Genetic variation in 15-hydroxyprostaglandin dehydrogenase and colon cancer susceptibility.

Abstract

BACKGROUND:

15-Hydroxyprostaglandin dehydrogenase (15-PGDH) is a metabolic antagonist of COX-2, catalyzing the degradation of inflammation mediator prostaglandin E2 (PGE2) and other prostanoids. Recent studies have established the 15-PGDH gene as a colon cancer suppressor.

METHODS:

We evaluated 15-PDGH as a colon cancer susceptibility locus in a three-stage design. We first genotyped 102 single-nucleotide polymorphisms (SNPs) in the 15-PGDH gene, spanning ∼50 kb up and down-stream of the coding region, in 464 colon cancer cases and 393 population controls. We then genotyped the same SNPs, and also assayed the expression levels of 15-PGDH in colon tissues from 69 independent patients for whom colon tissue and paired germline DNA samples were available. In the final stage 3, we genotyped the 9 most promising SNPs from stages 1 and 2 in an independent sample of 525 cases and 816 controls (stage 3).

RESULTS:

In the first two stages, three SNPs (rs1365611, rs6844282 and rs2332897) were statistically significant (p<0.05) in combined analysis of association with risk of colon cancer and of association with 15-PGDH expression, after adjustment for multiple testing. For one additional SNP, rs2555639, the T allele showed increased cancer risk and decreased 15-PGDH expression, but just missed statistical significance (p-adjusted = 0.063). In stage 3, rs2555639 alone showed evidence of association with an odds ratio (TT compared to CC) of 1.50 (95% CI = 1.05-2.15, p = 0.026).

CONCLUSIONS:

Our data suggest that the rs2555639 T allele is associated with increased risk of colon cancer, and that carriers of this risk allele exhibit decreased expression of 15-PGDH in the colon.

• Authors: Cheryl L Thompson, Stephen P Fink, James D Lutterbaugh, Robert C Elston, Martina L Veigl, Sanford D Markowitz, Li Li
• Journal: PloS one (PLoS One) Vol. 8 Issue 5 Pg. e64122 ( 2013) ISSN: 1932-6203 [Electronic] United States
• PMID: 23717544 (Publication Type: Journal Article, Meta-Analysis, Research Support, N.I.H., Extramural)

Chemical References

• Hydroxyprostaglandin Dehydrogenases
• 15-hydroxyprostaglandin dehydrogenase

Topics

• Alleles
• Case-Control Studies
• Colonic Neoplasms (genetics)
• Female
• Genetic Predisposition to Disease (genetics)
• Genotype
• Humans
• Hydroxyprostaglandin Dehydrogenases (genetics)
• Male
• Middle Aged
• Polymorphism, Single Nucleotide (genetics)
• Risk