Journal Article

BRAF V600E mutation and 9p21: CDKN2A/B and MTAP co-deletions - Markers in the clinical stratification of pediatric gliomas

do Carmo Martins, Maria, Pimentel, José, Sagarribay, Amets, Nunes, Vasco Moura, Faria, Claudia, Nunes, Sofia, Frazão, Laura, Mafra, Manuela, Roque, Lúcia, Salgado, Duarte, Miguéns, José, Matos, Mário

2018

Overview

Background Genetic alterations in pediatric primary brain tumors can be used as diagnostic and prognostic markers and are the basis for the development of new target therapies that, ideally, would be associated with lower mortality and morbidity. This study evaluates the incidence and interplay of the presence of BRAF V600E mutation and chromosomal 9p21 deletions in a series of 100 pediatric gliomas, aiming to determine the role of these alterations in recurrence and malignant transformation, and to verify if they could be used in the clinical set for stratifying patients for tailored therapies and surveillance. Methods Sanger sequencing was used for the assessment of BRAF mutations at exon 15 and Fluorescent In Situ Hybridization (FISH) with BAC: RP11–14192 for the detection of 9p21 alterations. Expression levels of the CDKN2A and MTAP by real-time PCR were evaluated in cases with 9p21 deletions. Statistical analysis of genetic and clinical data was performed using Graph Pad Prism 5 and SPSS Statistics 24 software. Results In our cohort it was observed that 7 /78 (8,9%) of the low-grade tumors recurred and 2 (2,6%) showed malignant transformation. BRAF V600E mutations were detected in 15 cases. No statistically significant correlations were found between the presence of BRAF V600E mutation and patient’s morphologic or clinical features. Deletions at 9p21 abrogating the CDKN2A/B and MTAP loci were rare in grade I gliomas (12.2%, p  = 0.0178) but frequent in grade IV gliomas (62.5%, p  = 0.0087). Moreover it was found that deletions at these loci were correlated with a shorter overall survival ( p  = 0.011) and a shorter progression-free survival ( p  = 0.016). Conclusions It was demonstrated that in these tumors BRAF V600E mutated and that CDKN2A/B MTAP co-deletions may be used for stratifying patients for a stricter surveillance. The Investigating and defining if glial tumors with CDKN2A/B and MTAP homozygous loss may be vulnerable to new forms of therapy, namely those affecting the methionine salvage pathway, was proven to be of importance.

• Publisher: BioMed Central,BioMed Central Ltd,Springer Nature B.V,BMC
• Subject: 5'-Methylthioadenosine phosphorylase / 9p21 chromosomal region / Analysis / Bacterial artificial chromosomes / Biomedical and Life Sciences / Biomedicine / BRAF / Brain cancer / Brain tumors / Cancer Research / Child health / Childhood cancer / Diagnosis / Fluorescence in situ hybridization / Gene mutation / Genetic analysis / Genetic aspects / Genetic transformation / Genetics / genomics and epigenetics / Glial / Glioma / Health Promotion and Disease Prevention / Kinases / Medicine/Public Health / Methionine / Morbidity / Mortality / Mutation / Oncology / Pediatric / Prognostic / Research Article / Risk factors / Statistical analysis / Surgical Oncology / Survival / Tumors