John Cunningham Virus and Colorectal Carcinogenesis: Current Evidence, Molecular Mechanisms, and Unresolved...

Colorectal cancer (CRC) remains a leading cause of cancer-related death worldwide, prompting ongoing research into infectious agents that may contribute to colorectal carcinogenesis. Among candidate oncogenic viruses, JC polyomavirus (JCPyV), a ubiquitous human polyomavirus, has attracted considerable attention due to its potential involvement in tumour initiation and progression. Although several studies have reported the presence of JCPyV viral DNA, transcripts, and proteins in colorectal adenomas and carcinomas, the prevalence and clinical significance of these findings vary considerably across populations and diagnostic methods. Mechanistically, the viral Large T Antigen (TAg) is implicated in several oncogenic processes through its interactions with key cellular regulators, including p53, retinoblastoma protein (pRb), and components of the Wnt/β-catenin signalling pathway. These interactions may cause genomic instability, aberrant cell cycle progression, impaired DNA repair, and aberrant cell proliferation, thereby creating an environment conducive to malignant transformation. In addition, emerging evidence suggests that JCPyV may contribute to chromosomal instability and epigenetic changes that facilitate tumour progression. Despite these observations, the causal role of JCPyV in colorectal cancer remains controversial. Inconsistent epidemiological data, discrepancies in virus detection, geographic variation, and the inability to confirm direct causation of carcinogenesis have generated ongoing debates about the involvement of JCPyV as a stimulator factor or cofactor in colorectal tumourigenesis. This review critically evaluates the current evidence linking JCPyV to colorectal cancer, summarises the proposed molecular mechanisms of viral carcinogenesis, and highlights key unresolved questions that need to be addressed to clarify the biological and clinical significance of JCPyV in colorectal carcinogenesis.