Background: The early detection of colorectal cancer (CRC) poses significant challenges, and there is a scarcity of available targeted therapies. The advancement of personalized medicine (PM) becomes paramount in enhancing the disease prognosis of cancer patients. The aim of this study was to optimize individualized targeted therapy for CRC patients by selecting new panel sequencing genes. Methods: We used a targeted region probe hybrid capture technology to perform panel sequencing on ctDNA from patients, and downloaded mRNA expression profiles and exon sequencing data from The Cancer Genome Atlas (TCGA) database. We also performed Single Nucleotide Variant (SNV), Insertion/Deletion (InDel), Copy Number Variation (CNV), and gene fusion detection, and coverage of 43 Single Nucleotide Polymorphism (SNP) loci on 70 genes were closely related to digestive system tumor occurrence, development, and drug application. Results: By taking the intersection of the mRNA differential expression genes, mutation genes, panel sequencing mutation genes, and panel sequencing genes in the TCGA database, we identified 5 intersection genes (BRCA2, BRCA1, POLD1, BLM, and NTHL1), which were significantly upregulated in tumors, and high expression of BRCA2 and BRCA1 suggested better prognosis. Based on module genes and Whole-Exome Sequencing (WES) performance in TCGA CRC mutation dataset, we identified the top 10 mutation detection rate genes (ASPM, CENPF, DST, PRKDC, AHNAK, CHD7, MKI67, SPAG17, POLQ, and PTPN13) Conclusion: ASPM, CENPF, and DST had higher mutation detection rates in the TCGA CRC mutation dataset, and the expression of ASPM, CENPF, and DST was associated with better prognosis in CRC patients.