Abstract
Head and neck squamous cell carcinoma (HNSCC) is the eighth most commonly diagnosed cancer in the United States. The risk of developing HNSCC increases with exposure to tobacco, alcohol and infection with human papilloma virus (HPV). HPV-associated HNSCCs have a distinct risk profile and improved prognosis compared to cancers associated with tobacco and alcohol exposure. Epigenetic changes are an important mechanism in carcinogenic progression, but how these changes differ between viral- and chemical-induced cancers remains unknown. CpG methylation at 1505 CpG sites across 807 genes in 68 well-annotated HNSCC tumor samples from the University of Michigan Head and Neck SPORE patient population were quantified using the Illumina Goldengate Methylation Cancer Panel. Unsupervised hierarchical clustering based on methylation identified 6 distinct tumor clusters, which significantly differed by age, HPV status, and three year survival. Weighted linear modeling was used to identify differentially methylated genes based on epidemiological characteristics. Consistent with previous in vitro findings by our group, methylation of sites in the CCNA1 promoter was found to be higher in HPV(+) tumors, which was validated in an additional sample set of 128 tumors. After adjusting for cancer site, stage, age, gender, alcohol consumption, and smoking status, HPV status was found to be a significant predictor for DNA methylation at an additional 11 genes, including CASP8 and SYBL1. These findings provide insight into the epigenetic regulation of viral vs. chemical carcinogenesis and could provide novel targets for development of individualized therapeutic and prevention regimens based on environmental exposures.
Highlights
Head and neck squamous cell carcinomas (HNSCCs), the eighth most commonly diagnosed cancer in the U.S population, have a complex etiology that includes life style behaviors, classical chemical carcinogenesis, and infection with high risk types of human papillomavirus (HPV)
The majority of the HNSCCs were from the oropharynx (47%), oral cavity (25%), and larynx (19%), with a large proportion of cancers diagnosed as late stage (22% stage III and 62% stage IV, Table 1)
The findings of this study expand upon our prior cell line work, identifying numerous loci in tumor samples that are differentially methylated between HPV(+) and HPV(2) tumors, those involved in cell cycle regulation and JAK-STAT signaling
Summary
Head and neck squamous cell carcinomas (HNSCCs), the eighth most commonly diagnosed cancer in the U.S population, have a complex etiology that includes life style behaviors, classical chemical carcinogenesis, and infection with high risk types of human papillomavirus (HPV). Patients with HPV(+) head and neck cancer have a distinct risk profile, associated with a less remarkable history of tobacco and alcohol use [4], a more beneficial micronutrient profile [5], and improved survival compared to those with HPV(2) tumors [6]. Both tobacco- and alcohol-related, as well as HPV-associated, head and neck cancers have a well-described multistep model of carcinogenesis [7]. HPV(+) head and neck cancers have a distinct clinical profile when compared to alcohol and tobacco-related HPV(2) tumors, the former of which are typically more responsive to treatment [13]
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