Chen Kang Mei, Stephen Josena K, Havard Shaleta, Mahan Meredith, Divine George, Worsham Maria J
Department of Otolaryngology-Head and Neck Research, Henry Ford Hospital, Detroit, Michigan.
Department of Public Health Sciences, Henry Ford Hospital, Detroit, Michigan.
JAMA Otolaryngol Head Neck Surg. 2015 Mar;141(3):257-63. doi: 10.1001/jamaoto.2014.3393.
Human papillomavirus (HPV) is a known causative agent for oropharyngeal squamous cell carcinoma (OPSCC). Whereas it is becoming more firmly established that HPV-positive head and neck squamous cell carcinoma is associated with better survival outcomes, believed to be because of better response to chemoradiation therapy, the specific mechanisms for these improved survival outcomes remain underexplored.
To examine the relationship between HPV status and promoter methylation in an OPSCC cohort.
DESIGN, SETTING, AND PARTICIPANTS: Real-time quantitative polymerase chain reaction was used to examine oncogenic HPV type 16 in a retrospective cohort of 121 patients with primary OPSCC. Aberrant promoter methylation of IGSF4, DAPK1, and ESR1 genes, known to be methylated in head and neck squamous cell carcinoma, including OPSCC, was examined by means of quantitative methylation-specific polymerase chain reaction.
Patients received standard therapy.
Univariate associations between HPV and methylation were analyzed using Fisher exact tests followed by multivariable logistic regression. Cox proportional-hazards regression was used to model the risk of death given age, race, sex, HPV status, methylation, stage, smoking, and treatment.
In univariate logistic regression analyses, HPV-positive status was significantly associated with Caucasian race (P = .02), treatment (radiotherapy only, P = .01; chemoradiotherapy, P = .007), and IGSF4 methylation (P = .005). The final multivariate logistic model, after controlling for patient characteristics (sex, age, smoking, race, and treatment) with backward variable selection among genes, retained IGSF4 methylation (OR, 4.5 [95% CI, 1.6-12.8]; P = .005), Caucasian race (OR, 2.9 [95% CI, 1.0-8.3]; P = .053), treatment (radiotherapy only vs neither: OR, 11.62 [95% CI, 2.02-66.82]; P = .02; chemoradiotherapy vs neither: OR, 11.15 [95% CI, 1.92-64.65]; P = .01), male sex (OR, 4.7 [95% CI, 1.3-17.0]; P = .02), and younger age (OR, 0.9 [95% CI, 0.90-1.0]; P = .008) as independent predictors of HPV-positive status. Cox regression modeling indicated HPV-negative status, age, male sex, smoking, and radiation treatment as independent predictors of mortality.
Methylation of IGSF4 is an independent predictor of HPV-positive status. DNA methylation in conjunction with HPV infection appears to play a role in OPSCC.
人乳头瘤病毒（HPV）是口咽鳞状细胞癌（OPSCC）的已知致病因素。虽然越来越明确HPV阳性的头颈部鳞状细胞癌与更好的生存结果相关，据信这是因为对放化疗有更好的反应，但这些改善的生存结果的具体机制仍未得到充分研究。
研究OPSCC队列中HPV状态与启动子甲基化之间的关系。
设计、背景和参与者：采用实时定量聚合酶链反应检测121例原发性OPSCC患者的回顾性队列中的致癌性HPV 16型。通过定量甲基化特异性聚合酶链反应检测IGSF4、DAPK1和ESR1基因的异常启动子甲基化，这些基因在包括OPSCC在内的头颈部鳞状细胞癌中已知会发生甲基化。
患者接受标准治疗。
使用Fisher精确检验分析HPV与甲基化之间的单变量关联，随后进行多变量逻辑回归。Cox比例风险回归用于根据年龄、种族、性别、HPV状态、甲基化、分期、吸烟和治疗情况对死亡风险进行建模。
在单变量逻辑回归分析中，HPV阳性状态与白种人（P = 0.02）、治疗（仅放疗，P = 0.01；放化疗，P = 0.007）和IGSF4甲基化（P = 0.005）显著相关。在对患者特征（性别、年龄、吸烟、种族和治疗）进行控制并在基因中进行反向变量选择后，最终的多变量逻辑模型保留了IGSF4甲基化（比值比[OR]，4.5[95%置信区间，1.6 - 12.8]；P = 0.005）、白种人（OR，2.9[95%置信区间，1.0 - 8.3]；P = 0.053）、治疗（仅放疗与均未接受治疗：OR，11.62[95%置信区间，2.02 - 66.82]；P = 0.02；放化疗与均未接受治疗：OR，11.15[95%置信区间，1.92 - 64.65]；P = 0.01）、男性（OR，4.7[95%置信区间，1.3 - 17.0]；P = 0.02）和较年轻年龄（OR，0.9[95%置信区间，0.90 - 1.0]；P = 0.008）作为HPV阳性状态的独立预测因素。Cox回归模型表明HPV阴性状态、年龄、男性、吸烟和放疗是死亡的独立预测因素。
IGSF4甲基化是HPV阳性状态的独立预测因素。DNA甲基化与HPV感染结合似乎在OPSCC中起作用。
