Unidade de Investigação em Patobiologia Molecular (UIPM) - IPOFG Cytogenetic Laboratory, Portuguese Cancer Institute, R. Professor Lima Basto, 1099-023, Lisbon, Portugal.
Laboratory of Neuropathology, Department of Neurology, Hospital de Santa Maria (CHLN; EPE), Institute of Molecular Medicine, Medicine Faculty of the Lisbon University, Lisbon, Portugal.
BMC Cancer. 2018 Dec 17;18(1):1259. doi: 10.1186/s12885-018-5120-0.
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.
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.
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).
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.
儿科原发性脑肿瘤中的遗传改变可用作诊断和预后标志物，也是开发新靶向治疗方法的基础，新的靶向治疗方法理想情况下应与较低的死亡率和发病率相关。本研究评估了 BRAF V600E 突变和染色体 9p21 缺失在 100 例儿科神经胶质瘤中的发生率和相互作用，旨在确定这些改变在复发和恶性转化中的作用，并验证它们是否可用于临床以对患者进行分层，以进行针对性治疗和监测。
使用 Sanger 测序评估 BRAF 外显子 15 的突变，使用 Fluorescent In Situ Hybridization (FISH) with BAC: RP11-14192 检测 9p21 的改变。通过实时 PCR 评估 9p21 缺失病例中 CDKN2A 和 MTAP 的表达水平。使用 Graph Pad Prism 5 和 SPSS Statistics 24 软件对遗传和临床数据进行统计分析。
在我们的队列中，观察到 7/78（8.9%）的低级别肿瘤复发，2 例（2.6%）发生恶性转化。在 15 例病例中检测到 BRAF V600E 突变。在 BRAF V600E 突变与患者形态或临床特征之间未发现统计学显著相关性。I 级神经胶质瘤中 9p21 缺失导致 CDKN2A/B 和 MTAP 缺失的频率较低（12.2%，p=0.0178），但 IV 级神经胶质瘤中较为常见（62.5%，p=0.0087）。此外，发现这些位点的缺失与总生存期缩短（p=0.011）和无进展生存期缩短（p=0.016）相关。
在这些肿瘤中，证实了 BRAF V600E 突变，并且 CDKN2A/B MTAP 共缺失可用于对患者进行分层以进行更严格的监测。研究并确定 CDKN2A/B 和 MTAP 纯合缺失的神经胶质肿瘤是否易受新的治疗方法的影响，即影响甲硫氨酸补救途径的治疗方法，被证明是重要的。
