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. 2009 Jul 15;15(14):4665-73.
doi: 10.1158/1078-0432.CCR-09-0401. Epub 2009 Jul 7.

Relationship of CDX2 loss with molecular features and prognosis in colorectal cancer

Yoshifumi Baba  1 , Katsuhiko Nosho, Kaori Shima, Ellen Freed, Natsumi Irahara, Juliet Philips, Jeffrey A Meyerhardt, Jason L Hornick, Ramesh A Shivdasani, Charles S Fuchs, Shuji Ogino
Affiliations

Relationship of CDX2 loss with molecular features and prognosis in colorectal cancer

Yoshifumi Baba et al. Clin Cancer Res. .

Abstract

Purpose: The homeodomain transcription factor CDX2 is a relatively specific immunohistochemical marker for gastrointestinal carcinoma. However, no study has comprehensively examined the relationship between CDX2 expression in colon cancer and clinical, pathologic, prognostic, and molecular features, including microsatellite instability and CpG island methylator phenotype (CIMP).

Experimental design: Utilizing 621 colorectal cancers with clinical outcome and molecular data, CDX2 loss was detected in 183 (29%) tumors by immunohistochemistry.

Results: In multivariate logistic regression analysis, CDX2 loss was associated with female gender [odds ratio (OR), 3.32; P < 0.0001], CIMP-high (OR, 4.42; P = 0.0003), high tumor grade (OR, 2.69; P = 0.0085), stage IV disease (OR, 2.03; P = 0.019), and inversely with LINE-1 hypomethylation (for a 30% decline; OR, 0.33; P = 0.0031), p53 expression (OR, 0.55; P = 0.011), and beta-catenin activation (OR, 0.60; P = 0.037), but not with body mass index, tumor location, microsatellite instability, BRAF, KRAS, PIK3CA, p21, or cyclooxygenase-2. CDX2 loss was not independently associated with patient survival. However, the prognostic effect of CDX2 loss seemed to differ according to family history of colorectal cancer (P(interaction) = 0.0094). CDX2 loss was associated with high overall mortality (multivariate hazard ratio, 2.40; 95% CI, 1.28-4.51) among patients with a family history of colorectal cancer; no such association was present (multivariate hazard ratio, 0.97; 95% CI, 0.66-1.41) among patients without a family history of colorectal cancer.

Conclusions: CDX2 loss in colorectal cancer is independently associated with female gender, CIMP-high, high-level LINE-1 methylation, high tumor grade, and advanced stage. CDX2 loss may be associated with poor prognosis among patients with a family history of colorectal cancer.

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Conflict of interest statement

The content is solely the responsibility of the authors and does not necessarily represent the official views of NCI or NIH. The funders had no role in study design, data collection and analysis, decision to publish, or preparation of the manuscript. No conflicts of interest exist.

Figures

Figure 1
Figure 1
CDX2 expression in normal colonic mucosa and colon cancer A. Nuclear CDX2 expression in normal colonic epithelial cells (arrow). B. Nuclear CDX2 expression in colon cancer cells (white arrow). C. Loss of CDX2 expression in colon cancer cells (arrowhead).
Figure 2
Figure 2
A. Smoothing spline plot for the CDX2 loss / LINE-1 relation, showing odds ratio (OR) for CDX2 loss (y axis) according to LINE-1 methylation level (x axis) with high LINE-1 methylation level as a referent. Hatched lines indicate 95% confidence interval B. Kaplan-Meier curves for colon cancer-specific survival (upper panel) and overall survival (lower panel) according to CDX2 status in colorectal cancer.
Figure 2
Figure 2
A. Smoothing spline plot for the CDX2 loss / LINE-1 relation, showing odds ratio (OR) for CDX2 loss (y axis) according to LINE-1 methylation level (x axis) with high LINE-1 methylation level as a referent. Hatched lines indicate 95% confidence interval B. Kaplan-Meier curves for colon cancer-specific survival (upper panel) and overall survival (lower panel) according to CDX2 status in colorectal cancer.
See this image and copyright information in PMC

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