TY - JOUR
T1 - Tumor necrosis factor-alpha polymorphisms in ulcerative colitis-associated colorectal cancer
AU - Garrity-Park, Megan M.
AU - Loftus, Edward V.
AU - Bryant, Sandra C.
AU - Sandborn, William J.
AU - Smyrk, Thomas C.
PY - 2008/2
Y1 - 2008/2
N2 - 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.
AB - 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.
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U2 - 10.1111/j.1572-0241.2007.01572.x
DO - 10.1111/j.1572-0241.2007.01572.x
M3 - Article
C2 - 18289203
AN - SCOPUS:39049098562
SN - 0002-9270
VL - 103
SP - 407
EP - 415
JO - American Journal of Gastroenterology
JF - American Journal of Gastroenterology
IS - 2
ER -