseñor, Neurosurgery Hospital Virgen de la Salud; Manuela Mollejo, Pathology Hospital Virgen de la Salud; José María Borrás, Neurosurgery Hospital General Universitario de Ciudad Real; Bárbara Meléndez, Molecular Pathology Research Unit

Glioblastoma (GBM) is the most common and most malignant primary tumor of the brain. Even with aggressive surgical resection, radiotherapy and chemotherapy treatments, the prognosis for GBM patients remains dismal: median survival after diagnosis is about 14 months. However, 3–5% of the patients survives for more than 3 years, which are considered long-term survivors. The clinical and molecular prognostic factors that contribute to the long-term survival are still unknown. We aimed to identify specific clinical and molecular parameters that might be associated with the long-term survival phenomenon in GBM. Primary glioblastoma patients that were diagnosed and treated at two hospitals from Castilla-La Mancha with survival longer than 24 months were retrospectively identified and their clinical data recovered. Next-generation sequencing (NGS) based on a custom AmpliSeq™ panel was designed for sequencing 30 relevant glioma-associated genes on Ion PGM™ Sequencer. Somatic mutation profiling and copy number alterations were evaluated using this custom platform by using DNA extracted from frozen or formalin-fixed paraffin-embedded tissue. We identified 25 long-term survival GBM patients, of which 12 survived more than 3 years. Median age at diagnosis was 51 years (range 24-78). Frontal (22%), parietal (30%) and temporal (35%) lobe affectations were represented in this sample set, and 48% of the patients were affected in more than one lobe. No bilateral tumors were identified. Most of them were subject to complete resection (91%). All patients were treated under standard regimens of chemo and radiotherapy. Somatic mutation analyses of the tumor samples detected mutations at least at 16 genes, including genes mutated in short-term GBM such as EGFR, PTEN, PIK3CA , PI3KR1 or PDGFRA, among others. However, other genes frequently identified in pediatric GBMs (H3F3A), in lower grade gliomas (IDH1, ATRX, TP53) and in frequently mutated in cancer (BRAF) were also identified in these LS-GBM patients. Our findings suggest the association of glioblastoma long-term survival with prognostically favorable clinical factors, such as the younger age at diagnosis, the complete resection or the end of treatment. In addition, molecular data reveal mutations that may be candidate for other treatment options.

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