Abstract Background: Carcinoembryonic antigen (CEA) is one of the most widely used tumor markers in colorectal cancer (CRC). High preoperative concentrations of CEA correlate with poor survival outcomes. Serial CEA measurements have been used for detecting recurrent CRC. However, the genomic characteristics of primary CRC according to the blood CEA level are still not clear. Though patients with low CEA levels are associated with good prognosis, some of these patients have progression of their tumor. It would aid in applying careful surveillance to identify a subset of patients at high risk for poor prognosis among those with low CEA level. In this study, the different types of molecular profiles were compared between CRC with low and high serum CEA levels. In addition, we compared the genomic characteristics between CRC without progression and with progression among patients with low CEA levels. Methods: Using data acquired from The Cancer Genome Atlas (TCGA), we performed survival and genomic analyses on 381 CRC patient samples with serum CEA levels. Differential mRNA expression, miRNA expression and DNA methylation were examined between CRC with low serum CEA levels (low CEA group; ≤ 5 ng/mL) and high serum CEA levels (high CEA group; > 5 ng/mL). Among the 140 patients with low CEA levels, the same analyses were performed between CRC without progression and with progression. Results: High CEA group was associated with higher pathologic stage, more venous and lymphatic invasion. High CEA group had worse overall and progression-free survival than low CEA group (p <0.001 and p <0.001, respectively). A total of 28 genes were identified as significantly differentially expressed genes between low and high CEA group. Functional annotation and pathway analyses of the differentially expressed genes identified the possible association of cell adhesion, cytokine-cytokine receptor interaction and Wnt signaling network. Two differentially expressed miRNAs (mir-486 and mir-509-1) and 3 differential CpG sites (cg07530063, cg24216966 and cg11622162) were identified between low and high CEA group. Between CRC without progression and with progression in low CEA group, we identified 20 differentially expressed genes that were associated with epithelial to mesenchymal transition and transport of organic acid, metal ion and amine compounds. Four differentially expressed miRNAs (mir-483, mir-9-1, mir-9-2, and mir-31) and no differential CpG sites were identified between CRC with and without progression. Conclusions: In this study, we have identified different molecular features between primary CRC with low and high CEA levels. Notably, specific genomic profiles may contribute to discriminating patients with poor outcomes in CRC with low CEA level. Citation Format: Ji Won Park, Manu Shivakumar, Eun Kyung Choe, Dokyoon Kim. Genomic characterization of primary tumor in colorectal cancer according to serum carcinoembryonic antigen level [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3626.