Dados do Trabalho


Investigation of potentially actionable somatic variants in medulloblastomas and their clinical impact


Medulloblastoma (MB) is a highly lethal malignant brain tumor affecting both pediatric and adult patients. Molecularly, MB is divided into four subgroups (MBSHH, MBWNT, MBGroup3, MBGroup4), and exhibits substantial heterogeneity and complexity. Moreover, current treatments come with significant toxicity and result in numerous patient-related complications, emphasizing the urgent need for uncovering potentially actionable new targets.


Characterizing the mutational profile of Ibero-American medulloblastomas and establishing associations between the molecular and clinical data of patients


A total of 62 formalin-fixed paraffin-embedded medulloblastoma cases (40 pediatrics and 22 adults) were molecularly subgrouped using nCounter® technology. Subsequently, DNA was isolated and next-generation sequencing (NGS) targeted panel TruSight Tumor 15 (Illumina) was used for mutational profile. NGS data were evaluated by SOPHiA DDMTM software, and variants with variant allele frequency (VAF) ≥10% and a depth ≥500x were selected. The selected variants were classified according to their clinical impact (Tier 1 and Tier 2) and oncogenicity. TP53 mutations were classified as disruptive and non-disruptive. In silico analysis was performed for patients with TP53 status from cBioPortal dataset (n=644). Then, Kaplan-Meier and Log-Rank test were performed using the IBM SPSS Statistics for overall survival (OS) analyses.


From 62 patients, 75.8% were MBSHH, 9.7% MBWNT, 1.6% MBGroup3 and 12.9% MBGroup4. We observed 52% (21/40) of pediatric cases and 45% (10/22) of adult cases harboring at least one mutation. From the 61 variants identified, 21 were classified as Tier 1 and 13 variants as Tier 2, in the following genes: TP53 (62%); KIT (14%); PIK3CA (12%); PDGFRA (6%); EGFR (3%); ERBB2 (3%). Considering the oncogenicity, 26/61 variants were classified as oncogenic or likely oncogenic. TP53 (80.8%, 21/26) was the most mutated gene, followed by PIK3CA (11.5%, 3/26), EGFR (3.8%, 1/26), and NRAS (3.8%, 1/26). Oncogenic/likely oncogenic TP53 variants showed lower OS than the wildtype patients (p=0.033). When classifying the TP53 variants as disruptive/non-disruptive, we observed that MBSHH patients harboring disruptive mutations (14 months) showed lower OS than wildtype (76 months) and non-disruptive (86 months) patients.


We observed that a subset of patients harbor alteration in potential target genes, namely PIK3CA. The functional characterization of TP53 mutations is associated with patient outcome.


Medulloblastoma; mutational profile; target therapies

Financiador do resumo


Estudo Clínico - Tumores do Sistema Nervoso Central


LETICIA GANEM RILLO PAZ BARATEIRO, Rodrigo de Oliveira Cavagna, Mariana Bisarro dos Reis, Flávia Escremim de Paula, Gustavo Ramos Teixeira, Iara Santana, Fabiano Pinto Saggioro, Luciano Neder Serafini, João Norberto Stavale, Suzana Maria Fleury Malheiros, Hernan Garcia-Rivello, Silvia Christiansen, Susana Nunes, Maria João Gil da Costa, Jorge Pinheiro, Daniel Antunes Moreno, Carlos Almeida Júnior, Bruna Minniti Mançano, Rui Manuel Reis