Open AccessHPV ‐positive oropharyngeal squamous cell carcinoma is associated with TIMP 3 and CADM 1 promoter hypermethylation
Author(s) -
Kempen Pauline M. W.,
Bockel Liselotte,
Braunius Weibel W.,
Moelans Cathy B.,
Olst Marina,
Jong Rick,
Stegeman Inge,
Diest Paul J.,
Grolman Wilko,
Willems Stefan M.
Publication year - 2014
Publication title -
cancer medicine
Language(s) - English
Resource type - Journals
SCImago Journal Rank - 1.403
H-Index - 53
ISSN - 2045-7634
DOI - 10.1002/cam4.313
Subject(s) - cancer research , basal cell , dna methylation , medicine , biology , gene , genetics , gene expression
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 OPSCC s 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 CDH 13 , DAPK 1 , 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 CADM 1 ( P < 0.001), CHFR ( P = 0.027), and TIMP 3 ( P < 0.001). CADM 1 and CHFR showed similar methylation patterns in OPSCC and cervical SCC , but TIMP 3 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 CADM 1 and TIMP 3 are significantly more frequently hypermethylated in HPV ‐positive OPSCC and CHFR in HPV ‐negative tumors.