A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV Infection
A Five-MicroRNA Signature Predicts Survival and Disease Control of Patients with Head and Neck Cancer Negative for HPV Infection
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DOI：
10.1158/1078-0432.ccr-18-0776
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发表时间：
2019-03-01
影响因子：
11.5
通讯作者：
Belka, Claus
中科院分区：
文献类型：
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作者：
Hess, Julia;Unger, Kristian;Belka, Claus
目的：人乳头瘤病毒（HPV）阴性的头颈部鳞状细胞癌（HNSCC）与预后不良，而独立的预后标志物仍有待defined.Experimental设计：我们回顾性进行了miRNA表达谱。患者因局部晚期HPV阴性HNSCC接受手术，并在八家不同的医院接受了放疗（DKTK-ROG; n = 85）。选择符合可比的人口统计学、治疗和随访特征。在独立的单中心患者样本（LMU-KKG; n = 77）中验证了结果。开发了无复发的预后miRNA标签，并测试了其他终点。对miRNA特征、肿瘤和淋巴结分期以及囊外淋巴结扩散进行递归分配分析。使用qRT-PCR进行技术验证。结果：DKTK-ROG和LMU-KKG患者的中位随访时间分别为5.1和5.3年，5年无复发率分别为63.5%和75.3%。一个五个miRNA的特征（hsa-let-7 g-3 p、hsamiR- 6508- 5 p、hsa-miR-210- 5 p、hsa-miR-4306和hsa-miR-7161- 3 p）预测DKTK-ROG中无复发[风险比（HR）4.42; 95%置信区间（CI）1.98-9.88，P < 0.001]，这在LMU-KKG中得到证实。（HR 4.24; 95% CI，1.40-12.81，P = 0.005）。该特征也预测了总体生存率（HR 3.03; 95% CI，1.50-6.12，P = 0.001），无复发生存期（HR 3.16; 95% CI，1.65-6.04，P < 0.001）和疾病特异性生存期（HR 5.12; 95% CI，1.88-13.92，P < 0.001），所有这些都在LMU-KKG数据中得到证实。相关协变量的调整维持了预测所有终点的miRNA特征。两个样本的递归划分分析将患者组合分类为低复发风险（n = 17）、低-中等复发风险（n = 80）、高-中等复发风险（n = 48）或高复发风险（n = 17）（P < 0.001）。
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; n = 85). Selection fulfilled comparable demographic, treatment, and follow-up characteristics. Findings were validated in an independent single-center patient sample (LMU-KKG; n = 77). A prognostic miRNA signature was developed for freedom from recurrence and tested for other endpoints. Recursivepartitioning 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, hsamiR- 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, P < 0.001], which was confirmed in LMU-KKG (HR 4.24; 95% CI, 1.40-12.81, P = 0.005). The signature also predicted overall survival (HR 3.03; 95% CI, 1.50-6.12, P = 0.001), recurrence-free survival (HR 3.16; 95% CI, 1.65-6.04, P < 0.001), and disease-specific survival (HR 5.12; 95% CI, 1.88-13.92, P < 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 (n = 17), low-intermediate (n = 80), high-intermediate (n = 48), or high risk (n = 17) for recurrence (P < 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.