Tumor Necrosis Factor-Alpha Polymorphisms in Ulcerative Colitis-Associated Colorectal Cancer.
Garrity-Park, Megan M. B.S. 1; Loftus, Edward V. Jr M.D. 2; Bryant, Sandra C. M.S. 3; Sandborn, William J. M.D. 2; Smyrk, Thomas C. M.D. 4
[Article]
American Journal of Gastroenterology.
103(2):407-415, February 2008.
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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-[alpha]) gene, a potent proinflammatory cytokine. TNF-[alpha] 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-[alpha] have been correlated with either increased or decreased production, indicating that regulation of TNF-[alpha] 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-[alpha] 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-[alpha] 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.
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