Basic Study
Copyright ©The Author(s) 2015. Published by Baishideng Publishing Group Inc. All rights reserved.
World J Gastroenterol. Feb 7, 2015; 21(5): 1457-1467
Published online Feb 7, 2015. doi: 10.3748/wjg.v21.i5.1457
Loss of CDX2 expression is associated with poor prognosis in colorectal cancer patients
Jeong Mo Bae, Tae Hun Lee, Nam-Yun Cho, Tae-You Kim, Gyeong Hoon Kang
Jeong Mo Bae, Tae Hun Lee, Nam-Yun Cho, Gyeong Hoon Kang, Laboratory of Epigenetics, Cancer Research Institute, Seoul National University College of Medicine, Seoul 110-799, South Korea
Jeong Mo Bae, Gyeong Hoon Kang, Department of Pathology, Seoul National University College of Medicine, Seoul 110-799, South Korea
Tae-You Kim, Department of Internal Medicine, Seoul National University College of Medicine, Seoul 110-799, South Korea
Author contributions: Bae JM and Lee TH contributed equally to this work; Bae JM, Lee TH, Kim TY and Kang GH designed the research; Bae JM, Lee TH and Cho NY performed research; Bae JM and Lee TH analyzed the data; Bae JM and Lee TH wrote the paper.
Supported by Grants from National RD Program for Cancer Control, Ministry of Health and Welfare, South Korea, No. 0720540; Korea Healthcare Technology R and D Project, Ministry for Health, Welfare and Family Affairs, South Korea, No. A091081; Basic Science Research Program through the National Research Foundation of Korea (NRF), No. 2010-0007579; and the Mid-career Researcher Program through an NRF grant funded by the Ministry of Education, Science and Technology (MEST), No. 2011-0015646.
Open-Access: This article is an open-access article which was selected by an in-house editor and fully peer-reviewed by external reviewers. It is distributed in accordance with the Creative Commons Attribution Non Commercial (CC BY-NC 4.0) license, which permits others to distribute, remix, adapt, build upon this work non-commercially, and license their derivative works on different terms, provided the original work is properly cited and the use is non-commercial. See: http://creativecommons.org/licenses/by-nc/4.0/
Correspondence to: Gyeong Hoon Kang, MD, PhD, Professor, Department of Pathology, Seoul National University College of Medicine, 103 Daehak-ro, Jongno-gu, Seoul 110-799, South Korea. ghkang@snu.ac.kr
Telephone: +82-2-20723312 Fax: +82-2-7435530
Received: August 8, 2014
Peer-review started: August 11, 2014
First decision: September 15, 2014
Revised: October 4, 2014
Accepted: November 19, 2014
Article in press: November 19, 2014
Published online: February 7, 2015
Abstract

AIM: To investigate the clinicopathologic characteristics and prognostic implications associated with loss of CDX2 expression in colorectal cancers (CRCs).

METHODS: We immunohistochemically evaluated CDX2 expression in 713 CRCs and paired our findings to clinicopathologic and molecular characteristics of each individual. Endpoints included cytokeratin 7 and CK20 expression, microsatellite instability, CpG island methylator phenotype, and KRAS and BRAF mutation statuses. Univariate and multivariate survival analysis was performed to reveal the prognostic value of CDX2 downregulation.

RESULTS: CDX2 expression was lost in 42 (5.9%) patients. Moreover, loss of CDX2 expression was associated with proximal location, infiltrative growth, advanced T, N, M and overall stage. On microscopic examination, loss of CDX2 expression was associated with poor differentiation, increased number of tumor-infiltrating lymphocytes, luminal serration and mucin production. Loss of CDX2 expression was also associated with increased CK7 expression, decreased CK20 expression, CpG island methylator phenotype, microsatellite instability and BRAF mutation. In a univariate survival analysis, patients with loss of CDX2 expression showed worse overall survival (P < 0.001) and progression-free survival (P < 0.001). In a multivariate survival analysis, loss of CDX2 expression was an independent poor prognostic factor of overall survival [hazard ratio (HR) = 1.72, 95%CI: 1.04-2.85, P = 0.034] and progression-free survival (HR = 1.94, 95%CI: 1.22-3.07, P = 0.005).

CONCLUSION: Loss of CDX2 expression is associated with aggressive clinical behavior and can be used as a prognostic marker in CRCs.

Keywords: CDX2, CpG island methylator phenotype, Microsatellite instability, Colorectal cancer, Survival

Core tip: CDX2 is considered a tumor-suppressor gene and its expression is decreased in some colorectal cancers (CRCs). Immunohistochemical analysis of two different anti-CDX2 primary antibodies revealed that 5.9% of CRCs showed loss of CDX2 expression. Loss of CDX2 expression is associated with CpG island methylator phenotype, microsatellite instability, aggressive tumor behavior and poor clinical outcome. Patients with loss of CDX2 expression showed poor clinical outcome in univariate and multivariate survival analyses. Loss of CDX2 expression can be used as an independent prognostic marker in CRCs, especially stage IV CRCs.