一种五 miRNA -signature 预测 HPV 感染阴性的头颈部癌症患者的生存和疾病控制。

A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV Infection.

机构信息

Research Unit Radiation Cytogenetics, Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.

Clinical Cooperation Group "Personalized Radiotherapy in Head and Neck Cancer," Helmholtz Zentrum München, German Research Center for Environmental Health GmbH, Neuherberg, Germany.

出版信息

Clin Cancer Res. 2019 Mar 1;25(5):1505-1516. doi: 10.1158/1078-0432.CCR-18-0776. Epub 2018 Aug 31.

DOI:10.1158/1078-0432.CCR-18-0776

PMID:30171046

Abstract

PURPOSE

Human papillomavirus (HPV)-negative head and neck squamous cell carcinoma (HNSCC) is associated with unfavorable prognosis, while independent prognostic markers remain to be defined.

EXPERIMENTAL DESIGN

We retrospectively performed miRNA expression profiling. Patients were operated for locally advanced HPV-negative HNSCC and had received radiochemotherapy in eight different hospitals (DKTK-ROG; = 85). Selection fulfilled comparable demographic, treatment, and follow-up characteristics. Findings were validated in an independent single-center patient sample (LMU-KKG; = 77). A prognostic miRNA signature was developed for freedom from recurrence and tested for other endpoints. Recursive-partitioning analysis was performed on the miRNA signature, tumor and nodal stage, and extracapsular nodal spread. Technical validation used qRT-PCR. An miRNA-mRNA target network was generated and analyzed.

RESULTS

For DKTK-ROG and LMU-KKG patients, the median follow-up was 5.1 and 5.3 years, and the 5-year freedom from recurrence rate was 63.5% and 75.3%, respectively. A five-miRNA signature (hsa-let-7g-3p, hsa-miR-6508-5p, hsa-miR-210-5p, hsa-miR-4306, and hsa-miR-7161-3p) predicted freedom from recurrence in DKTK-ROG [hazard ratio (HR) 4.42; 95% confidence interval (CI), 1.98-9.88, < 0.001], which was confirmed in LMU-KKG (HR 4.24; 95% CI, 1.40-12.81, = 0.005). The signature also predicted overall survival (HR 3.03; 95% CI, 1.50-6.12, = 0.001), recurrence-free survival (HR 3.16; 95% CI, 1.65-6.04, < 0.001), and disease-specific survival (HR 5.12; 95% CI, 1.88-13.92, < 0.001), all confirmed in LMU-KKG data. Adjustment for relevant covariates maintained the miRNA signature predicting all endpoints. Recursive-partitioning analysis of both samples combined classified patients into low ( = 17), low-intermediate ( = 80), high-intermediate ( = 48), or high risk ( = 17) for recurrence ( < 0.001).

CONCLUSIONS

The five-miRNA signature is a strong and independent prognostic factor for disease recurrence and survival of patients with HPV-negative HNSCC..

摘要

目的

人乳头瘤病毒（HPV）阴性的头颈部鳞状细胞癌（HNSCC）与不良预后相关，而独立的预后标志物仍有待确定。

实验设计

我们回顾性地进行了 miRNA 表达谱分析。患者因局部晚期 HPV 阴性 HNSCC 接受手术治疗，并在 8 家不同医院接受放化疗（DKTK-ROG；=85）。选择满足可比的人口统计学、治疗和随访特征。在一个独立的单中心患者样本（LMU-KKG；=77）中验证了这些发现。为了无复发率，我们开发了一个 miRNA 特征，并对其他终点进行了测试。对 miRNA 特征、肿瘤和淋巴结分期以及包膜外淋巴结扩散进行了递归分区分析。使用 qRT-PCR 进行技术验证。生成并分析了 miRNA-mRNA 靶标网络。

结果

对于 DKTK-ROG 和 LMU-KKG 患者，中位随访时间分别为 5.1 年和 5.3 年，5 年无复发率分别为 63.5%和 75.3%。一个由五个 miRNA（hsa-let-7g-3p、hsa-miR-6508-5p、hsa-miR-210-5p、hsa-miR-4306 和 hsa-miR-7161-3p）组成的特征预测了 DKTK-ROG 患者的无复发率[风险比（HR）4.42；95%置信区间（CI）1.98-9.88，<0.001]，在 LMU-KKG 中得到了证实（HR 4.24；95% CI，1.40-12.81，=0.005）。该特征还预测了总生存率（HR 3.03；95% CI，1.50-6.12，=0.001）、无复发生存率（HR 3.16；95% CI，1.65-6.04，<0.001）和疾病特异性生存率（HR 5.12；95% CI，1.88-13.92，<0.001），在 LMU-KKG 数据中均得到了证实。对相关协变量的调整维持了 miRNA 特征对所有终点的预测。对两个样本的递归分区分析将患者分为低风险（=17）、低-中风险（=80）、中-高风险（=48）或高风险（=17）复发（<0.001）。