Gene promoter methylation signature predicts survival of head and neck squamous cell carcinoma patients

Infection with high-risk types of human papilloma virus (HPV) is currently the best-established prognostic marker for head and neck squamous cell carcinoma (HNSCC), one of the most common and lethal human malignancies worldwide. Clinical trials have been launched to address the concept of treatment de-escalation for HPV-positive HNSCC with the final aim to reduce treatment related toxicity and debilitating long-term impacts on the quality of life. However, HPV-related tumors are mainly restricted to oropharyngeal SCC (OPSCC) and there is an urgent need to establish reliable biomarkers for all patients at high risk for treatment failure. A patient cohort (n=295) with mainly non-OPSCC (72.9%) and a low prevalence of HPV16-related tumors (8.8%) was analyzed by MassARRAY to determine a previously established prognostic methylation score (MS). Kaplan-Meier revealed a highly significant correlation between a high MS and a favorable survival for OPSCC (<i>P</i>=0.0004) and for non-OPSCC (<i>P</i>&lt;0.0001), which was confirmed for all HNSCC by multivariate Cox regression models (HR: 9.67, 95% CI [4.61–20.30], <i>P</i>&lt;0.0001). Next, we established a minimal methylation signature score (MMSS), which consists of ten most informative of the originally 62 CpG units used for the MS. The prognostic value of the MMSS was confirmed by Kaplan-Meier analysis for all HNSCC (<i>P</i>&lt;0.0001) and non-OPSCC (<i>P</i>=0.0002), and was supported by multivariate Cox regression models for all HNSCC (HR: 2.15, 95% CI [1.36–3.41], <i>P</i>=0.001). In summary, the MS and the MMSS exhibit an excellent performance as prognosticators for survival, which is not limited by the anatomical site, and both could be implemented in future clinical trials.

高危型人乳头瘤病毒（human papilloma virus, HPV）感染是目前头颈部鳞状细胞癌（head and neck squamous cell carcinoma, HNSCC）中证据最为充分的预后标志物，而头颈部鳞状细胞癌是全球范围内最常见且致死率最高的人类恶性肿瘤之一。针对HPV阳性头颈部鳞状细胞癌的降阶梯治疗理念，目前已启动相关临床试验，其最终目标为降低治疗相关毒性，并减轻其对患者生活质量造成的衰弱性长期影响。然而，HPV相关肿瘤主要局限于口咽鳞状细胞癌（oropharyngeal SCC, OPSCC），因此亟需为所有存在治疗失败高风险的患者建立可靠的生物标志物。本研究采用MassARRAY技术，对以非口咽鳞状细胞癌为主（占比72.9%）、HPV16型相关肿瘤患病率较低（仅8.8%）的295例患者队列进行分析，旨在验证此前已确立的预后甲基化评分（prognostic methylation score, MS）。Kaplan-Meier分析结果显示，高MS评分与OPSCC患者（P=0.0004）及非OPSCC患者（P<0.0001）的良好生存显著相关；多因素Cox回归模型进一步证实，该相关性在全部头颈部鳞状细胞癌患者中均成立（风险比HR=9.67，95%置信区间CI：4.61~20.30，P<0.0001）。随后，本研究构建了最小甲基化特征评分（minimal methylation signature score, MMSS），该评分由构建原始MS评分所用的62个CpG位点中信息价值最高的10个位点组成。Kaplan-Meier分析进一步证实，MMSS对全部头颈部鳞状细胞癌患者（P<0.0001）及非OPSCC患者（P=0.0002）均具有预后价值；多因素Cox回归模型同样验证了该结论（HR=2.15，95%CI：1.36~3.41，P=0.001）。综上，MS与MMSS均可作为优异的生存预后标志物，且其预后价值不受肿瘤解剖部位的限制，二者均可应用于未来的临床试验中。