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Cancer Epidemiology Biomarkers & Prevention Vol. 14, 616-619, March 2005
© 2005 American Association for Cancer Research

PTGS2 (COX-2) –765G > C Promoter Variant Reduces Risk of Colorectal Adenoma among Nonusers of Nonsteroidal Anti-inflammatory Drugs

Cornelia M. Ulrich1,2, John Whitton1, Joon-Ho Yu1,2, Justin Sibert1, Rachel Sparks1, John D. Potter1,2 and Jeannette Bigler1

1 Fred Hutchinson Cancer Research Center and 2 Department of Epidemiology, Seattle, Washington

Requests for reprints: Cornelia M. Ulrich, Cancer Prevention Program, Fred Hutchinson Cancer Research Center, 1100 Fairview Avenue N, M4-B402, Seattle, WA 98109-1024. Phone: 206-667-7617; Fax: 206-667-7850. E-mail: nulrich{at}fhcrc.org


   Abstract
Top
 Abstract
Introduction
 Materials and Methods
 Results
 Discussion
 References
 
Prostaglandin H synthase 2 (PTGS2) or cyclooxygenase-2 (COX-2) has been shown to play a key role in the regulation of inflammation, and its inhibition is associated with a reduced risk of colon cancer. The PTGS2 (COX-2) –765G > C promoter variant is located in a putative SP1 binding site and reduces PTGS2 expression. In a Minnesota-based case-control study of cases with adenomatous (n = 494) or hyperplastic polyps (n = 186) versus polyp-free controls (n = 584), we investigated the role of the PTGS2 –765G > C promoter polymorphism. Multiple logistic regression analysis was used, adjusting for age, body mass index, caloric intake, alcohol, fiber, sex, hormone use, and smoking. For colorectal adenoma, odds ratios (OR) compared with PTGS2 –765GG as reference were GC 1.00 [95% confidence interval (95% CI), 0.74-1.35] and CC 0.53 (95% CI, 0.22-1.28). For hyperplastic polyps, the comparable adjusted odds ratios were GC 0.97 (95% CI, 0.65-1.46) and CC 0.24 (95% CI, 0.05-1.11). Risk associated with the –765G > C variant differed by aspirin or other nonsteroidal anti-inflammatory drug (NSAID) use. Among nonusers of aspirin or other NSAIDs, the CC genotype conferred a significant decrease in risk of adenoma (OR, 0.26; 95% CI, 0.07-0.89). Use of aspirin or other NSAIDs reduced risk of adenoma only among those with the –765GG (wild type) and possibly –765CG genotypes (OR, 0.66; 95% CI, 0.48-0.92 and OR, 0.64; 95% CI, 0.40-1.02, respectively). These data suggest that COX-2 expression or activity may be beneficially suppressed, and risk of colorectal polyps reduced, by aspirin or other NSAIDs in PTGS2 –765GG (wild type) individuals and by the –765 CC variant genotype in nonusers of NSAIDs.


   Introduction
Top
 Abstract
 Introduction
Materials and Methods
 Results
 Discussion
 References
 
Prostaglandin H synthase (PTGS) or cycloogenase (COX) is a key enzyme in prostaglandin synthesis. This enzyme is bifunctional; the initial COX reaction converts arachidonic acid to prostaglandin G2; subsequently, the peroxidase reaction converts prostaglandin G2 to prostaglandin H2. Whereas PTGS1 has been generally found to be constitutively expressed and involved in cell-cell signaling and maintenance of tissue homeostasis, PTGS2 expression occurs in a more limited number of cell types and is regulated or induced by specific stimulatory events (1-10). Thus, PTGS2 plays a role in the prostanoid synthesis involved in inflammation and mitogenesis. A possible PTGS3 mRNA has been reported by several groups, although expression of a functional PTGS3 protein in vivo remains controversial (11-14).

Whereas PTGS2 expression is low in normal colonic epithelium, its expression is elevated in up to 90% of colon carcinomas and 40% of colon adenoma (15-17). Furthermore, evidence from mouse experiments implicates PTGS2 in colorectal carcinogenesis (18, 19), potentially through effects on prostaglandin E2 levels (20, 21). Oshima et al. (18) crossed Min mice (carrying an APC-truncating mutation) with a PTGS2-deficient strain and showed a substantial reduction in polyps at 10 weeks among the PTGS2–/– compared with PTGS2+/+ Min mice. These results provide direct genetic evidence that PTGS2 plays a key role in tumorigenesis at the stage of adenoma formation.

No nonsynonymous PTGS2 polymorphisms have yet been reported among Caucasians (22, 23). A V511A polymorphism, which occurs at about 5% allele frequency among African Americans, has been found to possibly decrease risk of both colorectal adenoma and colorectal cancer (24). A common polymorphism in the regulatory region of PTGS2 has been recently described (–765G > C; dbSNP rs20417); it results in reduced gene expression and is also associated with decreased serum concentrations of C-reactive protein in patients following coronary bypass surgery (25) and reduced risk of myocardial infarction and stroke (26). We investigated associations between the PTGS2 promoter variant and risk of colorectal adenomatous and hyperplastic polyps. Furthermore, we investigated interactions between the PTGS2 polymorphism and use of aspirin or other nonsteroidal anti-inflammatory drugs (NSAID), polymorphisms in TGFß1 (a PTGS2 inducer; ref. 27) and PTGS1.


   Materials and Methods
Top
 Abstract
 Introduction
 Materials and Methods
Results
 Discussion
 References
 
Study Subjects
Participant recruitment for the Minnesota case-control study has been described previously (28). Briefly, cases with colorectal adenomatous and/or hyperplastic polyps and polyp-free control subjects were recruited through a large multiclinical private gastroenterology practice in metropolitan Minneapolis. Patients ages 30 to 74 years who were scheduled for a colonoscopy between April 1991 and April 1994 were recruited before colonoscopy so as to blind patients and recruiters to the final diagnosis. The study was approved by the internal review boards of the University of Minnesota and each endoscopy site. Written informed consent was obtained.

Cases were identified as meeting eligibility criteria: resident of Twin Cities metropolitan area, English speaking, no known genetic syndrome associated with predisposition to colonic neoplasia, no individual history of cancer (except nonmelanoma skin cancer), no history of inflammatory bowel disease and having a first diagnosis of colon or rectal adenomatous (n = 521) or hyperplastic polyp (n = 194) at the time of the colonoscopy. Control subjects were free of polyps during colonoscopy (n = 621). Patients for whom the colonoscopy did not reach the cecum were ineligible; removed polyps were examined histologically using standard diagnostic criteria (29). Information on use of aspirin and NSAID, lifestyle factors and diet, anthropometry, demographics, and medical information, including family history of cancer and polyps, were obtained by questionnaire. Regular, current use of NSAIDS was defined as NSAID use >1/wk versus ≤1/wk. The participation rate for all colonoscoped patients was 68%.

Genotyping
Genomic DNA was extracted from peripheral WBCs using the Puregene kit (Gentra Systems, Minneapolis, MN). The –765G > C polymorphism in the COX-2 promoter region was genotyped on a 7900HT Sequence Detection System (Applied Biosystems, Foster City, CA) using a fluorescent allelic discrimination assay. Amplification was done in 20-µL reactions using the Taqman core reagent kit (Applied Biosystems) and minor groove binding probes with nonfluorescent quenchers (Applied Biosystems). The reactions included 4 mmol/L MgCl2, 200 nmol/L each of amplification primer (forward primer 5'-CATTAACTATTTACAGGGTAACTGCTTAGG-3' and reverse primer 5'-TCACCCCCTCCTTGTTTCTTG-3'), 100 nmol/L wild-type probe (5'6-FAM-TTTACCTTTCCCCCCTCTCT'-3'MGBNFQ), 150 nmol/L variant probe (5'VIC-TTTACCTTTCCCGCCTCTCT-3'-MGBNFQ), and 5 ng genomic DNA. Cycling was 50°C for 2 minutes, 95°C for 10 minutes, and 40 cycles of 95°C for 15 seconds, and 60°C for 1 minute. Each plate contained positive controls for all the genotypes as well as negative controls. For quality control purposes, 94 randomly selected samples were genotyped a second time. There were no discrepancies between the two results. The observed genotype frequencies did not deviate from Hardy-Weinberg equilibrium (P > 0.05).

Genotyping methods for polymorphisms in PTGS1 (R8W, L15-L16del, P17L, and L237M) or TGFß1 (L10P) by our group have been published previously (30, 31).

Statistical Data Analysis
Logistic regression analysis was used to estimate odds ratios (OR) and corresponding 95% confidence intervals (95% CI) comparing cases (with adenomatous or hyperplastic polyps) with polyp-free controls in association with PTGS2 genotypes. Multivariate adjustment by previously identified risk factors (age, sex, body mass index, dietary intakes of alcohol, fiber, kilocalories, hormone replacement therapy, or smoking) was used, because there was some confounding in the stratified analyses. To evaluate possible interactions between the PTGS2 polymorphism and aspirin/other NSAID use or polymorphisms in TGFß1 or PTGS1, the respective multiplicative interaction terms were included in the logistic regression models. All statistical tests were two sided and analyses were undertaken with SAS 8.02 (SAS Institute, Cary, NC).


   Results
Top
 Abstract
 Introduction
 Materials and Methods
 Results
Discussion
 References
 
Characteristics of the study population and risk factors for colorectal polyps have been described previously (28, 32-34). Briefly, adenoma cases were older than individuals with hyperplastic polyps or polyp-free controls and more likely to be male.

We investigated the risk of colorectal polyps associated with the –765G > C polymorphism in the promoter region of PTGS2 (variant allele frequency among controls = 0.17). ORs associated with the –765C variant are shown in Table 1. Risk of adenoma or hyperplastic polyps did not significantly differ by genotype, although there was an indication that the homozygote variant CC genotype may be associated with a reduced risk (adenoma OR, 0.53; 95% CI, 0.22-1.28); hyperplastic polyps OR 0.24 (95% CI, 0.05-1.11). These associations did not differ by polyp location (proximal, distal, or rectal) or polyp size (data not shown).


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  		Table 1. Risk of colorectal adenomatous and hyperplastic polyps associated with PTGS2 –765G > C genotype (multivariate-adjusted ORs)

 
Regular aspirin and NSAID use (>1/wk for at least 1 year) has been previously identified in this population as associated with reduced adenoma risk (age-adjusted OR, 0.70; 95% CI, 0.53-0.92 and sex-adjusted OR, 0.65; 95% CI, 0.53-0.92; ref. 34). We evaluated whether associations with current regular use of aspirin or NSAIDs differed depending on PTGS2 genotype (Table 2). The –765 CC genotype was associated with a reduced adenoma risk among nonusers of aspirin or other NSAIDs (OR, 0.26; 95% CI, 0.07-0.89). The inverse association with regular, current use of aspirin or other NSAIDs on risk of adenoma was observed only in wild-type (GG; OR, 0.66; 95% CI, 0.48-0.92) and heterozygous (GC; OR, 0.64; 95% CI, 0.40-1.02) individuals. However, no risk reduction was seen among those with homozygous variant genotype and regular NSAID use (OR, 0.82; 95% CI, 0.25-2.73). Although these results are intriguing from a pharmacogenetic perspective, we would like to caution that this stratification was based on a relatively small number of individuals in the homozygous variant group. The test for an interaction between regular, current use of NSAIDs and homozygous CC genotype versus GG or GC genotypes was borderline (P = 0.07). Results were similar when only long-term use of aspirin or other NSAIDs was considered and were similar both for aspirin or other NSAIDs (data not shown).


View this table:
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  		Table 2. PTGS2 –765G > C polymorphism, NSAID use, and colorectal adenoma risk (multivariate-adjusted ORs)

 
To evaluate more comprehensively genetic variability in the prostaglandin synthesis pathway, we investigated gene-gene interactions focusing on polymorphisms in TGFß1 (10L > P) and PTGS1 (R8W, L15-L16del, P17L, and L237M). TGFß1 induces PTGS2 (27); the 10L > P polymorphism in the signal peptide sequence of the TGFß1 gene has been associated with increased levels of TGFß1 mRNA and protein in individuals with the variant allele (35-37) and may reduce risk of hyperplastic polyps (31). With respect to the PTGS2-TGFß1 stratification, we observed a reduced risk of adenoma and hyperplastic polyps among –765 CC/10LP genotype individuals (adenoma OR, 0.18; 95% CI, 0.04-0.85 and hyperplastic OR, 0.14; 95% CI, 0.02-1.11). PTGS1 polymorphisms are rare, yet may increase risk of colorectal adenomas or modify risk reductions seen with NSAID use (30). No statistically significant interactions between PTGS1 and PTGS2 polymorphisms were observed. However, in this analysis several genotype groups had to be combined, due to the rarity of the variant alleles.


   Discussion
Top
 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
References
 
Our study adds to a large body of research that implicates PTGS2 in colorectal carcinogenesis. Previously, a study of concordantly affected early-onset sibling pairs concluded that variations in the PTGS2 gene were unlikely to be a source of individual susceptibility to colon neoplasia in humans (38). However, family-based studies often represent selected high-risk populations and are limited in their ability to explore gene-environment interactions. We show here that a common promoter variant is associated with a marginally reduced risk of colorectal adenomatous and hyperplastic polyps, a relationship that was statistically significant among nonusers of aspirin or other NSAIDs. The relatively low frequency of the CC genotype requires larger studies to establish the overall association between this variant and colorectal neoplasia. Nevertheless, our findings of a reduced risk are consistent with hypothesized biological mechanisms: overexpression of PTGS2 enhances polyp formation and colorectal carcinogenesis (15-17), and the variant C allele reduces PTGS2 expression and inflammatory response (25). These results may also be supported by a recent study by Campa et al. (39) who reported a nonsignificantly reduced risk of non–small cell lung cancer associated with the PTGS2 –765 CC genotype and by similar reports showing a reduced risk of myocardial infarction or stroke (26). Two recent investigations regarding the role of the PTGS2 –765G > C variant in colorectal cancer did not observe reduced risks (40, 41). However, both studies had limited sample sizes, and Koh et al. combined both heterozygous and homozygous variant groups. No information on NSAID use was available in these studies. Clearly, further studies among larger populations and with relevant exposure assessment are needed for understanding the role of this genetic variant during colorectal carcinogenesis. Of interest, variants in the 3' untranslated region may increase colorectal cancer risk, as also apparent in haplotype analyses (41). Furthermore, studies by Lin et al. provide support for a risk reduction associated with a nonsynonymous PTGS2 (V511A) polymorphism in colorectal carcinogenesis among African Americans (24). These combined studies indicate that genetic variability at the PTGS2 locus probably plays a role in carcinogenic processes under specific conditions or in specific populations.

The observed interaction between PTGS2 –765G > C and NSAID use also agrees with the underlying biology. Our study indicates that the reduced expression or activity of PTGS2, either genetically among individuals with a variant –765 CC genotype, or pharmacologically by use of NSAIDs, results in a reduced risk of colorectal adenomas. No further risk reduction was observed among individuals with the –765 CC genotype who used NSAIDs regularly and who should have presumably lowest PTGS2 expression. This finding may be attributable to chance, as the confidence intervals were wide. However, our study may also indicate that an excessive suppression of PTGS2 is not beneficial. A recent report of a randomized controlled trial of aspirin chemoprevention on adenoma recurrence showed a similar U-shaped relationship: low-dose aspirin (81 mg/d) was associated with a reduced risk of adenoma recurrence, whereas a higher dose (325 mg/d) was not (42).

Our risk estimates associated with the –765 CC genotype were similar for both adenomatous and hyperplastic polyps. This finding suggests that inflammatory processes play a role early in colorectal carcinogenesis and may affect multiple pathways. Several recent studies suggest that hyperplastic polyps have substantial heterogeneity and include a subset with significant malignant potential (43-45). Unfortunately, our study population lacked specific information regarding pathologic characteristics, such as the presence of serrated adenomas.

Whereas our statistical power for investigations of gene-gene interactions was limited, there was some indication that the PTGS2 variant is only associated with lower risk among individuals with putatively reduced TGFß levels (10LL or 10LP genotypes). Our sample size was insufficient with respect to investigating interactions between polymorphisms in PTGS1 and PTGS2, as several genotype groups had to be combined. Larger studies are needed to understand the interplay between genetic susceptibility in prostaglandin synthesis and related regulatory factors.

Inflammatory processes seem to play a role in the development of various types of cancer in addition to colon cancer. Epidemiologic evidence is accumulating that aspirin or NSAID use is protective for esophageal and gastric cancer and possibly also for cancers of the prostate and lung (46-49). The Women's Health Initiative cohort study showed a strong inverse association between aspirin use and breast cancer (50), which recently have been supported in a case-control study (51). Elevated concentrations of C-reactive protein, a hepatic acute-phase protein that is a marker for inflammatory processes, may increase colorectal cancer risk (52). Furthermore, antiplatelet therapy with aspirin reduces the risks of subsequent cardiovascular disease in primary and secondary prevention, acute myocardial infarction and acute occlusive stroke (53-55). Accordingly, there are many potential applications for aspirin and other NSAIDs in the primary and secondary prevention of chronic diseases. The PTGS2 –765G > C variant has been associated with reduced C-reactive protein levels after bypass surgery (25) and, more recently, with C-reactive protein concentrations among healthy individuals (26). Thus, this variant may affect risk of other conditions, as recently shown for myocardial infarction and stroke (26).

In summary, our study provides evidence that a common promoter variant in PTGS2 can affect polyp risk, possibly with a substantial risk reduction among nonusers of NSAIDs. Our findings suggest that NSAID use may not be beneficial for colorectal polyp chemoprevention among a genetically defined subgroup of individuals with already lowered COX-2 levels. These potential pharmacogenetic interactions will need to be elucidated further by genotyping of participants in aspirin chemoprevention trials (42, 56) and may have implications beyond colorectal carcinogenesis.


   Acknowledgments
 
We thank Dr. Richard Kulmacz for advice on the article and Linda Massey for assistance with the figures.


   Footnotes
 
Grant support: Grants R01CA89445 and R01CA59045.

The costs of publication of this article were defrayed in part by the payment of page charges.This article must therefore be hereby marked advertisement in accordance with 18 U.S.C.Section 1734 solely to indicate this fact.

Received 7/13/04; revised 9/23/04; accepted 10/ 1/04.


   References
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 Abstract
 Introduction
 Materials and Methods
 Results
 Discussion
 References
 

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