DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management
DNA methylation profiling to predict recurrence risk in meningioma: development and validation of a nomogram to optimize clinical management
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DOI：
10.1093/neuonc/noz061
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发表时间：
2019-07-01
期刊：
影响因子：
15.9
通讯作者：
Zadeh, Gelareh
中科院分区：
文献类型：
--
作者：
Nassiri, Farshad;Mamatjan, Yasin;Zadeh, Gelareh
背景：标准治疗分类的可变性妨碍了对脑膜瘤个体患者早期肿瘤复发的准确预测，限制了患者的适当选择，这些患者将受益于辅助放疗以延迟复发。我们的目的是建立一个结合临床和分子因素的脑膜瘤早期复发风险的个体化预测模型。方法利用多家机构临床注释肿瘤样本的DNA甲基化谱，建立5年无复发生存（RFS）的甲基化模型。随后，使用结合甲基组模型和已建立的预后临床因素的nomogram （nomogram）生成5年脑膜瘤复发评分。使用多个独立队列对两种模型的性能进行评估并与标准护理模型进行比较。结果在使用3个验证队列进行测试时，基于甲基组的5年RFS预测指标优于基于分级的预测指标（δ AUC = 0.10, 95% CI: 0.03-0.018），并且在调整组织病理分级、切除程度和拷贝数改变负担后与RFS独立相关（风险比3.6,95% CI: 1.8-7.2, P < 0.001）。在2个独立验证队列中，甲基组预测因子与临床因素相结合的nomogram（标准差AUC = 0.25, 95% CI: 0.22-0.27）比单独使用临床因素的nomogram（标准差AUC = 0.25, 95% CI: 0.22-0.27）具有更强的辨别性，并导致两组具有不同的复发模式（风险比7.7,95% CI: 5.3-11.1, P < 0.001），具有临床意义。本研究建立并验证的模型提供了重要的预后信息，这些信息未被先前建立的临床和分子因素所捕获，可用于个性化术后治疗干预决策，特别是是否对患者进行辅助放疗或单独观察。
Background Variability in standard-of-care classifications precludes accurate predictions of early tumor recurrence for individual patients with meningioma, limiting the appropriate selection of patients who would benefit from adjuvant radiotherapy to delay recurrence. We aimed to develop an individualized prediction model of early recurrence risk combining clinical and molecular factors in meningioma.Methods DNA methylation profiles of clinically annotated tumor samples across multiple institutions were used to develop a methylome model of 5-year recurrence-free survival (RFS). Subsequently, a 5-year meningioma recurrence score was generated using a nomogram that integrated the methylome model with established prognostic clinical factors. Performance of both models was evaluated and compared with standard-of-care models using multiple independent cohorts.Results The methylome-based predictor of 5-year RFS performed favorably compared with a grade-based predictor when tested using the 3 validation cohorts (Delta AUC = 0.10, 95% CI: 0.03-0.018) and was independently associated with RFS after adjusting for histopathologic grade, extent of resection, and burden of copy number alterations (hazard ratio 3.6, 95% CI: 1.8-7.2, P < 0.001). A nomogram combining the methylome predictor with clinical factors demonstrated greater discrimination than a nomogram using clinical factors alone in 2 independent validation cohorts (Delta AUC = 0.25, 95% CI: 0.22-0.27) and resulted in 2 groups with distinct recurrence patterns (hazard ratio 7.7, 95% CI: 5.3-11.1, P < 0.001) with clinical implications.Conclusions The models developed and validated in this study provide important prognostic information not captured by previously established clinical and molecular factors which could be used to individualize decisions regarding postoperative therapeutic interventions, in particular whether to treat patients with adjuvant radiotherapy versus observation alone.