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

// Tao Fu 1 , Yanliang Liu 1 , Kai Li 1 , Weiwei Wan 1 , Emmanouil P. Pappou 2 , Christine A. Iacobuzio-Donahue 3 , Zachary Kerner 4 , Stephen B. Baylin 5 , Christopher L. Wolfgang 4 , Nita Ahuja 4, 5, 6 1 Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan 430060, China 2 Department of Colon and Rectal Surgery, Columbia University Medical Center, New York, NY 10032, USA 3 Department of Pathology and David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA 4 Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 5 Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA 6 Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA Correspondence to: Tao Fu, email: tfu@tmmu.edu.cn Nita Ahuja, email: nahuja1@jhmi.edu Keywords: CpG island methylator phenotype, MLH1, methylation, colorectal cancer, prognosis Received: August 02, 2016      Accepted: November 09, 2016      Published: November 18, 2016 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.