Tumors with unmethylated MLH1 and the CpG island methylator phenotype are associated with a poor prognosis in stage II colorectal cancer patients.

Tao Fu,Christine A Iacobuzio-Donahue,Stephen B Baylin,Christopher L Wolfgang,Yanliang Liu,Zachary Kerner,Kai Li,Emmanouil P Pappou,Weiwei Wan,Nita Ahuja

doi:10.18632/oncotarget.13441

Abstract

We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status. Here, we tested the prognostic value of this model in stage II colorectal cancer (CRC) patients. Tumors were assigned to CIMP+/MLH1-unmethylated (MLH1-U), CIMP+/MLH1-methylated (MLH1-M), CIMP−/MLH1-U, or CIMP−/MLH1-M groups. Age, tumor location, lymphovascular invasion, and mucin production differed among the four patient subgroups, and CIMP+/MLH1-U tumors were more likely to have lymphovascular invasion and mucin production. Kaplan-Meier analyses revealed differences in both disease-free survival (DFS) and overall survival (OS) among the four groups. In a multivariate analysis, CIMP/MLH1 methylation status was predictive of both DFS and OS, and DFS and OS were shortest in CIMP+/MLH1-U stage II CRC patients. These results suggest that tumor subtype classification based on the combination of CIMP and MLH1 methylation status is informative in stage II CRC patients, and that CIMP+/MLH1-U tumors exhibit aggressive features and are associated with poor clinical outcomes.

Highlights

Colorectal cancer (CRC) is the third most common cause of cancer-related death in the United States [1], and an estimated 134,490 new cases will be diagnosed in 2016 [2]
We previously developed a novel tumor subtype classification model for duodenal adenocarcinomas based on a combination of the CpG island methylator phenotype (CIMP) and MLH1 methylation status
CIMP/MLH1 methylation status was predictive of both disease-free survival (DFS) and overall survival (OS), and DFS and OS were shortest in CIMP+/ MLH1-U stage II colorectal cancer (CRC) patients

Summary

Introduction

Colorectal cancer (CRC) is the third most common cause of cancer-related death in the United States [1], and an estimated 134,490 new cases will be diagnosed in 2016 [2]. The 5-year relative survival rate for CRC patients is 65% [2]. The 5-year relative survival rate for stage II CRCs is about 82.5% [3]; approximately 20% of patients with tumors of this stage die of recurrent disease. Stage II CRC patients are generally considered to be at low risk of postoperative recurrence; routine adjuvant chemotherapy is generally not recommended for these patients [6]. A recent study found that stage IIIa CRC patients www.impactjournals.com/oncotarget who received chemotherapy survived longer than stage IIb patients who did not [3]. The ability of current histopathologyand imaging-based staging to predict CRC prognosis is limited, suggesting that molecular classifications should be refined [7]

Methods

Results

Conclusion