Khwaja Shariq S, Baker Callie, Haynes Wesley, Spencer Christopher R, Gay Hiram, Thorstad Wade, Adkins Douglas R, Nussenbaum Brian, Chernock Rebecca D, Lewis James S, Wang Xiaowei
Department of Radiation Oncology, Washington University School of Medicine, St. Louis, Missouri.
Division of Medical Oncology, Department of Internal Medicine, Washington University School of Medicine, St. Louis, Missouri.
Int J Radiat Oncol Biol Phys. 2016 Jul 15;95(4):1132-41. doi: 10.1016/j.ijrobp.2016.03.001. Epub 2016 Mar 10.
Patients with human papillomavirus (HPV)-positive oropharyngeal squamous cell carcinoma (OPSCC) have a favorable prognosis. As a result, de-escalation clinical trials are under way. However, approximately 10% of patients will experience distant recurrence even with standard-of-care treatment. Here, we sought to identify novel biomarkers to better risk-stratify HPV-positive patients with OPSCC.
Gene expression profiling by RNA sequencing (RNA-seq) and quantitative polymerase chain reaction was performed on HPV-positive OPSCC primary tumor specimens from patients with and without distant metastasis (DM).
RNA-seq analysis of 39 HPV-positive OPSCC specimens revealed that patients with DM had 2-fold higher E6 gene expression levels than did patients without DM (P=.029). This observation was confirmed in a validation cohort comprising 93 patients with HPV-positive OPSCC. The mean normalized E6 expression level in the 17 recurring primary specimens was 13 ± 2 compared with 8 ± 1 in the remaining 76 nonrecurring primaries (P=.001). Receiver operating characteristic analysis established an E6 expression level of 7.3 as a cutoff for worse recurrence-free survival (RFS). Patients from this cohort with high E6 gene expression (E6-high) (n=51, 55%) had more cancer-related deaths (23% vs 2%, P<.001) and DM (26% vs 5%, P<.001) than did patients with low E6 gene expression (E6-low) (n=42, 45%). Kaplan-Meier survival analysis revealed that E6-high had worse RFS (95% vs 69%, P=.004) and cancer-specific survival (97% vs 79%, P=.007). E6-high maintained statistical significance in multivariate regression models balancing surgery, chemotherapy, nodal stage, and smoking status. Gene set enrichment analysis demonstrated that tumors with high E6 expression were associated with P53, epidermal growth factor receptor, activating transcription factor-2, and transforming growth factor-β signaling pathways.
High E6 gene expression level identifies HPV-positive OPSCC patients with 5-fold greater risk of distant disease recurrence and worse cancer-specific survival. Validation in a multi-institutional prospective clinical trial is required to assess the utility of E6 gene expression as a clinically useful prognostic biomarker.
人乳头瘤病毒（HPV）阳性的口咽鳞状细胞癌（OPSCC）患者预后良好。因此，正在进行降阶梯临床试验。然而，即使采用标准治疗，仍有大约10%的患者会发生远处复发。在此，我们试图确定新的生物标志物，以更好地对HPV阳性的OPSCC患者进行风险分层。
对有或无远处转移（DM）的HPV阳性OPSCC患者的原发肿瘤标本进行RNA测序（RNA-seq）和定量聚合酶链反应的基因表达谱分析。
对39例HPV阳性OPSCC标本的RNA-seq分析显示，发生DM的患者E6基因表达水平比未发生DM的患者高2倍（P=0.029）。这一观察结果在一个包含93例HPV阳性OPSCC患者的验证队列中得到证实。17例复发原发标本的平均标准化E6表达水平为13±2，而其余76例未复发原发标本的平均标准化E6表达水平为8±1（P=0.001）。受试者工作特征分析确定E6表达水平为7.3作为无复发生存期（RFS）较差的临界值。该队列中E6基因高表达（E6高）（n=51，55%）的患者比E6基因低表达（E6低）（n=42，45%）的患者有更多的癌症相关死亡（23%对2%，P<0.001）和DM（26%对5%，P<0.001）。Kaplan-Meier生存分析显示，E6高的患者RFS较差（95%对69%，P=0.004），癌症特异性生存率也较差（97%对79%，P=0.007）。在平衡手术、化疗、淋巴结分期和吸烟状况的多变量回归模型中，E6高仍具有统计学意义。基因集富集分析表明，E6高表达的肿瘤与P53、表皮生长因子受体、激活转录因子-2和转化生长因子-β信号通路相关。
E6基因高表达水平可识别远处疾病复发风险高5倍且癌症特异性生存率较差的HPV阳性OPSCC患者。需要在多机构前瞻性临床试验中进行验证，以评估E6基因表达作为临床有用的预后生物标志物的效用。
