Tumor necrosis factor-alpha polymorphisms in ulcerative colitis-associated colorectal cancer

Megan M. Garrity-Park, Edward Vincent Loftus, Jr, Sandra C. Bryant, William J. Sandborn, Thomas Christopher Smyrk

Research output: Contribution to journalArticle

52 Citations (Scopus)

Abstract

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.

Original languageEnglish (US)
Pages (from-to)407-415
Number of pages9
JournalAmerican Journal of Gastroenterology
Volume103
Issue number2
DOIs
StatePublished - Feb 2008

Fingerprint

Ulcerative Colitis
Colorectal Neoplasms
Tumor Necrosis Factor-alpha
Single Nucleotide Polymorphism
Genes
Inflammation
Chromosomes, Human, Pair 6
Immunologic Factors
Colitis
Genetic Predisposition to Disease
Genetic Promoter Regions
Paraffin
Formaldehyde
Carcinogenesis
Alleles
Genotype
Cytokines
Polymerase Chain Reaction

ASJC Scopus subject areas

  • Gastroenterology

Cite this

Tumor necrosis factor-alpha polymorphisms in ulcerative colitis-associated colorectal cancer. / Garrity-Park, Megan M.; Loftus, Jr, Edward Vincent; Bryant, Sandra C.; Sandborn, William J.; Smyrk, Thomas Christopher.

In: American Journal of Gastroenterology, Vol. 103, No. 2, 02.2008, p. 407-415.

Research output: Contribution to journalArticle

Garrity-Park, Megan M. ; Loftus, Jr, Edward Vincent ; Bryant, Sandra C. ; Sandborn, William J. ; Smyrk, Thomas Christopher. / Tumor necrosis factor-alpha polymorphisms in ulcerative colitis-associated colorectal cancer. In: American Journal of Gastroenterology. 2008 ; Vol. 103, No. 2. pp. 407-415.
@article{bba19813c941454fa1a287060f4b0eff,
title = "Tumor necrosis factor-alpha polymorphisms in ulcerative colitis-associated colorectal cancer",
abstract = "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.",
author = "Garrity-Park, {Megan M.} and {Loftus, Jr}, {Edward Vincent} and Bryant, {Sandra C.} and Sandborn, {William J.} and Smyrk, {Thomas Christopher}",
year = "2008",
month = "2",
doi = "10.1111/j.1572-0241.2007.01572.x",
language = "English (US)",
volume = "103",
pages = "407--415",
journal = "American Journal of Gastroenterology",
issn = "0002-9270",
publisher = "Nature Publishing Group",
number = "2",

}

TY - JOUR

T1 - Tumor necrosis factor-alpha polymorphisms in ulcerative colitis-associated colorectal cancer

AU - Garrity-Park, Megan M.

AU - Loftus, Jr, Edward Vincent

AU - Bryant, Sandra C.

AU - Sandborn, William J.

AU - Smyrk, Thomas Christopher

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.

UR - http://www.scopus.com/inward/record.url?scp=39049098562&partnerID=8YFLogxK

UR - http://www.scopus.com/inward/citedby.url?scp=39049098562&partnerID=8YFLogxK

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

VL - 103

SP - 407

EP - 415

JO - American Journal of Gastroenterology

JF - American Journal of Gastroenterology

SN - 0002-9270

IS - 2

ER -