青少年和年轻成年患者群体中出现的异柠檬酸脱氢酶（IDH）和组蛋白H3野生型高级别胶质瘤亚组的谱系。
The spectrum of IDH- and H3-wildtype high-grade glioma subgroups occurring across teenage and young adult patient populations.
作者信息
Pereira Rita, Mackay Alan, Grabovska Yura, Bradley Amelia, Bloom Tabitha, Nicoll James, Boche Delphine, Procter John, Maybury Mellissa, Schagen Johanna, Walker Liam, Roncaroli Federico, Karabatsou Konstantina, Ogunbiyi Olumide, van Dalen Thijs, Sidpra Jai, Rossi Sabrina, Miele Evelina, Ziegler David S, Shi Zhifeng, Jacques Thomas S, Hargrave Darren, Zebian Bassel, Bleil Cristina, Yates Joseph, Norton Emma, Mandeville Henry, Creak Antonia, Welsh Liam, Marshall Lynley, Carceller Fernando, Vaidya Sucheta J, Reisz Zita, Al-Sarraj Safa, Mastronuzzi Angela, Carai Andrea, Vinci Maria, Kurian Kathreena M, Ng Ho-Keung, Brandner Sebastian, Jones Chris, Clarke Matthew
机构信息
Institute of Cancer Reseach, Sutton, Surrey, United Kingdom.
Institute of Cancer Research, London, United Kingdom.
出版信息
Clin Cancer Res. 2025 Mar 10. doi: 10.1158/1078-0432.CCR-24-1256.
BACKGROUND
High-grade gliomas (HGG) occur in any central nervous system (CNS) location and any age. HGGs in teenagers/young adults (TYA) are understudied. This project aimed to characterise these tumours to support accurate patient stratification.
METHODS
207 histone/IDH-wildtype tumours from patients aged 13-30 years were collected. DNA methylation profiling (Illumina EPIC BeadArrays, brain tumour classifier (MNPv12.6 R package)) classified cases against reference cohorts. Calibrated scores guided characterisation workflows (RNA-based ArcherDx fusion panel (n=92), whole exome sequencing (WES) (n=107), histological review).
RESULTS
53.4% (n=86) matched paediatric-type subgroups (pedHGG_RTK1A/B/C (31.7%, n=51 PDGFRA, CDKN2A/B, SETD2, NF1 alterations), pedHGG_MYCN (8.1%, n=13, MYCN/ID2 amplifications), and pedHGG_RTK2A/B (7.5%, n=12, TP53, BCOR, ATRX, EGFR alterations)). 18.0% (n=29) classified as adult-type subgroups (GBM_MES (15.5%, n=25, RB1, PTEN, NF1 alterations) and GBM_RTK1/2 (2.5%, n=4, CDK4 amplifications)). 23 cases (14.7%) classified as novel, poorly-characterised subgroups with distinct methylation profiles and molecular features (pedHGG_A/B (n=10 6.2%), HGG_E (n=6 3.7%), HGG_B (n=2 1.0%), GBM_CBM (n=5 3.1%)) with variable histological morphology. 8 cases (5.1%) showed hypermutator phenotypes, enriched in HGG_E, including siblings with constitutional mismatch repair deficiency (CMMRD). TYA HGGs also develop on a background of childhood cancer treatments. Age-distribution comparisons using publicly available methylation/sequencing data (HGG_B (n=19), GBM_CBM (n=35), GBM_MES_ATYP (n=102)), irrespective of age, show HGG_B is TYA-specific (median 29 years) and GBM_CBM and GBM_MES_ATYP show TYA distribution peaks, with GBM_MES_ATYP showing copy number differences and worse survival compared with adult-specific GBM_MES_TYP.
CONCLUSION
TYA HGGs comprise novel methylation subgroups with distinct molecular profiles. Accurate stratification will open opportunities to utilise more effective treatments.
背景
高级别胶质瘤（HGG）可发生于中枢神经系统（CNS）的任何部位及任何年龄段。青少年/青年（TYA）的HGG研究较少。本项目旨在对这些肿瘤进行特征描述，以支持准确的患者分层。
方法
收集了207例年龄在13 - 30岁的组蛋白/异柠檬酸脱氢酶（IDH）野生型肿瘤。DNA甲基化谱分析（Illumina EPIC BeadArrays，脑肿瘤分类器（MNPv12.6 R包））将病例与参考队列进行分类。校准分数指导特征描述工作流程（基于RNA的ArcherDx融合检测板（n = 92）、全外显子组测序（WES）（n = 107）、组织学检查）。
结果
53.4%（n = 86）符合儿童型亚组（pedHGG_RTK1A/B/C（31.7%，n = 51，血小板衍生生长因子受体A（PDGFRA）、细胞周期蛋白依赖性激酶抑制剂2A/2B（CDKN2A/B）、组蛋白赖氨酸N - 甲基转移酶3（SETD2）、神经纤维瘤病1型（NF1）改变），pedHGG_MYCN（8.1%，n = 13，MYCN/ID2扩增），以及pedHGG_RTK2A/B（7.5%，n = 12，肿瘤蛋白p53（TP53）、含BCOR结构域蛋白（BCOR）、α - 地中海贫血/智力发育迟缓综合征X连锁基因（ATRX）、表皮生长因子受体（EGFR）改变））。18.0%（n = 29）分类为成人型亚组（胶质母细胞瘤间充质亚型（GBM_MES，15.5%，n = 25，视网膜母细胞瘤1（RB1）、磷酸酶和张力蛋白同源物（PTEN）、NF1改变）和GBM_RTK1/2（2.5%，n = 4，细胞周期蛋白依赖性激酶4（CDK4）扩增））。23例（14.7%）分类为新的、特征描述不佳的亚组，具有独特的甲基化谱和分子特征（pedHGG_A/B（n = 10，6.2%）、HGG_E（n = 6，3.7%）、HGG_B（n = 2，1.0%）、GBM_CBM（n = 5，3.1%）），组织学形态各异。8例（5.1%）表现出高突变表型，在HGG_E中富集，包括患有遗传性错配修复缺陷（CMMRD）的同胞。TYA的HGG也在儿童癌症治疗的背景下发生。使用公开可用的甲基化/测序数据（HGG_B（n = 19）、GBM_CBM（n = 35）、GBM_MES非典型亚型（GBM_MES_ATYP，n = 102））进行年龄分布比较，无论年龄如何，显示HGG_B是TYA特有的（中位年龄29岁），GBM_CBM和GBM_MES_ATYP显示出TYA分布峰值，与成人特有的GBM_MES典型亚型（GBM_MES_TYP）相比，GBM_MES_ATYP显示出拷贝数差异且生存率更差。
结论
TYA的HGG包括具有独特分子谱的新甲基化亚组。准确分层将为采用更有效的治疗方法提供机会。
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