Cancer-Specific Thresholds Adjust for Whole Exome Sequencing-Based Tumor Mutational Burden Distribution
Cancer-Specific Thresholds Adjust for Whole Exome Sequencing-Based Tumor Mutational Burden Distribution
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DOI：
10.1200/po.18.00400
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发表时间：
2019-07-31
影响因子：
4.6
通讯作者：
Song, Wei
中科院分区：
文献类型：
--
作者：
Fernandez, Evan M.;Eng, Kenneth;Song, Wei
目的了解肿瘤突变负荷（tumor mutational burden，TMB）的临床背景，比较泛癌阈值和癌症特异性阈值。材料和方法使用癌症基因组图谱中原发性肿瘤的全外显子组测序数据（n = 3，534）和来自Weill Cornell Medicine Advanced的晚期和/或转移性肿瘤（n = 696），使用泛癌症和癌症特异性阈值确定TMB状态。生存曲线，被归类为TMB高的样本数量，和预测的新抗原被用来评估thresholds.Results之间的差异TMB的分布在癌症类型之间变化很大。癌症特异性阈值能够针对不同的TMB分布进行调整，而泛癌症阈值通常过于严格。与静态泛癌阈值相比，癌症特异性阈值的动态性质导致更多的肿瘤被分类为TMB高。此外，与泛癌症阈值相比，癌症特异性阈值的生存结局无显著差异。此外，癌症特异性阈值保持较高的预测新抗原负荷的TMB-高的样品相比，TMB-低的样品，即使当阈值低于泛癌threshold.CONCLUSION TMB的癌症类型，转移状态和疾病阶段的背景下确定。与泛癌症阈值相比，癌症特异性阈值将更多患者分类为TMB高，同时保持临床结果没有显著差异。此外，癌症特异性阈值识别具有大量预测新抗原的患者。由于对癌症患者护理的潜在影响，TMB状态应以癌症特异性方式确定。(C)2019年美国临床肿瘤学会
PURPOSE To understand the clinical context of tumor mutational burden (TMB) when comparing a pan-cancer threshold and a cancer-specific threshold.MATERIALS AND METHODS Using whole exome sequencing data from primary tumors in The Cancer Genome Atlas (n = 3,534) and advanced and/or metastatic tumors from Weill Cornell Medicine Advanced (n = 696), TMB status was determined using a pan-cancer and cancer-specific threshold. Survival curves, number of samples classified as TMB high, and predicted neoantigens were used to evaluate the differences between thresholds.RESULTS The distribution of TMB varied dramatically among cancer types. A cancer-specific threshold was able to adjust for the different TMB distributions, whereas the pan-cancer threshold was often too stringent. The dynamic nature of the cancer-specific threshold resulted in more tumors being classified as TMB high compared with the static pan-cancer threshold. In addition, no significant difference in survival outcomes was found with the cancer-specific threshold compared with the pan-cancer threshold. Furthermore, the cancer-specific threshold maintained higher predicted neoantigen load for the TMB-high samples compared with the TMB-low samples, even when the threshold was lower than the pan-cancer threshold.CONCLUSION TMB is determined within the context of cancer type, metastatic state, and disease stage. Compared with a pan-cancer threshold, a cancer-specific threshold classifies more patients as TMB high while maintaining clinical outcomes that are not significantly different. Furthermore, the cancer-specific threshold identifies patients with a high number of predicted neoantigens. Because of the potential impact in the care of patients with cancer, TMB status should be determined in a cancer-specific manner. (C) 2019 by American Society of Clinical Oncology