Line Region Hypomethylation is Associated with Lifestyle and Differs by Human Papillomavirus (HPV) Status in Head and Neck Squamous Cell Carcinomas

摘要

Genomic hypomethylation is a hallmark of essentially all cancers but the degree of this hypomethylation differs amongst individual tumors. Little work has explored what leads to these differences and or asked whether they are clinically meaningful. In this study of head and neck squamous cell carcinoma (HNSCC), we assessed hypomethylation in tumors, using a semi-quantitative fragment analysis approach to determine the relative methylation status of the line retroviral element LRE1 (Line-1.2). As this is an established marker of genomic methylation status, we examined the relationship between the relative methylation, patient demographics and other risk factors for HNSCC. We determined relative methylation status for 303 patients, 193 of which had complete data for all variables of interest. Using a generalized linear model, we found that patient body mass index was significantly positively associated with tumor LRE1 methylation level. Smoking duration, particularly in tumors lacking human papillomavirus (HPV) DNA, was significantly negatively associated with relative methylation level. Having previously assessed relative methylation in blood-derived DNA, we compared tumor with the blood DNA methylation level and observed these to be independent. Finally, the lower LRE1 methylation in patients whose tumors were HPV DNA negative was associated with poorer patient survival (HR 1.6, 95% CI 1.0, 2.6). These findings suggest that HPV-associated tumors differ molecularly from those arising after heavy tobacco use and that this epigenetic alteration may impact survival in HPV negative patients already exhibiting more aggressive disease.