Exploring potential therapeutic targets for colorectal tumors based on whole genome sequencing of colorectal tumors and paracancerous tissues

Yufan Sheng¹Sen Niu¹Da Li¹Chunyuan Meng^2*Tong Wang^1*

• ¹Department of General Surgery, Wuxi People's Hospital Affiliated to Nanjing Medical University, Wuxi, China
• ²Department of General Surgery, First Affiliated Hospital, Nanjing Medical University, Nanjing, Jiangsu Province, China

Objective: Colorectal cancer (CRC) is the third most common tumor worldwide and the second leading cause of cancer-related deaths. Colorectal cancer progresses slowly, and patients have to endure pain for a long time, both before and after surgery. The incidence rate has been increasing year by year in recent years, and the survival rate of patients is low. A significant percentage of colorectal cancers are hereditary. Therefore, it is important to analyze the genomic profiles of colorectal cancer and its paraneoplastic tissues, explore the disease-causing risk genes, and search for the potential novel therapeutic targets to improve the therapeutic efficacy of colorectal cancer.Methods: Whole genome sequencing was performed on tumor and paraneoplastic tissue samples from 26 colorectal cancer patients to obtain somatic and germ line mutation data. The mutation spectrum, mutation characteristics, high-frequency copy number variants, and high-frequency mutated and susceptibility genes were derived from these data. Genome maps of the tumor and paraneoplastic tissue samples were then drawn. Finally, pan-cancer species expression analysis, differential gene expression analysis, and protein blotting, immunohistochemistry, cell scratch, and cell viability assays were performed on the related susceptibility gene, SH3BP1, to verify its expression level and function.Result：Significant differences in gene mutations were found between tumor tissues and normal tissues adjacent to the cancer through whole genome sequencing. Based on the mutation data, SH3BP1 was selected as a target gene. The differential expression of SH3BP1 in tumor and paraneoplastic normal tissues was demonstrated through pan-cancer species and gene expression difference analyses, as well as through immunohistochemistry and protein blotting. Cell scratch and CCK8 experiments revealed that tumor cells with low SH3BP1 expression exhibited slower proliferation and migration. These results suggest that SH3BP1 may promote the proliferation and migration of colorectal cancer tumors.Conclusion: Whole genome sequencing revealed dramatic changes in the genome, particularly in the non-coding regions, during the transformation of normal tissue adjacent to cancer into cancerous tissue. Additionally, SH3BP1, a susceptibility gene identified in this study, plays a role in promoting colorectal cancer and is expected to be a new target for treatment.