Pan-Cancer Analysis of WRN: From Multi-Omics Biomarker Discovery to Therapy-Guiding Functional Evidence

The RecQ DNA helicase family member WRN is an important protein for maintaining genome stability. The concept of attention as a synthetic lethal target for MSI-H tumors has garnered significant attention in recent years. However, the role of WRN in cancer development, diagnosis, and prognosis has not yet been systematically evaluated at the pan-cancer level.

On the basis of multiple public cancer databases, we employed bioinformatics techniques to systematically assess WRN expression, variation, and interaction pathways across various cancers, along with the impact of WRN expression on immune profiling, drug sensitivity, and treatment, as a diagnostic tool. Additionally, we used three cancer cell lines to evaluate the suppressor function of WRN inactivation.

WRN is highly expressed in rapidly proliferating tissues and is dysregulated in a cancer-specific manner, particularly in tumors with hereditary DNA repair deficiencies and myeloid malignancies. WRN expression and variants are correlated with prognosis and immune activation potential in cancers. In digestive cancer and endometrial cancer with a high proportion of MSI-H tumors, WRN is positively associated with MSI/TMB signatures. Pharmacogenomic analyses revealed significant correlations between WRN expression levels and sensitivity to the DNA synthesis inhibitors PI3K, ALK, and IFG1R and other target agents and immunomodulators. In vitro validation using WRN inhibitors demonstrated potent suppression of malignant phenotypes (proliferation, clonogenicity, migration, invasion) in colorectal, endometrial, and ovarian cancer models.

Our study suggests that WRN plays a role in cancer diagnosis and therapy, especially in cancers characterized by replicative stress or defective DNA damage repair, and that WRN can serve as a potential target for cancer immunotherapy or targeted therapies and as a prognostic marker for certain tumors.