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

Abstract

BackgroundGenetic 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.MethodsSanger 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.ResultsIn 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).ConclusionsIt 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.Electronic supplementary materialThe online version of this article (10.1186/s12885-018-5120-0) contains supplementary material, which is available to authorized users.

Tumor mutational burden and driver mutations: Characterizing the genomic landscape of pediatric brain tumors

“…In BRAF V600E, TP53, or IDH1 altered tumors, concurrent CDKN2A/B deletions portend a worse prognosis. 49,50 Several ongoing clinical trials are exploring the role of targeted therapeutics in pediatric brain tumors. BRAF, MEK, PD-1, and CTLA-4…”

Loss of 5′-Methylthioadenosine Phosphorylase (MTAP) is Frequent in High-Grade Gliomas; Nevertheless, it is Not Associated with Higher Tumor Aggressiveness

“…Metabolic changes in tumors, especially those relating to polyamines metabolism, demonstrate that many mechanisms underlying MTAP function need to still be clarified [35,36]. In gliomas, loss of MTAP locus is also frequently reported [37][38][39][40][41]. Nevertheless, the clinical and the biological impacts of MTAP are poorly explored in gliomas [37,38,42].…”

Prognostic impact of distinct genetic entities in pediatric diffuse glioma WHO‐grade II—Report from the German/Swiss SIOP‐LGG 2004 cohort

“…BRAF‐V600‐ mutation was found in 18% of the tumors of our cohort, and was reported at variable frequencies up to 25% for pediatric DG2 6,10,14,15,23,47,48 . Although the presence of this mutation was rated as unfavorable with more frequent non‐response to adjuvant treatment and shorter PFS in the basket group of LGG, 14,23 no specific data are available for DG2.…”

“…Thus, re‐biopsy of recurrent or progressing lesions is warranted even in early progression. Malignant transformation of pediatric LGG has been shown for BRAF‐V600E ‐mutated tumors and was linked to the concurrent presence of CDKN2A ‐deletion 6,23,48,49 . Although the underlying molecular alteration was already traced in the initial biopsy in the report of Mistry et al, 49 and identical genetic alterations were found in primary and recurrent tumors in the series of Bergthold et al, 47 its later evolution cannot be ruled out.…”