Prognostic value of aberrant promoter hypermethylation of tumor-related genes in early-stage head and neck cancer.

Kiyoshi Misawa,Atsushi Imai,Shiori Endo,Takeharu Kanazawa,Yuki Misawa,Hiroyuki Mineta,Masato Mima,Thomas E Carey,Daiki Mochizuki

doi:10.18632/oncotarget.8317

Abstract

Staging and pathological grading are useful, but imperfect predictors of recurrence in head and neck squamous cell carcinoma (HNSCC). Accordingly, molecular biomarkers that predict the risk of recurrence are necessary to improve clinical outcomes. The methylation statuses of the promoters of 11 tumor-related genes (p16, RASSF1A, E-cadherin, H-cadherin, MGMT, DAPK, DCC, COL1A2, TAC1, SST, and GALR1) were analyzed in 133 HNSCC cases using quantitative methylation-specific PCR. We detected frequent methylation of p16 (44%), RASSF1A (18%), E-cadherin (53%), H-cadherin (35%), MGMT (35%), DAPK (53%), DCC (42%), COL1A2 (44%), TAC1 (61%), SST (64%), and GALR1 (44%) in HNSCC. Disease-free survival was lower in patients with 6–11 methylated genes than in those with 0–5 methylated genes (log-rank test, P = 0.001). In a multivariate Cox proportional hazards analysis, the methylation of E-cadherin, COL1A2, TAC1, and GALR1 was associated with poor survival, with hazard ratios of 4.474 (95% CI, 1.241–16.124). In a joint analysis of these four genes, patients with 2–4 methylated genes had a significantly lower survival rate than those with 0–1 methylated genes in early-stage HNSCC. Importantly, the methylation of some genes was closely related to poor prognosis in early-stage HNSCC, providing strong evidence that these hypermethylated genes are valuable biomarkers for prognostic evaluation.

Highlights

The treatment strategy for patients with head and neck squamous cell carcinoma (HNSCC) is generally guided by tumor–node–metastasis (TNM)classification and clinical staging
In a multivariate Cox proportional hazards analysis, the methylation of E-cadherin, COL1A2, TAC1, and GALR1 was associated with poor survival, with hazard ratios of 4.474
After adjusting for age, gender, smoking status, stage, we found that hypermethylation of E-cadherin, COL1A2, TAC1, and

Summary

INTRODUCTION

The treatment strategy for patients with HNSCC is generally guided by tumor–node–metastasis (TNM). Methylation of the promoters of other genes was not associated with age at onset, gender, alcohol exposure, smoking status, tumor site, tumor size, lymph-node status, or clinical stage (Table 1). After adjusting for age, gender, smoking status, stage, we found that hypermethylation of E-cadherin, COL1A2, TAC1, and GALR1 was associated with significantly reduced survival, with hazard ratios of 2.263 (95% CI, 1.103–4.641), 3.824. In 100 stage III and IV patients, the DFS was statistically significantly worse in the group with a high number of methylated genes (log-rank test, P = 0.007) (Figure 2G). Patients with 2 to 4 methylated genes (in an analysis of E-cadherin, COL1A2, TAC1, and GALR1) had a trend toward worse survival than those with 0 to 1 methylated genes

RESULTS

DISCUSSION

MATERIALS AND METHODS