Prognostic and predictive value of CpG island methylator phenotype in patients with locally advanced nonmetastatic sporadic colorectal cancer.

Yuwei Wang,Guoxiang Cai,Ye Xu,Junjie Peng,Sanjun Cai,Yadong Long,Peng Lian,Zuqing Guan

doi:10.1155/2014/436985

Abstract

Purpose. In the present study, the prognostic significance of CpG island methylator phenotype (CIMP) in stage II/III sporadic colorectal cancer was evaluated using a five-gene panel. Methods. Fifty stage II/III colorectal cancer patients who received radical resection were included in this study. Promoter methylation of p14ARF, hMLH1, p16INK4a, MGMT, and MINT1 was determined by methylation specific polymerase chain reaction (MSP). CIMP positive was defined as hypermethylation of three or more of the five genes. Impact factors on disease-free survival (DFS) and overall survival (OS) were analyzed using Kaplan-Meier method (log-rank test) and adjusted Cox proportional hazards model. Results. Twenty-four percent (12/50) of patients were characterized as CIMP positive. Univariate analysis showed stage III (P = 0.049) and CIMP positive (P = 0.014) patients who had significantly inferior DFS. In Cox regression analysis, CIMP positive epigenotype was independently related with poor DFS with HR = 2.935 and 95% CI: 1.193–7.220 (P = 0.019). In patients with CIMP positive tumor, those receiving adjuvant chemotherapy had a poor DFS than those without adjuvant chemotherapy (P = 0.023). Conclusions. CIMP positive was significantly correlated with decreased DFS in stage II/III colorectal cancer. Patients with CIMP positive locally advanced sporadic colorectal cancers may not benefit from 5-fluorouracil based adjuvant chemotherapy.

Highlights

Colorectal cancer is a major cause of mortality and morbidity throughout the world
Evidence of our study showed that in patients with CpG island methylator phenotype (CIMP) positive stage II/III disease, patients treated with adjuvant chemotherapy showed inferior disease-free survival (DFS) than those without adjuvant chemotherapy
Our data suggested that CIMP positive was an unfavorable independent prognostic factor in stage II/III sporadic colorectal cancer in Chinese population

Summary

Introduction

Colorectal cancer is a major cause of mortality and morbidity throughout the world. With adjuvant chemotherapy as standard management following surgery to treat stage III and stage II patients with high risk factors, the 5-year relative survival rate of locally advanced colorectal cancer was still 69.2% compared with 90.1% among patients with localized disease [1], which highlighted the need of better prognostic and predictive markers to identify those high-risk individuals.Promoter CpG island hypermethylation resulting in the transcriptional silencing of tumor suppressor genes has been widely observed in colorectal cancer and been increasingly recognized to contribute to the pathogenesis of colorectal cancer. Colorectal cancer is a major cause of mortality and morbidity throughout the world. With adjuvant chemotherapy as standard management following surgery to treat stage III and stage II patients with high risk factors, the 5-year relative survival rate of locally advanced colorectal cancer was still 69.2% compared with 90.1% among patients with localized disease [1], which highlighted the need of better prognostic and predictive markers to identify those high-risk individuals. Tumor-specific hypermethylated loci of p14ARF, hMLH1, p16INK4a, MGMT, and MINT1 were proved to be closely related with colorectal cancers [2, 6]. The prognostic and predictive value of CIMP in sporadic locally advanced colorectal cancer determined by the five-gene panel had not been evaluated before

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Discussion

Conclusion