Abstract Background Tumorigenesis and embryogenesis have many similar biological characteristics, such as proliferation, invasion, metabolism and immunity. The development of villi is a physiological process, it will stop after the fetus is born. Trophoblast have been defined as "physiological metastasis" or "pseudo-malignant". However, tumorigenesis is a pathological process that will go on indefinitely. We hypothesize that if the interactions between gene and gene in tumors deviate from the interactions in villi, it is more likely to develop into malignant tumors and have worse prognosis. Methods We collected tissue samples including human chorionic villus samples at 6 to 10 weeks of gestation (n = 15) and leaf chorionic samples from postpartum placental tissue (n = 6), then extracted RNA and carried out RNA sequencing. We processed bioinformatics analysis in combination with multi-stage colorectal cancer (CRC) transcriptome data, including normal (n = 12), low-grade adenoma (n = 21), high-grade adenoma (n = 30), cancer (n = 25). Results We found that CRC progress and villi development involve many genes with similar biological behaviors, such as proliferation, immunity, metabolism and invasion, but the genes of the relevant biological behavior are different between CRC and villi. Then we filtered those genes, of which the interactions in CRC are far from that in villi. Twenty-four genes, such as CBL, COL1A1, ATP5C1, CDC42 etc were finally selected. Abnormal expression of the 24 genes was significantly associated with poor survival in six independent CRC cohorts (The Cancer Genome Atlas, P<0.001; GSE39084, P= 0.002; GSE14333, P<0.001; GSE17536, P=0.003; GSE39582, P<0.001; GSE29621, P=0.001). Conclusions Villi development is a reliable and strictly regulated model that can illuminate the trajectory of human cancer development. Our study indicated that the interactions between gene and gene in CRC development deviate from that in villi, the deviation interactions of gene may have some substantial impacts on CRC development and reveal novel prognostic biomarkers. Citation Format: Botao Zhang, Lin Feng, Ting Xiao, Shujun Cheng. Identify prognostic biomarkers for colorectal cancer by human villi development model [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3622.