Department of Anatomical and Cellular Pathology, The Chinese University of Hong Kong, Prince of Wales Hospital, 30-32 Ngan Shing Street, Shatin, Hong Kong SAR, China.
Shenzhen Research Institute, The Chinese University of Hong Kong, No. 10, 2nd Yuexing Road, Nanshan District, Shenzhen, 518057, China.
Acta Neuropathol. 2018 Oct;136(4):641-655. doi: 10.1007/s00401-018-1874-3. Epub 2018 Jun 14.
Pediatric low-grade gliomas (PLGGs) consist of a number of entities with overlapping histological features. PLGGs have much better prognosis than the adult counterparts, but a significant proportion of PLGGs suffers from tumor progression and recurrence. It has been shown that pediatric and adult low-grade gliomas are molecularly distinct. Yet the clinical significance of some of newer biomarkers discovered by genomic studies has not been fully investigated. In this study, we evaluated in a large cohort of 289 PLGGs a list of biomarkers and examined their clinical relevance. TERT promoter (TERTp), H3F3A and BRAF V600E mutations were detected by direct sequencing. ATRX nuclear loss was examined by immunohistochemistry. CDKN2A deletion, KIAA1549-BRAF fusion, and MYB amplification were determined by fluorescence in situ hybridization (FISH). TERTp, H3F3A, and BRAF V600E mutations were identified in 2.5, 6.4, and 7.4% of PLGGs, respectively. ATRX loss was found in 4.9% of PLGGs. CDKN2A deletion, KIAA1549-BRAF fusion and MYB amplification were detected in 8.8, 32.0 and 10.6% of PLGGs, respectively. Survival analysis revealed that TERTp mutation, H3F3A mutation, and ATRX loss were significantly associated with poor PFS (p < 0.0001, p < 0.0001, and p = 0.0002) and OS (p < 0.0001, p < 0.0001, and p < 0.0001). BRAF V600E was associated with shorter PFS (p = 0.011) and OS (p = 0.032) in a subset of PLGGs. KIAA1549-BRAF fusion was a good prognostic marker for longer PFS (p = 0.0017) and OS (p = 0.0029). MYB amplification was also a favorable marker for a longer PFS (p = 0.040). Importantly, we showed that these molecular biomarkers can be used to stratify PLGGs into low- (KIAA1549-BRAF fusion or MYB amplification), intermediate-I (BRAF V600E and/or CDKN2A deletion), intermediate-II (no biomarker), and high-risk (TERTp or H3F3A mutation or ATRX loss) groups with distinct PFS (p < 0.0001) and OS (p < 0.0001). This scheme should aid in clinical decision-making.
小儿低级别胶质瘤（PLGGs）由具有重叠组织学特征的多种实体组成。PLGGs 的预后明显优于成人，但相当一部分 PLGGs 会出现肿瘤进展和复发。已经表明，小儿和成人低级别胶质瘤在分子上是不同的。然而，基因组研究发现的一些新生物标志物的临床意义尚未得到充分研究。在这项研究中，我们在 289 例 PLGGs 的大队列中评估了一系列生物标志物，并检查了它们的临床相关性。通过直接测序检测 TERT 启动子（TERTp）、H3F3A 和 BRAF V600E 突变。通过免疫组织化学检测 ATRX 核丢失。通过荧光原位杂交（FISH）确定 CDKN2A 缺失、KIAA1549-BRAF 融合和 MYB 扩增。在 2.5%、6.4%和 7.4%的 PLGGs 中分别发现了 TERTp、H3F3A 和 BRAF V600E 突变。在 4.9%的 PLGGs 中发现了 ATRX 缺失。在 8.8%、32.0%和 10.6%的 PLGGs 中分别检测到 CDKN2A 缺失、KIAA1549-BRAF 融合和 MYB 扩增。生存分析显示，TERTp 突变、H3F3A 突变和 ATRX 缺失与较差的 PFS（p<0.0001、p<0.0001 和 p=0.0002）和 OS（p<0.0001、p<0.0001 和 p<0.0001）显著相关。BRAF V600E 在亚组 PLGGs 中与较短的 PFS（p=0.011）和 OS（p=0.032）相关。KIAA1549-BRAF 融合是较长 PFS（p=0.0017）和 OS（p=0.0029）的良好预后标志物。MYB 扩增也是较长 PFS（p=0.040）的有利标志物。重要的是，我们表明这些分子生物标志物可用于将 PLGGs 分为低风险（KIAA1549-BRAF 融合或 MYB 扩增）、中风险-I（BRAF V600E 和/或 CDKN2A 缺失）、中风险-II（无标志物）和高风险（TERTp 或 H3F3A 突变或 ATRX 缺失）组，具有不同的 PFS（p<0.0001）和 OS（p<0.0001）。该方案应有助于临床决策。
