Identification of methylation markers for the prediction of nodal metastasis in oral and oropharyngeal squamous cell carcinoma.
Hypermethylation is an important mechanism for the dynamic regulation of gene expression, necessary for metastasizing tumour cells. Our aim is to identify methylation tumour markers that have a predictive value for the presence of regional lymph node metastases in patients with oral and oropharyngeal squamous cell carcinoma (OOSCC). Significantly differentially expressed genes were retrieved from four reported microarray expression profiles comparing pN0 and pN+ head-neck tumours, and one expression array identifying functionally hypermethylated genes. Additional metastasis-associated genes were included from the literature. Thus genes were selected that influence the development of nodal metastases and might be regulated by methylation. Methylation-specific PCR (MSP) primers were designed and tested on 8 head-neck squamous cell carcinoma cell lines and technically validated on 10 formalin-fixed paraffin-embedded (FFPE) OOSCC cases. Predictive value was assessed in a clinical series of 70 FFPE OOSCC with pathologically determined nodal status. Five out of 28 methylation markers (OCLN, CDKN2A, MGMT, MLH1 and DAPK1) were frequently differentially methylated in OOSCC. Of these, MGMT methylation was associated with pN0 status (P = 0.02) and with lower immunoexpression (P = 0.02). DAPK1 methylation was associated with pN+ status (P = 0.008) but did not associate with protein expression. In conclusion, out of 28 candidate genes, two (7%) showed a predictive value for the pN status. Both genes, DAPK1 and MGMT, have predictive value for nodal metastasis in a clinical group of OOSCC. Therefore DNA methylation markers are capable of contributing to diagnosis and treatment selection in OOSCC. To efficiently identify additional new methylation markers, genome-wide methods are needed.
['Melchers|L J|LJ|', 'Clausen|M J A M|MJ|', 'Mastik|M F|MF|', 'Slagter-Menkema|L|L|', 'van der Wal|J E|JE|', 'Wisman|G B A|GB|', 'Roodenburg|J L N|JL|', 'Schuuring|E|E|']
D000328:Adult D000368:Aged D000369:Aged, 80 and over D014408:Biomarkers, Tumor D002294:Carcinoma, Squamous Cell D045744:Cell Line, Tumor D019175:DNA Methylation D015254:DNA Modification Methylases D045643:DNA Repair Enzymes D064550:Death-Associated Protein Kinases D005260:Female D015972:Gene Expression Regulation, Neoplastic D006801:Humans D008207:Lymphatic Metastasis D008297:Male D008875:Middle Aged D009062:Mouth Neoplasms D009959:Oropharyngeal Neoplasms D011237:Predictive Value of Tests D012307:Risk Factors D012680:Sensitivity and Specificity D025521:Tumor Suppressor Proteins
methylation expression MGMT DAPK1 biomarker head and neck cancer lymph node metastasis oral cancer