616 Cancer Epidemiology, Biomarkers & Prevention PTGS2 (COX-2) -765G > C Promoter Variant Reduces Risk of Colorectal Adenoma among Nonusers of Nonsteroidal Anti-inflammatory Drugs

Cornelia M. Ulrich,1,2 John Whitton,1 Joon-Ho Yu,1,2 Justin Sibert,1 Rachel Sparks,1 John D. Potter,1,2 and Jeannette Bigler1 1Fred Hutchinson Cancer Research Center and 2Department of Epidemiology, Seattle, Washington

Abstract

Prostaglandin H synthase 2 (PTGS2) or -2 were GC 0.97 (95% CI, 0.65-1.46) and CC 0.24 (95% CI, 0.05- (COX-2) has been shown to play a key role in the regulation 1.11). Risk associated with the À765G > C variant differed of inflammation, and its inhibition is associated with a by or other nonsteroidal anti-inflammatory drug reduced risk of colon cancer. The PTGS2 (COX-2) À765G > (NSAID) use. Among nonusers of aspirin or other NSAIDs, C promoter variant is located in a putative SP1 binding site the CC genotype conferred a significant decrease in risk of and reduces PTGS2 expression. In a Minnesota-based case- adenoma (OR, 0.26; 95% CI, 0.07-0.89). Use of aspirin or control study of cases with adenomatous (n = 494) or other NSAIDs reduced risk of adenoma only among those hyperplastic polyps (n = 186) versus polyp-free controls with the À765GG (wild type) and possibly À765CG (n = 584), we investigated the role of the PTGS2 À765G > C genotypes (OR, 0.66; 95% CI, 0.48-0.92 and OR, 0.64; 95% promoter polymorphism. Multiple logistic regression ana- CI, 0.40-1.02, respectively). These data suggest that COX-2 lysis was used, adjusting for age, body mass index, caloric expression or activity may be beneficially suppressed, and intake, alcohol, fiber, sex, hormone use, and smoking. For risk of colorectal polyps reduced, by aspirin or other colorectal adenoma, odds ratios (OR) compared with PTGS2 NSAIDs in PTGS2 À765GG (wild type) individuals and À765GG as reference were GC 1.00 [95% confidence interval by the À765 CC variant genotype in nonusers of (95% CI), 0.74-1.35] and CC 0.53 (95% CI, 0.22-1.28). For NSAIDs. (Cancer Epidemiol Biomarkers Prev 2005; hyperplastic polyps, the comparable adjusted odds ratios 14(3):616–9)

Introduction

Prostaglandin H synthase (PTGS) or cyclooxygenase (COX) is a No nonsynonymous PTGS2 polymorphisms have yet been key in prostaglandin synthesis. This enzyme is reported among Caucasians (22, 23). A V511A polymorphism, bifunctional; the initial COX reaction converts which occurs at about 5% allele frequency among African to ; subsequently, the peroxidase reaction Americans, has been found to possibly decrease risk of both converts prostaglandin G2 to . Whereas colorectal adenoma and colorectal cancer (24). A common PTGS1 has been generally found to be constitutively expressed polymorphism in the regulatory region of PTGS2 has been and involved in cell- and maintenance of tissue recently described (À765G > C; dbSNP rs20417); it results in , PTGS2 expression occurs in a more limited reduced expression and is also associated with decreased number of cell types and is regulated or induced by specific serum concentrations of C-reactive protein in patients following stimulatory events (1-10). Thus, PTGS2 plays a role in the coronary bypass surgery (25) and reduced risk of myocardial synthesis involved in inflammation and mitogene- infarction and stroke (26). We investigated associations between sis. A possible PTGS3 mRNA has been reported by several the PTGS2 promoter variant and risk of colorectal adenomatous groups, although expression of a functional PTGS3 protein and hyperplastic polyps. Furthermore, we investigated inter- in vivo remains controversial (11-14). actions between the PTGS2 polymorphism and use of aspirin or Whereas PTGS2 expression is low in normal colonic epithe- other nonsteroidal anti-inflammatory drugs (NSAID), poly- lium, its expression is elevated in up to 90% of colon carcinomas morphisms in TGFb1 (a PTGS2 inducer; ref. 27) and PTGS1. and 40% of colon adenoma (15-17). Furthermore, evidence from mouse experiments implicates PTGS2 in colorectal carcinogen- esis (18, 19), potentially through effects on prostaglandin E2 levels (20, 21). Oshima et al. (18) crossed Min mice (carrying an Materials and Methods APC-truncating mutation) with a PTGS2-deficient and showed a substantial reduction in polyps at 10 weeks among the Study Subjects. Participant recruitment for the Minnesota PTGS2À/À compared with PTGS2+/+ Min mice. These results case-control study has been described previously (28). Briefly, provide direct genetic evidence that PTGS2 plays a key role in cases with colorectal adenomatous and/or hyperplastic polyps tumorigenesis at the stage of adenoma formation. 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 Received 7/13/04; revised 9/23/04; accepted 10/1/04. recruited before colonoscopy so as to blind patients and Grant support: Grants R01CA89445 and R01CA59045. recruiters to the final diagnosis. The study was approved by 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. the internal review boards of the University of Minnesota and Section 1734 solely to indicate this fact. each endoscopy site. Written informed consent was obtained. Requests for reprints: Cornelia M. Ulrich, Cancer Prevention Program, Fred Hutchinson Cases were identified as meeting eligibility criteria: resident Cancer Research Center, 1100 Fairview Avenue N, M4-B402, Seattle, WA 98109-1024. Phone: 206-667-7617; Fax: 206-667-7850. E-mail: [email protected] of Twin Cities metropolitan area, English speaking, no known Copyright D 2005 American Association for Cancer Research. genetic syndrome associated with predisposition to colonic

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Table 1. Risk of colorectal adenomatous and hyperplastic Genotyping methods for polymorphisms in PTGS1 (R8W, polyps associated with PTGS2 À765G > C genotype L15-L16del, P17L, and L237M) or TGFb1 (L10P) by our group (multivariate-adjusted ORs) have been published previously (30, 31). Case versus PTGS2 À No. cases/ ORs* Statistical Data Analysis. Logistic regression analysis was polyp-free control 765G > C controls (95% CI) used to estimate odds ratios (OR) and corresponding 95% confidence intervals (95% CI) comparing cases (with adeno- Adenoma GG (wt) 344/405 1.00 (reference) GC (het) 140/159 1.00 (0.74-1.35) matous or hyperplastic polyps) with polyp-free controls in CC (hzv) 10/20 0.53 (0.22-1.28) association with PTGS2 genotypes. Multivariate adjustment by Hyperplastic GG (wt) 136/405 1.00 (reference) previously identified risk factors (age, sex, body mass index, polyps dietary intakes of alcohol, fiber, kilocalories, hormone replace- GC (het) 47/159 0.97 (0.65-1.46) ment therapy, or smoking) was used, because there was some CC (hzv) 3/20 0.24 (0.05-1.11) confounding in the stratified analyses. To evaluate possible NOTE: Abbreviations: wt, wild type; het, heterozygote; hzv, homozygote variant. interactions between the PTGS2 polymorphism and aspirin/ * Sex, age, body mass index, caloric intake, alcohol, fiber, hormone use, and other NSAID use or polymorphisms in TGFb1 or PTGS1, the smoking. 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 neoplasia, no individual history of cancer (except nonmela- Institute, Cary, NC). noma 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 Results colonoscopy. Control subjects were free of polyps during colonoscopy (n = 621). Patients for whom the colonoscopy did Characteristics of the study population and risk factors for not reach the cecum were ineligible; removed polyps were colorectal polyps have been described previously (28, 32-34). examined histologically using standard diagnostic criteria (29). Briefly, adenoma cases were older than individuals with Information on use of aspirin and NSAID, lifestyle factors and hyperplastic polyps or polyp-free controls and more likely to diet, anthropometry, demographics, and medical information, be male. including family history of cancer and polyps, were obtained We investigated the risk of colorectal polyps associated with by questionnaire. Regular, current use of NSAIDS was defined the À765G > C polymorphism in the promoter region of as NSAID use >1/wk versus V1/wk. The participation rate for PTGS2 (variant allele frequency among controls = 0.17). ORs all colonoscoped patients was 68%. associated with the À765C variant are shown in Table 1. Risk of adenoma or hyperplastic polyps did not significantly differ Genotyping. Genomic DNA was extracted from peripheral by genotype, although there was an indication that the WBCs using the Puregene kit (Gentra Systems, Minneapolis, homozygote variant CC genotype may be associated with a MN). The À765G > C polymorphism in the COX-2 promoter reduced risk (adenoma OR, 0.53; 95% CI, 0.22-1.28); hyper- region was genotyped on a 7900HT Sequence Detection System plastic polyps OR 0.24 (95% CI, 0.05-1.11). These associations (Applied Biosystems, Foster City, CA) using a fluorescent allelic did not differ by polyp location (proximal, distal, or rectal) or discrimination assay. Amplification was done in 20-AL reactions polyp size (data not shown). using the Taqman core reagent kit (Applied Biosystems) and Regular aspirin and NSAID use (>1/wk for at least 1 year) minor groove binding probes with nonfluorescent quenchers has been previously identified in this population as associated (Applied Biosystems). The reactions included 4 mmol/L MgCl2, with reduced adenoma risk (age-adjusted OR, 0.70; 95% CI, 200 nmol/L each of amplification primer (forward primer 5V- 0.53-0.92 and sex-adjusted OR, 0.65; 95% CI, 0.53-0.92; ref. 34). CATTAACTATTTACAGGGTAACTGCTTAGG-3Vand reverse We evaluated whether associations with current regular use of primer 5V-TCACCCCCTCCTTGTTTCTTG-3V), 100 nmol/L aspirin or NSAIDs differed depending on PTGS2 genotype wild-type probe (5V6-FAM-TTTACCTTTCCCCCCTCTCTV- (Table 2). The À765 CC genotype was associated with a 3VMGBNFQ), 150 nmol/L variant probe (5VVIC-TTTACCTTT- reduced adenoma risk among nonusers of aspirin or other CCCGCCTCTCT-3V-MGBNFQ), and 5 ng genomic DNA. NSAIDs (OR, 0.26; 95% CI, 0.07-0.89). The inverse association Cycling was 50jC for 2 minutes, 95jC for 10 minutes, and 40 with regular, current use of aspirin or other NSAIDs on risk of cycles of 95jC for 15 seconds, and 60jC for 1 minute. Each plate adenoma was observed only in wild-type (GG; OR, 0.66; 95% contained positive controls for all the genotypes as well as CI, 0.48-0.92) and heterozygous (GC; OR, 0.64; 95% CI, 0.40- negative controls. For quality control purposes, 94 randomly 1.02) individuals. However, no risk reduction was seen among selected samples were genotyped a second time. There were no those with homozygous variant genotype and regular NSAID discrepancies between the two results. The observed genotype use (OR, 0.82; 95% CI, 0.25-2.73). Although these results are frequencies did not deviate from Hardy-Weinberg equilibrium intriguing from a pharmacogenetic perspective, we would like (P > 0.05). to caution that this stratification was based on a relatively

Table 2. PTGS2 À765G > C polymorphism, NSAID use, and colorectal adenoma risk (multivariate-adjusted ORs)

PTGS2 À765G > C genotype Current, regular use of aspirin or other NSAIDs

No Yes

OR* (95% CI) Cases/controls OR* (95% CI) Cases/controls

GG (wt) 1.00 (reference) 217/228 0.66 (0.48-0.92) 127/177 GC (het) 1.02 (0.69-1.51) 90/85 0.64 (0.40-1.02) 59/74 CC (hzv) 0.26 (0.07-0.89) 5/11 0.82 (0.25-2.73) 5/9

NOTE: Abbreviations: wt, wild type; het, heterozygote; hzv, homozygote variant. * Sex, age, body mass index, caloric intake, alcohol, fiber, hormone use, and smoking.

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small number of individuals in the homozygous variant group. The observed interaction between PTGS2 À765G > C and The test for an interaction between regular, current use of NSAID use also agrees with the underlying biology. Our study NSAIDs and homozygous CC genotype versus GG or GC indicates that the reduced expression or activity of PTGS2, genotypes was borderline (P = 0.07). Results were similar either genetically among individuals with a variant À765 CC when only long-term use of aspirin or other NSAIDs was genotype, or pharmacologically by use of NSAIDs, results in a considered and were similar both for aspirin or other NSAIDs reduced risk of colorectal adenomas. No further risk reduction (data not shown). was observed among individuals with the À765 CC genotype To evaluate more comprehensively genetic variability in the who used NSAIDs regularly and who should have presumably prostaglandin synthesis pathway, we investigated gene-gene lowest PTGS2 expression. This finding may be attributable to interactions focusing on polymorphisms in TGFb1 (10L > P) chance, as the confidence intervals were wide. However, our and PTGS1 (R8W, L15-L16del, P17L, and L237M). TGFh1 study may also indicate that an excessive suppression of induces PTGS2 (27); the 10L > P polymorphism in the signal PTGS2 is not beneficial. A recent report of a randomized peptide sequence of the TGFh1 gene has been associated with controlled trial of aspirin chemoprevention on adenoma increased levels of TGFh1 mRNA and protein in individuals recurrence showed a similar U-shaped relationship: low-dose with the variant allele (35-37) and may reduce risk of aspirin (81 mg/d) was associated with a reduced risk of hyperplastic polyps (31). With respect to the PTGS2-TGFh1 adenoma recurrence, whereas a higher dose (325 mg/d) was stratification, we observed a reduced risk of adenoma and not (42). hyperplastic polyps among À765 CC/10LP genotype individ- Our risk estimates associated with the À765 CC genotype uals (adenoma OR, 0.18; 95% CI, 0.04-0.85 and hyperplastic were similar for both adenomatous and hyperplastic polyps. OR, 0.14; 95% CI, 0.02-1.11). PTGS1 polymorphisms are rare, This finding suggests that inflammatory processes play a role yet may increase risk of colorectal adenomas or modify risk early in colorectal carcinogenesis and may affect multiple reductions seen with NSAID use (30). No statistically pathways. Several recent studies suggest that hyperplastic significant interactions between PTGS1 and PTGS2 poly- polyps have substantial heterogeneity and include a subset morphisms were observed. However, in this analysis several with significant malignant potential (43-45). Unfortunately, our genotype groups had to be combined, due to the rarity of the study population lacked specific information regarding path- variant alleles. ologic characteristics, such as the presence of serrated adenomas. Whereas our statistical power for investigations of gene- Discussion gene interactions was limited, there was some indication that the PTGS2 variant is only associated with lower risk among Our study adds to a large body of research that implicates individuals with putatively reduced TGFh levels (10LL or PTGS2 in colorectal carcinogenesis. Previously, a study of 10LP genotypes). Our sample size was insufficient with respect concordantly affected early-onset sibling pairs concluded that to investigating interactions between polymorphisms in variations in the PTGS2 gene were unlikely to be a source of PTGS1 and PTGS2, as several genotype groups had to be individual susceptibility to colon neoplasia in humans (38). combined. Larger studies are needed to understand the However, family-based studies often represent selected high- interplay between genetic susceptibility in prostaglandin risk populations and are limited in their ability to explore synthesis and related regulatory factors. gene-environment interactions. We show here that a common Inflammatory processes seem to play a role in the deve- promoter variant is associated with a marginally reduced risk lopment of various types of cancer in addition to colon cancer. of colorectal adenomatous and hyperplastic polyps, a relation- Epidemiologic evidence is accumulating that aspirin or NSAID ship that was statistically significant among nonusers of use is protective for esophageal and gastric cancer and aspirin or other NSAIDs. The relatively low frequency of the possibly also for cancers of the prostate and lung (46-49). The CC genotype requires larger studies to establish the overall Women’s Health Initiative cohort study showed a strong association between this variant and colorectal neoplasia. inverse association between aspirin use and breast cancer (50), Nevertheless, our findings of a reduced risk are consistent which recently have been supported in a case-control study with hypothesized biological mechanisms: overexpression of (51). Elevated concentrations of C-reactive protein, a hepatic PTGS2 enhances polyp formation and colorectal carcinogene- acute-phase protein that is a marker for inflammatory sis (15-17), and the variant C allele reduces PTGS2 expression processes, may increase colorectal cancer risk (52). Further- and inflammatory response (25). These results may also be more, antiplatelet therapy with aspirin reduces the risks of supported by a recent study by Campa et al. (39) who reported subsequent cardiovascular disease in primary and secondary a nonsignificantly reduced risk of non–small cell lung cancer prevention, acute myocardial infarction and acute occlusive associated with the PTGS2 À765 CC genotype and by similar stroke (53-55). Accordingly, there are many potential applica- reports showing a reduced risk of myocardial infarction or tions for aspirin and other NSAIDs in the primary and stroke (26). Two recent investigations regarding the role of the secondary prevention of chronic diseases. The PTGS2 À765G PTGS2 À765G > C variant in colorectal cancer did not observe > C variant has been associated with reduced C-reactive reduced risks (40, 41). However, both studies had limited protein levels after bypass surgery (25) and, more recently, sample sizes, and Koh et al. combined both heterozygous and with C-reactive protein concentrations among healthy indi- homozygous variant groups. No information on NSAID use viduals (26). Thus, this variant may affect risk of other was available in these studies. Clearly, further studies among conditions, as recently shown for myocardial infarction and larger populations and with relevant exposure assessment are stroke (26). needed for understanding the role of this genetic variant In summary, our study provides evidence that a common during colorectal carcinogenesis. Of interest, variants in the 3V promoter variant in PTGS2 can affect polyp risk, possibly with untranslated region may increase colorectal cancer risk, as also a substantial risk reduction among nonusers of NSAIDs. Our apparent in haplotype analyses (41). Furthermore, studies by findings suggest that NSAID use may not be beneficial for Lin et al. provide support for a risk reduction associated with a colorectal polyp chemoprevention among a genetically defined nonsynonymous PTGS2 (V511A) polymorphism in colorectal subgroup of individuals with already lowered COX-2 levels. carcinogenesis among African Americans (24). These com- These potential pharmacogenetic interactions will need to be bined studies indicate that genetic variability at the PTGS2 elucidated further by genotyping of participants in aspirin locus probably plays a role in carcinogenic processes under chemoprevention trials (42, 56) and may have implications specific conditions or in specific populations. beyond colorectal carcinogenesis.

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Cornelia M. Ulrich, John Whitton, Joon-Ho Yu, et al.

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