AbstractBackground and AimDifferentially expressed (DE) genes detected at the population‐level through case–control comparison provide no information on the dysregulation frequencies of DE genes in a cancer. In this work, we aimed to identify the genes with universally upregulated or downregulated expressions in colorectal cancer (CRC).MethodsWe firstly clarified that DE genes in an individual cancer tissue should be the disease‐relevant genes, which are dysregulated in the cancer tissue in comparison with its own previously normal state. Then, we identified DE genes at the individual level for 2233 CRC samples collected from multiple data sources using the RankComp algorithm.ResultsWe found 26 genes that were upregulated or downregulated in almost all the 2233 CRC samples and validated the results using 124 CRC tissues with paired adjacent normal tissues. Especially, we found that two genes (AJUBA and EGFL6), upregulated universally in CRC tissues, were extremely lowly expressed in normal colorectal tissues, which were considered to be oncogenes in CRC oncogenesis and development. Oppositely, we found that one gene (LPAR1), downregulated universally in CRC tissues, was silenced in CRC tissues but highly expressed in normal colorectal tissues, which were considered to be tumor suppressor genes in CRC. Functional evidences revealed that these three genes may induce CRC through deregulating pathways for ribosome biogenesis, cell proliferation, and cell cycle.ConclusionsIn conclusion, the individual‐level DE genes analysis can help us find genes dysregulated universally in CRC tissues, which may be important diagnostic biomarkers and therapy targets.