Tumor Necrosis Factor-Alpha Polymorphisms in Ulcerative Colitis-Associated Colorectal Cancer

OBJECTIVES Ulcerative colitis (UC) is characterized by chronic recurrent mucosal inflammation. Genetic studies in UC have indicated linkage to chromosome 6 in the region of the tumor necrosis factor-alpha (TNF-α) gene, a potent proinflammatory cytokine. TNF-α production is influenced by multiple factors including the type of immune cell and its level of activation. However, several single nucleotide polymorphisms (SNP) in the promoter region of TNF-α have been correlated with either increased or decreased production, indicating that regulation of TNF-α is in part genetic. Because UC patients are at increased risk for developing colorectal cancer (CRC), we investigated if there was an association between SNPs in the promoter of the TNF-α gene and UC-CRC. METHODS DNA was extracted from formalin-fixed, paraffin-embedded tissue from 114 UC-CRC cases and 114 UC-no CRC controls. Controls were frequency matched on duration and extent of colitis, age, ethnicity, and gender. All 228 tissue samples were analyzed for five TNF-α promoter polymorphisms (−238[G→A], −308[G→A], −857[C→T], −863[C→A], and −1031[T→C]) using PCR and sequencing. RESULTS The −308(G→A) SNP was significantly associated with UC-CRC cases at both the allele and genotype level (P < 0.0001). No other SNPs were significantly associated with UC-CRC. CONCLUSION We report a novel finding of a strong association between the −308(G→A) SNP and UC-CRC. Complete elucidation of the mechanism of UC-CRC carcinogenesis will require investigation of other genes involved in modulating inflammation, but our results suggest that some UC patients may have additional genetic predispositions toward developing UC-CRC.