Interference of tumour mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group
Interference of tumour mutational burden with outcome of patients with head and neck cancer treated with definitive chemoradiation: a multicentre retrospective study of the German Cancer Consortium Radiation Oncology Group
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DOI：
10.1016/j.ejca.2019.04.015
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发表时间：
2019-07-01
影响因子：
8.4
通讯作者：
Tinhofer, I
中科院分区：
文献类型：
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作者：
Eder, T.;Hess, A. K.;Tinhofer, I
背景：从整个外显子组测序或全面基因面板估算的肿瘤突变负担（TMB）先前已被确定为对免疫检查点抑制剂（ICIS）的反应因素。其对并发化学放疗的疗效（CCRTX）的预测价值是ICI的潜在组合伙伴，仍然未知。方法：在癌症基因组（TCGA）头部建立了内部327基因面板TMB估计的准确性。和颈部鳞状细胞癌（HNSCC）数据集。 CCRTX后TMB的干扰在局部晚期HNSCC均匀治疗的局部晚期HNSCC患者中确定CCRTX后结果。有针对性的下一代测序成功地应用于101个福尔马林固定的，石蜡包裹的预处理预处理肿瘤样品中。在一部分病例（n = 40）的一部分中，肿瘤RNA用于通过纳米弹力平台进行免疫相关的基因表达分析。 TMB与TP53基因型，人乳头瘤病毒（HPV）状态，免疫表达特征和存活参数相关。结果在TCGA HNSCC队列中得到了验证。回报：建立了327基因面板TMB估计的高精度。高TMB与TP53突变的患病率和免疫基因表达模式显着相关，与T细胞增强的基因表达谱无关。 Kaplan-Meier分析显示，TMB高的患者组的总体存活率显着降低（死亡危险比：1.79，95％置信区间：1.02-3.14; P = 0.042），在多元模型中的混杂因子纠正后，这些置信度显着。 TMB的预后价值在TCGA HNSCC队列中得到了证实。结论：高TMB识别CCRTX后结果较差的HNSCC患者，他们可能优先从CRTX-ICI组合中受益。 （c）2019 Elsevier Ltd.保留所有权利。
Background: Tumour mutational burden (TMB) estimated from whole exome sequencing or comprehensive gene panels has previously been established as predictive factor of response to immune checkpoint inhibitors (ICIs). Its predictive value for the efficacy of concurrent chemoradiation (cCRTX), a potential combination partner of ICI, remains unknown.Methods: The accuracy of TMB estimation by an in-house 327-gene panel was established in the Cancer Genome Atlas (TCGA) head and neck squamous cell carcinoma (HNSCC) data set. Interference of TMB with outcome after cCRTX was determined in a multicentre cohort of patients with locally advanced HNSCC uniformly treated with cCRTX. Targeted next-generation sequencing was successfully applied in 101 formalin-fixed, paraffin-embedded pretreatment tumour samples. In a subset of cases (n = 40), tumour RNA was used for immune-related gene expression profiling by the nanoString platform. TMB was correlated with TP53 genotype, human papilloma virus (HPV) status, immune expression signatures and survival parameters. Results were validated in the TCGA HNSCC cohort.Results: A high accuracy of TMB estimation by the 327-gene panel was established. High TMB was significantly associated with an increased prevalence of TP53 mutations and immune gene expression patterns unrelated to T cell-inflamed gene expression profiles. Kaplan-Meier analysis revealed significantly reduced overall survival in the patient group with high TMB (hazard ratio for death: 1.79, 95% confidence interval: 1.02-3.14; P = 0.042) which remained significant after correcting for confounding factors in the multivariate model. The prognostic value of TMB was confirmed in the TCGA HNSCC cohort.Conclusion: High TMB identifies HNSCC patients with poor outcome after cCRTX who might preferentially benefit from CRTX-ICI combinations. (C) 2019 Elsevier Ltd. All rights reserved.