title: HPV status-independent association of alcohol and tobacco exposure or prior radiation therapy with promoter methylation of FUSSEL18, EBF3, IRX1, and SEPT9, but not SLC5A8, in head and neck squamous cell carcinomas.
abstract: Head and neck squamous cell carcinoma (HNSCC) is an aggressive malignancy with more than half a million people being diagnosed with the disease annually. Within the last 2 decades, the human papillomavirus (HPV) has been found to be associated with this malignancy. More recently, HPV-infected HNSCC has been found to exhibit higher levels of global DNA methylation. In a recent study, we identified five tumor suppressive genes (IRX1, EBF3, SLC5A8, SEPT9, and FUSSEL18) as frequently methylated in HNSCC biopsies using a global methylation analysis via restriction landmark genomic scanning. In this study, we verify these genes as valid methylation markers in two separate sets of HNSCC specimens. By using the available clinical information linked to the patient specimens, we found a strong association between promoter methylation of FUSSEL18, IRX1, and EBF3 and prior radiation therapy (P < 0.0001) irrespective of HPV status. Also, promoter methylation of FUSSEL18 and SEPTIN9 was found to correlate significantly with exposure to alcohol and tobacco (P = 0.021). Importantly, in this study, we preliminarily show a trend between HPV16 positivity and specific target gene hypermethylation of IRX1, EBF3, SLC5A8, and SEPT9. If replicated in a larger study, the HPV status may be a patient selection biomarker when determining the most efficacious treatment modality for these different subsets of patients (e.g., inclusion or exclusion of epigenetic therapies). Equally notable and independent of HPV status, hypermethylation of the promoters of a subset of these genes in recurrences especially in the setting of prior radiation or in the setting of alcohol and tobacco use might help guide adjunctive inclusion or exclusion or epigenetic therapy.
authors.affiliation: Genomic Medicine Institute Lerner Research Institute, Cleveland Clinic, Cleveland, OH 44195, USA.
authors.forename: Kristi L
authors.initials: KL
authors.lastname: Bennett
authors.forename: Walter
authors.initials: W
authors.lastname: Lee
authors.forename: Eric
authors.initials: E
authors.lastname: Lamarre
authors.forename: Xiatong
authors.initials: X
authors.lastname: Zhang
authors.forename: Rahul
authors.initials: R
authors.lastname: Seth
authors.forename: Joseph
authors.initials: J
authors.lastname: Scharpf
authors.forename: Jennifer
authors.initials: J
authors.lastname: Hunt
authors.forename: Charis
authors.initials: C
authors.lastname: Eng
mesh_terms: D000428:Alcohol Drinking / Q000009:adverse effects*; D014408:Biomarkers, Tumor / Q000235:genetics / Q000378:metabolism; D002294:Carcinoma, Squamous Cell / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy / Q000821:virology; D027682:Cation Transport Proteins / Q000235:genetics / Q000378:metabolism; D003598:Cytoskeletal Proteins / Q000235:genetics / Q000378:metabolism; D019175:DNA Methylation; D003627:Data Interpretation, Statistical; D019204:GTP-Binding Proteins / Q000235:genetics / Q000378:metabolism; D016147:Genes, Tumor Suppressor; D006258:Head and Neck Neoplasms / Q000209:etiology* / Q000235:genetics / Q000378:metabolism / Q000532:radiotherapy / Q000821:virology; D018398:Homeodomain Proteins / Q000235:genetics / Q000378:metabolism; D052162:Human papillomavirus 16 / Q000302:isolation & purification*; D006801:Humans; D008869:Microtubule-Associated Proteins / Q000235:genetics / Q000378:metabolism; D027501:Monocarboxylic Acid Transporters; D009419:Nerve Tissue Proteins / Q000235:genetics / Q000378:metabolism; D011401:Promoter Regions, Genetic; D011518:Proto-Oncogene Proteins / Q000235:genetics / Q000378:metabolism; D011878:Radiotherapy / Q000009:adverse effects; D058112:Septins; D012907:Smoking / Q000009:adverse effects*; D014157:Transcription Factors / Q000235:genetics / Q000378:metabolism
chemical_list: D014408:Biomarkers, Tumor; D027682:Cation Transport Proteins; D003598:Cytoskeletal Proteins; D018398:Homeodomain Proteins; C501591:IRX1 protein, human; C403664:MAPRE3 protein, human; D008869:Microtubule-Associated Proteins; D027501:Monocarboxylic Acid Transporters; D009419:Nerve Tissue Proteins; D011518:Proto-Oncogene Proteins; C506647:SKOR2 protein, human; C476760:SLC5A8 protein, human; D014157:Transcription Factors; D019204:GTP-Binding Proteins; C474315:SEPTIN9 protein, human; D058112:Septins