Clinical Correlates of Promoter Hypermethylation of Four Target Genes in Head and Neck Cancer: A Cooperative Group Correlative Study

• Published in: Clinical cancer research 2013-05, Vol.19 (9), p.2528-2540
• Main Authors: ROH, Jong-Lyel, WANG, Xin Victoria, MANOLA, Judith, SIDRANSKY, David, FORASTIERE, Arlene A, KOCH, Wayne M
• Format: Article
• Language: English
• Subjects: Aged; Antineoplastic agents; Biological and medical sciences; Carcinoma, Squamous Cell - genetics; Carcinoma, Squamous Cell - mortality; Cyclin-Dependent Kinase Inhibitor p16 - genetics; DCC Receptor; DNA Methylation; Female; Gene Expression Regulation, Neoplastic; Head and Neck Neoplasms - genetics; Head and Neck Neoplasms - mortality; Humans; Kaplan-Meier Estimate; Kinesin - genetics; Linear Models; Male; Medical sciences; Middle Aged; Multiple tumors. Solid tumors. Tumors in childhood (general aspects); Multivariate Analysis; Mutation; Otorhinolaryngology (head neck, general aspects and miscellaneous); Otorhinolaryngology. Stomatology; Pharmacology. Drug treatments; Promoter Regions, Genetic; Prospective Studies; Receptor, Endothelin B - genetics; Receptors, Cell Surface - genetics; Tumor Suppressor Protein p53 - genetics; Tumor Suppressor Proteins - genetics; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.ccr-12-3047

Promoter hypermethylation is a well-documented mechanism for tumor-specific alteration of suppressor gene activity in human malignancy including head and neck cancer (HNC). The abrogation of specific suppressor gene activity may influence tumor behavior and clinical outcome. In this study we examined methylation of DCC, KIF1A, EDNRB, and p16(INK4a) in a large cohort of HNC patients from Eastern Cooperative Group (ECOG) 4393/Radiation Therapy Oncology Group (RTOG) 9614 to identify clinical correlates of methylation of these genes. Methylation was assessed by quantitative methylation-specific PCR in DNA from tumor specimens and was considered as a continuous and a binary variable. Clinical data including demographics, stage, risk factor exposure, treatment, and outcome were collected by ECOG and RTOG. Methylation status was also correlated with mutation of TP53 (previously reported) and human papilloma virus status. Methylation results were available for 368 cases, 353 of which also have p53 mutation status. At least one methylation event was present in all tumors. In multivariate analysis of the entire cohort, methylation of p16 was associated with decreased survival (HR = 1.008; P = 0.045). However, in tumors with disruptive TP53 mutation (poor prognostic group), the additional presence of methylation of p16 was protective (P = 0.019 considering p16 methylation as a continuous variable). Methylation of tumor-related genes contributes to the biological behavior of HNC and influences overall survival in conjunction with other known prognostic molecular events.