p16、pRB、cyclin D1 和 p53 等细胞周期相关蛋白在切除的口咽癌中的预后意义。
Prognostic significance of cell cycle-associated proteins p16, pRB, cyclin D1 and p53 in resected oropharyngeal carcinoma.
机构信息
Department of Otorhinolaryngology, Head and Neck Surgery, Kantonsspital St.Gallen, St. Gallen, Switzerland.
Department of Otorhinolaryngology, University Hospital Heidelberg, Heidelberg, Germany.
出版信息
J Otolaryngol Head Neck Surg. 2018 Sep 6;47(1):53. doi: 10.1186/s40463-018-0298-3.
BACKGROUND
Human papillomavirus (HPV)-related oropharyngeal squamous cell carcinoma (OPSCC) has an improved outcome and may allow for treatment de-escalation. High-risk HPV (HR-HPV) infection is associated with deregulated expression of the cell cycle-associated proteins p16, pRB, cyclin D1 and p53. The objective of this study was to assess cell cycle proteins as potential surrogate markers for HR-HPV DNA testing to identify OPSCC with favorable prognosis after resection.
METHODS
Tissue microarray cores of 313 surgically treated OPSCC were stained for p16, pRB, cyclin D1 and p53 using immunohistochemistry. Protein expression was scored as high or low based on the proportion of positive carcinoma cells. Tumor samples were analysed for HR-HPV DNA with polymerase chain reaction-based testing. Associations between cell cycle protein expression and HR-HPV DNA status were evaluated by calculating sensitivity, specificity, predictive values, and diagnostic odds ratios (DOR). Kaplan-Meier and Cox regression analysis were applied to evaluate associations between cell cycle protein expression and patient outcome.
RESULTS
High expression of p16, cyclin D1, pRB and p53 in tumor cells were observed in 51.8%, 51.4%, 41.9% and 33.5% of OPSCC, respectively. HR-HPV DNA positive were 158/313 (50.5%) tumor samples (HPV16: 147, HPV18: 1, HPV33: 5, HPV35: 2, HPV56: 2, and HPV59: 1). P16 showed a higher DOR to predict HR-HPV DNA positivity than pRB, cyclin D1 and p53. Both the p16/pRB and the p16/pRB/cyclin D1/p53 signatures had lower DOR than p16 alone. Improved 5-year overall and disease-specific survival were associated with HR-HPV DNA positivity, high p16, low pRB, low cyclin D1, and low p53 expression. Associations with improved outcome were also observed for the marker combinations high p16/positive HR-HPV DNA, high p16/low pRB and high p16/low pRB/low cyclin D1/low p53. In a multivariate analysis adjusted for age, smoking history, pT and pN category, high p16 expression showed the lowest hazard ratio for death.
CONCLUSIONS
High p16 expression is a reliable marker for survival prognostication in surgically treated OPSCC patients. Protein signatures including the pRB, cyclin D1 and p53 proteins do not further increase the prognostic performance of p16 as a single marker.
背景
人乳头瘤病毒（HPV）相关的口咽鳞状细胞癌（OPSCC）的预后较好，可能允许治疗降级。高危型 HPV（HR-HPV）感染与细胞周期相关蛋白 p16、pRB、cyclin D1 和 p53 的表达失调有关。本研究的目的是评估细胞周期蛋白作为 HR-HPV DNA 检测的潜在替代标志物，以鉴定接受切除术治疗的 OPSCC 中具有良好预后的患者。
方法
使用免疫组织化学方法对 313 例接受手术治疗的 OPSCC 的组织微阵列核心进行 p16、pRB、cyclin D1 和 p53 染色。根据阳性癌细胞的比例将蛋白表达评分高或低。使用聚合酶链反应（PCR）检测 HR-HPV DNA。通过计算敏感性、特异性、预测值和诊断比值比（DOR）评估细胞周期蛋白表达与 HR-HPV DNA 状态之间的相关性。应用 Kaplan-Meier 和 Cox 回归分析评估细胞周期蛋白表达与患者预后之间的关系。
结果
在 OPSCC 中，p16、cyclin D1、pRB 和 p53 分别在 51.8%、51.4%、41.9%和 33.5%的肿瘤细胞中高表达。在 313 例肿瘤样本中，HR-HPV DNA 阳性者为 158/313（50.5%）（HPV16：147、HPV18：1、HPV33：5、HPV35：2、HPV56：2 和 HPV59：1）。与 pRB、cyclin D1 和 p53 相比，p16 对预测 HR-HPV DNA 阳性具有更高的 DOR。p16/pRB 和 p16/pRB/cyclin D1/p53 标志物组合的 DOR 均低于单独的 p16。HR-HPV DNA 阳性、高 p16、低 pRB、低 cyclin D1 和低 p53 表达与 5 年总生存率和疾病特异性生存率的提高相关。高 p16/阳性 HR-HPV DNA、高 p16/低 pRB 和高 p16/低 pRB/低 cyclin D1/低 p53 标志物组合也与改善预后相关。在调整年龄、吸烟史、pT 和 pN 分期的多变量分析中，高 p16 表达显示死亡风险最低。
结论
高 p16 表达是手术治疗 OPSCC 患者生存预后的可靠标志物。包括 pRB、cyclin D1 和 p53 蛋白在内的蛋白标志物并不能进一步提高 p16 作为单一标志物的预后性能。
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