CDX2 Expression as a Potential Surrogate Marker for CpG Island Methylator Phenotype in Colorectal Cancers.
Inti Zlobec, Michel Bihl, Anja Foerster, Alex Rufle, Alessandro Lugli. University Hospital Basel, Switzerland
Background: CpG Island Methylator Phenotype (CIMP) is currently being investigated for its role in colorectal cancer pathogenesis and impact on clinical outcome. However, the assessment of CIMP in routine diagnostic pathology is complicated by the technical challenge and costs associated with its assessment. The aim of this study was to identify a protein marker capable of predicting CIMP status from a panel of 50 potential candidates.
Design: 404 patients were included in this study. MSI-H was defined as instability in ≥2 Bethesda-panel markers. CIMP-high was defined as methylation in ≥4/5 loci including CACNA1G, CDKN2A, CRABP1, MLH1, and Neurog1. Using tissue microarrays, 50 tumor and immune cell markers were investigated by immunohistochemistry.
Results: Only 7/50 markers were associated with CIMP-high including increased numbers of granzyme B+ (p=0.002; AUC:0.65), and CD8+ (p<0.001; AUC:0.66) cells, increased tumor cell expression of nuclear MST1 (p=0.012; AUC:0.67), and loss of cytoplasmic RKIP (p=0.007; AUC: 0.64), membranous/cytoplasmic EphB2 (p=0.007; AUC:0.7), and cytoplasmic CK20 (p=0.002; AUC:0.67). However, loss of cytoplasmic CDX2 was the strongest predictor of CIMP-high (p<0.001; AUC: 0.81). Of the 206 tumors with diffuse CDX2 staining, 202 (98%) were CIMP-negative/low. Similarly, of the 23 CIMP-high cases, 19 (82.6%) showed a loss of CDX2 expression.
Conclusions: CIMP-high colorectal cancers show a considerable loss of CDX2 expression. Since loss of CDX2 has previously been associated with BRAF mutation and MSI-H, two features closely related to CIMP, these preliminary results suggest that CDX2 may be useful as a possible surrogate marker for the determination of CIMP status.
Wednesday, March 2, 2011 9:30 AM
Poster Session V # 46, Wednesday Morning