Research Papers:

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

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

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Oncotarget. 2016; 7:86480-86489. https://doi.org/10.18632/oncotarget.13441

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Tao Fu1, Yanliang Liu1, Kai Li1, Weiwei Wan1, Emmanouil P. Pappou2, Christine A. Iacobuzio-Donahue3, Zachary Kerner4, Stephen B. Baylin5, Christopher L. Wolfgang4, Nita Ahuja4,5,6

1Department of Gastrointestinal Surgery II, Key Laboratory of Hubei Province for Digestive System Disease, Renmin Hospital, Wuhan University, Wuhan 430060, China

2Department of Colon and Rectal Surgery, Columbia University Medical Center, New York, NY 10032, USA

3Department of Pathology and David Rubenstein Pancreatic Cancer Research Center, Memorial Sloan Kettering Cancer Center, New York, NY 10065, USA

4Department of Surgery, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

5Department of Oncology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

6Department of Urology, The Johns Hopkins University School of Medicine, Baltimore, MD 21287, USA

Correspondence to:

Tao Fu, email: [email protected]

Nita Ahuja, email: [email protected]

Keywords: CpG island methylator phenotype, MLH1, methylation, colorectal cancer, prognosis

Received: August 02, 2016     Accepted: November 09, 2016     Published: November 18, 2016


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.

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