DNA methylation-based immune response signature improves patient diagnosis in multiple cancers
DNA methylation-based immune response signature improves patient diagnosis in multiple cancers
复制标题
DOI：
10.1172/jci91095
复制
发表时间：
2017-08-01
影响因子：
15.9
通讯作者：
Fuks, Francois
中科院分区：
文献类型：
--
作者：
Jeschke, Jana;Bizet, Martin;Fuks, Francois
背景。肿瘤免疫反应与乳腺癌和其他癌症更好的临床结果越来越相关。然而，肿瘤浸润淋巴细胞（TIL）的评估依赖于组织病理学测量，其准确性和再现性有限。在这里，我们对 DNA 甲基化标记进行了分析，以确定 TIL (MeTIL) 特征的甲基化，该特征概括了 TIL 评估及其对乳腺癌 (BC) 长期结果的预后价值。 MeTIL 特征评分与反映总体或无病生存率的临床终点相关，以及布鲁塞尔 Jules Bordet 研究所的 3 个 BC 队列和癌症基因组图谱中其他癌症类型对术前蒽环类药物治疗的病理完全缓解。 结果。 MeTIL 特征以灵敏的方式测量 TIL 分布，并分别比 TIL 的组织病理学评估或基于基因表达的免疫标记更好地预测 BC 的生存和化疗反应。 MeTIL 特征还改善了其他恶性肿瘤的生存预测，包括黑色素瘤和肺癌。此外，MeTIL 特征预测了恶性肿瘤的生存差异，而 TIL 尚不知道其具有预后价值。最后，我们表明可以通过对福尔马林固定、石蜡包埋的肿瘤组织中的少量 DNA 进行亚硫酸氢盐焦磷酸测序来测定 MeTIL 标记，支持该方法的临床应用。结论。这项研究强调了 DNA 甲基化在评估肿瘤免疫反应方面的力量，以及这种方法改善乳腺癌和其他癌症诊断和治疗的潜力。
BACKGROUND. The tumor immune response is increasingly associated with better clinical outcomes in breast and other cancers. However, the evaluation of tumor-infiltrating lymphocytes (TILs) relies on histopathological measurements with limited accuracy and reproducibility. Here, we profiled DNA methylation markers to identify a methylation of TIL (MeTIL) signature that recapitulates TIL evaluations and their prognostic value for long-term outcomes in breast cancer (BC).METHODS. MeTIL signature scores were correlated with clinical endpoints reflecting overall or disease-free survival and a pathologic complete response to preoperative anthracycline therapy in 3 BC cohorts from the Jules Bordet Institute in Brussels and in other cancer types from The Cancer Genome Atlas.RESULTS. The MeTIL signature measured TIL distributions in a sensitive manner and predicted survival and response to chemotherapy in BC better than did histopathological assessment of TILs or gene expression-based immune markers, respectively. The MeTIL signature also improved the prediction of survival in other malignancies, including melanoma and lung cancer. Furthermore, the MeTIL signature predicted differences in survival for malignancies in which TILs were not known to have a prognostic value. Finally, we showed that MeTIL markers can be determined by bisulfite pyrosequencing of small amounts of DNA from formalin-fixed, paraffin-embedded tumor tissue, supporting clinical applications for this methodology.CONCLUSIONS. This study highlights the power of DNA methylation to evaluate tumor immune responses and the potential of this approach to improve the diagnosis and treatment of breast and other cancers.