MRC Integrative Epidemiology Unit at the University of Bristol, Bristol, UK.
Population Health Sciences, Bristol Medical School, University of Bristol, Bristol, UK.
Clin Epigenetics. 2020 Jun 29;12(1):95. doi: 10.1186/s13148-020-00870-0.
Smoking status, alcohol consumption and HPV infection (acquired through sexual activity) are the predominant risk factors for oropharyngeal cancer and are thought to alter the prognosis of the disease. Here, we conducted single-site and differentially methylated region (DMR) epigenome-wide association studies (EWAS) of these factors, in addition to ∼ 3-year survival, using Illumina Methylation EPIC DNA methylation profiles from whole blood in 409 individuals as part of the Head and Neck 5000 (HN5000) study. Overlapping sites between each factor and survival were then assessed using two-step Mendelian randomization to assess whether methylation at these positions causally affected survival.
Using the MethylationEPIC array in an OPC dataset, we found novel CpG associations with smoking, alcohol consumption and ~ 3-year survival. We found no CpG associations below our multiple testing threshold associated with HPV16 E6 serological response (used as a proxy for HPV infection). CpG site associations below our multiple-testing threshold (P < 0.05) for both a prognostic factor and survival were observed at four gene regions: SPEG (smoking), GFI1 (smoking), PPT2 (smoking) and KHDC3L (alcohol consumption). Evidence for a causal effect of DNA methylation on survival was only observed in the SPEG gene region (HR per SD increase in methylation score 1.28, 95% CI 1.14 to 1.43, P 2.12 × 10).
Part of the effect of smoking on survival in those with oropharyngeal cancer may be mediated by methylation at the SPEG gene locus. Replication in data from independent datasets and data from HN5000 with longer follow-up times is needed to confirm these findings.
吸烟状况、饮酒和 HPV 感染（通过性行为获得）是口咽癌的主要危险因素，被认为会改变疾病的预后。在这里，我们对这些因素进行了单站点和差异甲基化区域（DMR）全基因组关联研究（EWAS），此外还对 409 名个体的全血 Illumina Methylation EPIC DNA 甲基化图谱进行了约 3 年的生存分析，这些个体是 Head and Neck 5000（HN5000）研究的一部分。然后，使用两步孟德尔随机化评估每个因素与生存之间重叠的位点，以评估这些位置的甲基化是否会对生存产生因果影响。
我们在 OPC 数据集的甲基化 EPIC 阵列中发现了与吸烟、饮酒和~3 年生存率相关的新 CpG 关联。我们没有发现与 HPV16 E6 血清学反应（用作 HPV 感染的替代物）相关的 CpG 关联低于我们的多重测试阈值。在四个基因区域观察到与预后因素和生存相关的 CpG 位点关联低于我们的多重测试阈值（P<0.05）：SPEG（吸烟）、GFI1（吸烟）、PPT2（吸烟）和 KHDC3L（饮酒）。仅在 SPEG 基因区域观察到 DNA 甲基化对生存的因果影响（每增加一个 SD 的甲基化评分 HR 为 1.28，95%CI 为 1.14 至 1.43，P=2.12×10）。
在口咽癌患者中，吸烟对生存的部分影响可能是由 SPEG 基因座的甲基化介导的。需要在独立数据集的数据和 HN5000 更长随访时间的数据中进行复制，以证实这些发现。
