DNA 甲基化特征可预测脉络丛肿瘤的侵袭性。
DNA methylation signature is prognostic of choroid plexus tumor aggressiveness.
机构信息
Genetics and Genome Biology Program, Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.
Center for Computational Medicine, Hospital for Sick Children, PGCRL, 686 Bay Street, Toronto, Ontario, M5G 0A4, Canada.
出版信息
Clin Epigenetics. 2019 Aug 13;11(1):117. doi: 10.1186/s13148-019-0708-z.
BACKGROUND
Histological grading of choroid plexus tumors (CPTs) remains the best prognostic tool to distinguish between aggressive choroid plexus carcinoma (CPC) and the more benign choroid plexus papilloma (CPP) or atypical choroid plexus papilloma (aCPP); however, these distinctions can be challenging. Standard treatment of CPC is very aggressive and often leads to severe damage to the young child's brain. Therefore, it is crucial to distinguish between CPC and less aggressive entities (CPP or aCPP) to avoid unnecessary exposure of the young patient to neurotoxic therapy. To better stratify CPTs, we utilized DNA methylation (DNAm) to identify prognostic epigenetic biomarkers for CPCs.
METHODS
We obtained DNA methylation profiles of 34 CPTs using the HumanMethylation450 BeadChip from Illumina, and the data was analyzed using the Illumina Genome Studio analysis software. Validation of differentially methylated CpG sites chosen as biomarkers was performed using pyrosequencing analysis on additional 22 CPTs. Sensitivity testing of the CPC DNAm signature was performed on a replication cohort of 61 CPT tumors obtained from Neuropathology, University Hospital Münster, Germany.
RESULTS
Generated genome-wide DNAm profiles of CPTs showed significant differences in DNAm between CPCs and the CPPs or aCPPs. The prediction of clinical outcome could be improved by combining the DNAm profile with the mutational status of TP53. CPCs with homozygous TP53 mutations clustered as a group separate from those carrying a heterozygous TP53 mutation or CPCs with wild type TP53 (TP53-wt) and showed the worst survival outcome. Specific DNAm signatures for CPCs revealed AK1, PER2, and PLSCR4 as potential biomarkers for CPC that can be used to improve molecular stratification for diagnosis and treatment.
CONCLUSIONS
We demonstrate that combining specific DNAm signature for CPCs with histological approaches better differentiate aggressive tumors from those that are not life threatening. These findings have important implications for future prognostic risk prediction in clinical disease management.
背景
脉络丛肿瘤（CPT）的组织学分级仍然是区分侵袭性脉络丛癌（CPC）和更良性的脉络丛乳头状瘤（CPP）或非典型脉络丛乳头状瘤（aCPP）的最佳预后工具；然而，这些区别可能具有挑战性。CPC 的标准治疗非常激进，往往会导致幼儿大脑严重受损。因此，区分 CPC 和侵袭性较低的实体（CPP 或 aCPP）以避免年轻患者不必要地暴露于神经毒性治疗至关重要。为了更好地区分 CPT，我们利用 DNA 甲基化（DNAm）来识别 CPC 的预后表观遗传生物标志物。
方法
我们使用 Illumina 的 HumanMethylation450 BeadChip 获得了 34 个 CPT 的 DNA 甲基化谱，并使用 Illumina Genome Studio 分析软件对数据进行了分析。选择作为生物标志物的差异甲基化 CpG 位点的验证是通过对另外 22 个 CPT 进行焦磷酸测序分析来完成的。对来自德国明斯特大学医院神经病理学的 61 个 CPT 肿瘤的复制队列进行了 CPC DNAm 特征的敏感性测试。
结果
CPT 的全基因组 DNAm 谱显示 CPC 与 CPP 或 aCPP 之间的 DNAm 存在显著差异。通过将 DNAm 谱与 TP53 的突变状态相结合，可以提高临床结果的预测能力。携带纯合 TP53 突变的 CPC 聚类为一组，与携带杂合 TP53 突变或 CPC 与野生型 TP53（TP53-wt）的 CPC 分开，表现出最差的生存结果。CPC 的特定 DNAm 特征揭示了 AK1、PER2 和 PLSCR4 作为 CPC 的潜在生物标志物，可用于改善诊断和治疗的分子分层。
结论
我们证明了将 CPC 的特定 DNAm 特征与组织学方法相结合，可以更好地区分侵袭性肿瘤和不会危及生命的肿瘤。这些发现对未来临床疾病管理中的预后风险预测具有重要意义。
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