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Colorectal cancer is a heterogeneous disease at the histomorphological, clinical and molecular level. Approximately 20% of cases may progress through the “serrated” pathway characterized by BRAF mutation and high-level CpG Island Methylator Phenotype (CIMP). A large subgroup are additionally microsatellite instable (MSI) and demonstrate significant loss of tumor suppressor Cdx2. The aim of this study is to determine the specificity of Cdx2 protein expression and CpG promoter hypermethylation for BRAFV600E and high-level CIMP in colorectal cancer. Cdx2, Mlh1, Msh2, Msh6, and Pms2 were analyzed by immunohistochemistry using a multi-punch tissue microarray (TMA;n= 220 patients). KRAS and BRAFV600E mutation analysis, CDX2 methylation and CIMP were investigated. Loss of Cdx2 was correlated with larger tumor size (P= 0.0154), right-sided location (P= 0.0014), higher tumor grade (P< 0.0001), more advanced pT (P= 0.0234) and lymphatic invasion (P= 0.0351). Specificity was 100% for mismatch repair (MMR)-deficiency (P< 0.0001), 92.2% (P< 0.0001) for BRAFV600E and 91.8% for CIMP-high. Combined analysis of BRAFV600E/CIMP identified Cdx2 loss as sensitive (80%) and specific (91.5%) for mutation/high status. These results were validated on eight well-established colorectal cancer cell lines. CDX2 methylation correlated with BRAFV600E (P= 0.0184) and with Cdx2 protein loss (P= 0.0028). These results seem to indicate that Cdx2 may play a role in the serrated pathway to colorectal cancer as underlined by strong relationships with BRAFV600E, CIMP-high and MMR-deficiency. Whether this protein can only be used as a “surrogate” marker, or is functionally involved in the progression of these tumors remains to be elucidated.Some colorectal cancers have aberrant methylation of CpG islands, mutations in the BRAF gene, and deactivation of the tumor suppressor Cdx2. Previous studies have shown that patients with CpG methylation do worse than those without. This study sought to determine whether loss of Cdx2 also means poorer outcomes, and how it correlates with CpG methylation and BRAF mutation. Without Cdx2, they found, tumors grew larger and attained a higher grade; loss of Cdx2 also strongly predicted BRAF mutation and CpG methylation, and methylation of the CDX2 gene correlated with Cdx2 protein loss. Cdx2 might, therefore, play a role in spurring colorectal cancer.