METHODS: Methylation profiles of 68 chordoma surgical samples were obtained between 1996-2018 across three international centres along with matched plasma methylomes where available.
RESULTS: Consensus clustering identified two stable tissue clusters with a disease-specific survival difference that was independent of clinical factors in a multivariate Cox analysis (HR=14.2, 95%CI: 2.1-94.8, p=0.0063). Immune-related pathways with genes hypomethylated at promoters and increased immune cell abundance were observed in the poor-performing \"Immune-infiltrated\" subtype. Cell-to-cell interaction plus extracellular matrix pathway hypomethylation and higher tumor purity was observed in the better-performing \"Cellular\" subtype. The findings were validated in additional DNA methylation and RNA sequencing datasets as well as with immunohistochemical staining. Plasma methylomes distinguished chordomas from other clinical differential diagnoses by applying fifty chordoma-versus-other binomial generalized linear models in random 20% testing sets (mean AUROC=0.84, 95%CI: 0.52-1.00). Tissue-based and plasma-based methylation signals were highly correlated in both prognostic clusters. Additionally, leave-one-out models accurately classified all tumors into their correct cluster based on plasma methylation data.
CONCLUSIONS: Here, we show the first identification of prognostic epigenetic chordoma subtypes and first use of plasma methylome-based biomarkers to non-invasively diagnose and subtype chordomas. These results may transform patient management by allowing treatment aggressiveness to be balanced with patient risk according to prognosis.
方法:1996年至2018年期间,在三个国际中心获得了68个脊索瘤手术样本的甲基化谱,以及可用的匹配血浆甲基化组。
结果:共识聚类确定了两个稳定的组织簇,其疾病特异性生存差异在多变量Cox分析中独立于临床因素(HR=14.2,95CI:2.1-94.8,p=0.0063)。在表现不佳的“免疫浸润”亚型中观察到基因在启动子处低甲基化和免疫细胞丰度增加的免疫相关途径。在表现更好的“细胞”亚型中观察到细胞间相互作用加上细胞外基质途径低甲基化和更高的肿瘤纯度。这些发现在其他DNA甲基化和RNA测序数据集以及免疫组织化学染色中得到了验证。通过在随机20%测试集中应用50个脊索瘤与其他二项广义线性模型(平均AUROC=0.84,95CI:0.52-1.00),血浆甲基化将脊索瘤与其他临床鉴别诊断区分开。基于组织和基于血浆的甲基化信号在两个预后簇中高度相关。此外,留一法模型根据血浆甲基化数据将所有肿瘤准确地分类为正确的簇。
结论:这里,我们首次发现了预后性表观遗传脊索瘤亚型,首次使用基于血浆甲基化的生物标志物进行非侵入性诊断和亚型脊索瘤.这些结果可以通过根据预后使治疗积极性与患者风险平衡来改变患者管理。