title: HPV-positive oropharyngeal squamous cell carcinoma is associated with TIMP3 and CADM1 promoter hypermethylation.
abstract: Oropharyngeal squamous cell carcinoma (OPSCC) is associated with human papillomavirus (HPV) in a proportion of tumors. HPV-positive OPSCC is considered a distinct molecular entity with a prognostic advantage compared to HPV-negative cases. Silencing of cancer-related genes by DNA promoter hypermethylation may play an important role in the development of OPSCC. Hence, we examined promoter methylation status in 24 common tumor suppressor genes in a group of 200 OPSCCs to determine differentially methylated genes in HPV-positive versus HPV-negative primary OPSCC. Methylation status was correlated with HPV status, clinical features, and patient survival using multivariate methods. Additionally, methylation status of 16 cervical squamous cell carcinomas (SCC) was compared with HPV-positive OPSCC. Using methylation-specific probe amplification, HPV-positive OPSCC showed a significantly higher cumulative methylation index (CMI) compared to HPV-negative OPSCC (P=0.008). For the genes CDH13, DAPK1, and RARB, both HPV-positive and HPV-negative OPSCC showed promoter hypermethylation in at least 20% of the tumors. HPV status was found to be an independent predictor of promoter hypermethylation of CADM1 (P < 0.001), CHFR (P = 0.027), and TIMP3 (P < 0.001). CADM1 and CHFR showed similar methylation patterns in OPSCC and cervical SCC, but TIMP3 showed no methylation in cervical SCC in contrast to OPSCC. Methylation status of neither individual gene nor CMI was associated with survival. These results suggest that HPV-positive tumors are to a greater extent driven by promotor hypermethylation in these tumor suppressor genes. Especially CADM1 and TIMP3 are significantly more frequently hypermethylated in HPV-positive OPSCC and CHFR in HPV-negative tumors.
authors: Department of Otorhinolaryngology - Head and Neck Surgery, University Medical Center Utrecht, Utrecht, The Netherlands; Brain Center Rudolf Magnus, University Medical Center Utrecht, Utrecht, The Netherlands.
authors: Pauline M W
authors: PM
authors: van Kempen
authors: Liselotte
authors: L
authors: van Bockel
authors: Weibel W
authors: WW
authors: Braunius
authors: Cathy B
authors: CB
authors: Moelans
authors: Marina
authors: M
authors: van Olst
authors: Rick
authors: R
authors: de Jong
authors: Inge
authors: I
authors: Stegeman
authors: Paul J
authors: PJ
authors: van Diest
authors: Wilko
authors: W
authors: Grolman
authors: Stefan M
authors: SM
authors: Willems
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D002294:Carcinoma, Squamous Cell / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules / Q000235:genetics*; D019175:DNA Methylation; D005260:Female; D006801:Humans; D007136:Immunoglobulins / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D009367:Neoplasm Staging; D009959:Oropharyngeal Neoplasms / Q000235:genetics* / Q000401:mortality / Q000473:pathology / Q000628:therapy / Q000821:virology; D027383:Papillomaviridae / Q000235:genetics; D030361:Papillomavirus Infections / Q000150:complications; D011379:Prognosis; D011401:Promoter Regions, Genetic; D012307:Risk Factors; D019717:Tissue Inhibitor of Metalloproteinase-3 / Q000235:genetics*; D047368:Tumor Burden
chemical_list: C403514:CADM1 protein, human; D000075982:Cell Adhesion Molecule-1; D015815:Cell Adhesion Molecules; D007136:Immunoglobulins; D019717:Tissue Inhibitor of Metalloproteinase-3
keywords: CADM1; CHFR; HPV; TIMP3; hypermethylation; oropharynx squamous cell carcinoma