PO.MCB08.04 · 分子与细胞生物学

弥漫性胶质瘤中WHO 2021标准、WGS与DNA甲基化分类的诊断一致性：一项单中心队列研究

Diagnostic concordance of WHO 2021 standards, WGS, and DNA methylation classification in diffuse gliomas: A single-center cohort study

编号 5925 展板 13 时间 4/21 02:00–05:00 区域 Section 21 主讲 Jungyu Kim, MD

分会场 Genetic and Transcriptomic Dissection of Cancer Evolution

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作者与单位 Authors & Affiliations

Jungyu Kim¹, Yongjae Lee¹, Jeong Seok Lee¹, Tae Hoon Roh², YOUNG SEOK JU¹

¹Korea Advanced Institute of Science and Technology, Daejeon, Korea, Republic of,²Neurosurgery, Ajou University School of Medicine, Daejeon, Korea, Republic of

摘要 Abstract

中文摘要

背景：弥漫性胶质瘤表现出显著的临床和分子异质性。然而，WHO 2021临床诊断、全基因组测序（WGS）与基于DNA甲基化的分类之间在真实世界中的一致性仍有待充分阐明。方法：我们回顾性分析了2013—2022年在Ajou大学医院接受治疗的111例胶质瘤患者。经过严格的质量控制（排除肿瘤分数<20%、样本混淆及仅复发的病例）后，93例患者（104个肿瘤）接受了WGS、酶法甲基化测序（EM-seq）和bulk RNA测序。临床诊断采用常规免疫组化和靶向panel测序更新至WHO 2021标准（星形细胞瘤，n=14；胶质母细胞瘤，n=76；少突胶质细胞瘤，n=14）。利用WGS根据IDH突变、TERT启动子突变、EGFR扩增以及7号染色体获得/10号染色体缺失来完善分类。甲基化类别（如GBM RTK I/II、Mesenchymal、MID、HGNET-BCOR）采用基于Illumina芯片数据（约20,000个CpG）训练的AI驱动分类器进行判定。我们评估了这三个层面的诊断一致性。结果：在临床、WGS和甲基化各层面，IDH突变型星形细胞瘤和少突胶质细胞瘤的诊断一致性为100%。相比之下，在临床诊断为胶质母细胞瘤的病例中出现了差异。一例被重新分类为儿童型弥漫性半球胶质瘤，H3 G34突变型。另一例13岁患者的肿瘤携带复杂改变（ATRX、PTEN、TP53、PIK3R1、PTPRD、CDKN2A），被赋予了非GBM甲基化标签（CONTR/INFLAM），无法进行明确的亚分类。在经甲基化分类为GBM RTK I（9/10）、GBM RTK II（18/18）或Mesenchymal（15/16）的肿瘤中，几乎所有肿瘤均符合分子胶质母细胞瘤标准（IDH野生型、TERTp突变、EGFR扩增、chr7+/10-）。相反，MID及非GBM甲基化类别的肿瘤往往缺乏这些典型特征（17/21）。值得注意的是，WGS在一份具有HGNET-BCOR甲基化谱的样本中鉴定出BCOR::EP300易位——这是一种常规临床检测未能发现的融合——将BCOR改变的中枢神经系统肿瘤谱系拓展至经典内部串联重复之外。结论：本单中心队列中整合的WGS与甲基化分析表明，基于DNA甲基化的分类可完善WHO 2021诊断，尤其是对常规诊断为胶质母细胞瘤的肿瘤。该方法能揭示罕见实体，如儿童型胶质瘤和BCOR改变型肿瘤，这些实体单靠靶向panel可能被遗漏。我们的研究结果支持采用多组学框架，以捕捉因有限分子标志物而被掩盖的生物学异质性。

查看英文原文 English abstract

Background: Diffuse gliomas exhibit significant clinical and molecular heterogeneity. However, the real-world concordance among WHO 2021 clinical diagnoses, whole-genome sequencing (WGS), and DNA methylation-based classification remains to be fully characterized. Methods: We retrospectively analyzed 111 glioma patients treated at Ajou University Hospital (2013-2022). Following strict quality control (excluding low tumor fraction <20%, sample swaps, and recurrent-only cases), 93 patients (104 tumors) underwent WGS, enzymatic methyl-seq (EM-seq), and bulk RNA sequencing. Clinical diagnoses were updated to WHO 2021 standards using routine immunohistochemistry and targeted panel sequencing (astrocytoma, n=14; glioblastoma, n=76; oligodendroglioma, n=14). WGS was utilized to refine classifications based on IDH mutation, TERT promoter mutation, EGFR amplification, and chromosome 7 gain/10 loss. Methylation classes (e.g., GBM RTK I/II, Mesenchymal, MID, HGNET-BCOR) were assigned using an AI-driven classifier trained on Illumina array data (~20,000 CpGs). We evaluated the diagnostic concordance across these three layers. Results: Diagnostic concordance was 100% for IDH -mutant astrocytomas and oligodendrogliomas across clinical, WGS, and methylation layers. In contrast, discrepancies emerged in cases clinically diagnosed as glioblastoma. One case was reclassified as pediatric-type diffuse hemispheric glioma, H3 G34-mutant . Another tumor in a 13-year-old patient, harboring complex alterations ( ATRX, PTEN, TP53, PIK3R1, PTPRD, CDKN2A ), was assigned non-GBM methylation labels (CONTR/INFLAM), precluding definitive subclassification. Among tumors classified as GBM RTK I (9/10), GBM RTK II (18/18), or Mesenchymal (15/16) by methylation, nearly all fulfilled molecular glioblastoma criteria ( IDH -wildtype, TERTp mutation, EGFR amp, chr7+/10-). Conversely, tumors in the MID and non-GBM methylation classes frequently lacked these canonical features (17/21). Notably, WGS identified a BCOR::EP300 translocation in a sample with an HGNET-BCOR methylation profile-a fusion undetected by routine clinical testing-expanding the spectrum of BCOR -altered CNS tumors beyond canonical internal tandem duplications. Conclusions: Integrated WGS and methylation profiling in this single-center cohort demonstrate that DNA methylation-based classification refines WHO 2021 diagnoses, particularly for tumors routinely diagnosed as glioblastoma. This approach uncovers rare entities, such as pediatric-type gliomas and BCOR -altered tumors, that may be missed by targeted panels alone. Our findings support the implementation of a multi-omics framework to capture biological heterogeneity obscured by limited molecular markers.

利益披露 Disclosure

J. Kim, None.. Y. Lee, None. J. Lee, Inocras Inc. Employment, g., Board of Directors, non-salaried role), Stock Option. T. Roh, None. Y. Ju, Inocras Inc. Employment, g., Board of Directors, non-salaried role), Stock Option.

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