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


METHODS
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.
Baba
Yoshifumi
Y
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, Massachusetts, USA.
Nosho
Katsuhiko
K
Shima
Kaori
K
Freed
Ellen
E
Irahara
Natsumi
N
Philips
Juliet
J
Meyerhardt
Jeffrey A
JA
Hornick
Jason L
JL
Shivdasani
Ramesh A
RA
Fuchs
Charles S
CS
Ogino
Shuji
S
D000368:Aged; D000071616:CDX2 Transcription Factor; D015179:Colorectal Neoplasms / Q000235:genetics / Q000378:metabolism / Q000473:pathology*; D018899:CpG Islands / Q000235:genetics; D050759:Cyclin-Dependent Kinase Inhibitor p21 / Q000378:metabolism; D051546:Cyclooxygenase 2 / Q000378:metabolism; D019175:DNA Methylation; D005260:Female; D018398:Homeodomain Proteins / Q000378:metabolism*; D006801:Humans; D007150:Immunohistochemistry; D016015:Logistic Models; D008297:Male; D053842:Microsatellite Instability; D008875:Middle Aged; D015999:Multivariate Analysis; D009367:Neoplasm Staging; D016017:Odds Ratio; D019869:Phosphatidylinositol 3-Kinases / Q000378:metabolism; D011379:Prognosis; D048493:Proto-Oncogene Proteins B-raf / Q000378:metabolism; D016019:Survival Analysis; D016159:Tumor Suppressor Protein p53 / Q000378:metabolism; D051176:beta Catenin / Q000378:metabolism
C493956:CDKN1A protein, human; D000071616:CDX2 Transcription Factor; C491270:CDX2 protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D018398:Homeodomain Proteins; D016159:Tumor Suppressor Protein p53; D051176:beta Catenin; D051546:Cyclooxygenase 2; D019869:Phosphatidylinositol 3-Kinases; C482119:BRAF protein, human; D048493:Proto-Oncogene Proteins B-raf