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Journal of Clinical Oncology, Vol 24, No 31 (November 1), 2006: pp. 5010-5016 Published by the American Society of Clinical Oncology DOI: 10.1200/JCO.2006.06.4931 Prospective Study of Urinary Prostaglandin E2 Metabolite and Colorectal Cancer Risk
From the Department of Medicine, Center for Epidemiology Research, and Vanderbilt-Ingram Cancer Center; Departments of Medicine and Pharmacology, Vanderbilt University School of Medicine, Vanderbilt University, Nashville, TN; Department of Epidemiology, Shanghai Cancer Institute, Shanghai, China; and the Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD Address reprint requests to Wei Zheng, MD, PhD, Vanderbilt Center for Epidemiology Research, Vanderbilt University School of Medicine, Medical Center North, S-1121, 1161 21st Ave South, Nashville, TN 37232-2587; e-mail: wei.zheng{at}vanderbilt.edu
Purpose: Overexpression of cyclooxygenase-2 (COX-2) has been shown to play a major role in colorectal cancer pathogenesis. However, no human study has directly investigated whether biomarkers of COX-2 overexpression may predict colorectal cancer risk. We evaluated the association of urinary prostaglandin E2 metabolite (PGE-M) levels and colorectal cancer risk Methods: A nested case-control study was conducted within the Shanghai Women's Health Study, in which 74,942 Chinese women ages 40 to 70 years were recruited from 1997 to 2000. Urinary PGE-M in 150 cohort members who developed colorectal cancer during the follow-up were compared with 150 matched controls. Results: The baseline level of urinary PGE-M was more than 50% higher in cases than in controls. The relative risks (RRs) of developing colorectal cancer were elevated from 1.0 to 2.5 (95% CI, 1.1 to 5.8), 4.5 (95% CI, 1.9 to 10.9), and 5.6 (95% CI, 2.4 to 13.5) with increasing quartiles of urinary PGE-M levels (P for trend < .001). The positive association was observed for both colon cancer (RR = 4.9; 95% CI, 1.7 to 14.7 for the highest v lowest quartile; P for trend = .009) and rectal cancer (RR = 7.2; 95% CI, 1.7 to 30.7; P for trend = .048), and for colorectal cancer cases diagnosed in the first 30 months (RR = 7.6; 95% CI, 1.8 to 32.0; P for trend = .035) and subsequent months (RR = 4.4, 95% CI, 1.5 to 13.3; P for trend = .012) of follow-up. Conclusion: Given its strong association with colorectal cancer risk, urinary PGE-M may be a promising biomarker for risk assessment of this common malignancy.
Colorectal cancer is the third most common cancer and the fourth most frequent cause of cancer deaths worldwide.1 The incidence rates of this common cancer are typically higher in developed countries, such as those in Europe and North America, than developing countries.1-3 Cumulative evidence suggests that chronic inflammation plays a role in the pathogenesis of cancer, including colorectal cancer.4-6 Patients with inflammatory bowel diseases (chronic ulcerative colitis and Crohn's disease) are subject to an increased risk of developing colorectal cancer.7-10
Epidemiologic studies have consistently shown a 40% to 50% reduction in colorectal cancer risk associated with the use of nonsteroidal anti-inflammatory drugs (NSAIDs).11-13 Clinical trials have demonstrated that anti-inflammatory agents can reduce the risk of developing adenomatous colon polyps.14-16 The chemopreventive effects of NSAIDs are thought to be largely mediated through their roles in the inhibition of cyclooxygenase-2 (COX-2) and prostaglandin (PG) production.17-19 Other possible mechanisms, such as inhibition of nuclear factor kappa B (NF- Recently, we developed and validated an accurate and precise method to quantify PGE2 production in humans by measuring the major urinary metabolite of PGE2 (PGE-M, 11 alpha-hydroxy-9,15-dioxo-2,3,4,5-tetranor-prostane-1,20-dioic acid).29 In this study, we evaluated the association of urinary PGE-M levels and colorectal cancer risk in the Shanghai Women's Health Study (SWHS), a large population-based, prospective cohort study conducted among Chinese women.
Study Subjects and Materials The detailed methodology for the SWHS has been published elsewhere.30 The study was approved by the institutional review boards of all collaborating institutions. From 1997 to 2000, 74,942 Chinese women between the ages of 40 and 70 years and residing in seven urban communities of Shanghai were recruited onto the cohort study. Each woman signed a consent form at the time of enrollment and completed an in-person survey that included information on medical history and medication use, demographic characteristics, anthropometrics, usual dietary habits, physical activities, and other lifestyle factors. The participation rate for the baseline survey was 92.7%. Of the study participants, 65,754 (87.7%) provided a spot urine sample and 56,831 (75.8%) provided a blood sample. Urine samples were collected into a sterilized cup containing 125 mg ascorbic acid to prevent oxidation of labile metabolites. After collection, the samples were kept in a portable Styrofoam box with ice packs (at approximately 0 to 4°C) and processed within 6 hours for long-term storage at –70°C. At the time of sample procurement, a biospecimen collection form was completed for each woman, which included the date and time of sample collection, time of last meal, and day of last menstruation (for premenopausal women), as well as intake of selected foods, smoking, and use of any medications over the previous 24 hours and during the previous week. The cohort was followed through biennial home visits as well as record linkage to cancer incidence and mortality data collected by the Shanghai Cancer Registry and death certificate data collected by the Shanghai Vital Statistics Unit. In a recent follow-up survey conducted approximately 5 years after the baseline survey, only 1.03% of cohort members could not be contacted in person or through their next of kin. For cohort members who were diagnosed with cancer, medical charts were reviewed to verify the diagnosis, and detailed information on the pathologic characteristics of the cancer was obtained.
The nested case-control study described in this report includes 152 incident colorectal cancer cases that provided a urine sample at baseline and were diagnosed with cancer before February 2003. In the nested case-control study, we included only participants who donated a urine sample before any cancer diagnosis. All lab assays were performed in 2005. The incidence-density method was used for case-control matching. For each case, a control was selected from women who donated a urine sample at baseline and were free of any cancer at the time of cancer diagnosis for the index case. In addition, cases and controls were individually matched on age at baseline (± 2 years), date (
Laboratory Measurements
Statistical Analyses
The distributions of selected baseline demographic characteristics and major risk factors for colorectal cancer cases and matched controls are shown in Table 1. Because of matching, cases and controls were similar in age and menopausal status. Cases and controls were comparable in body mass index, waist-to-hip ratio, total fruit and vegetable intake, and meat intake. Compared with controls, cases were slightly less educated, more likely to have a family history of colorectal cancer, and exercised less regularly. None of the differences, however, were statistically significant. Very few women in this cohort regularly smoked cigarettes, drank alcoholic beverages, or took aspirin or hormone-replacement therapy. The median time interval between colorectal cancer diagnosis and urine sample collection was 30 months (range, 1 to 65 months).
Baseline urinary PGE-M levels were higher among women who subsequently developed colorectal cancer than those who remained cancer-free (P < .001; Table 2; Fig 1). Colorectal cancer cases had 50.5% (geometric mean) or 65.7% (median) higher baseline urinary PGE-M levels than controls. Higher levels of PGE-M were observed for both colon and rectal cancers compared to the controls. Colon cancer and rectal cancer cases had 54.6% (geometric mean) and 44.5% (geometric mean) higher baseline urinary PGE-M levels than controls, respectively.
The RR of developing colorectal cancer increased with increasing levels of urinary PGE-M (Table 3). The RRs were increased from 1.0 to 2.5 (95% CI, 1.1 to 5.8), 4.5 (95% CI, 1.9 to 10.9), and 5.6 (95% CI, 2.4 to 13.5) with increasing urinary PGE-M quartiles, and a significant dose-response association was observed (P for trend < .001). The positive association was observed for both colon and rectal cancer (Table 3). To evaluate the shape of the dose-response relationship, we included nonlinear terms using the restricted cubic spline function with four knots. The risk of colorectal cancer was increased in general as urinary PGE-M levels rose, although curvature was apparent (Fig 2). Tests for nonlinearity, however, were not statistically significant for colon cancer (P = .11) and rectal cancer (P = .36), and were of borderline significance for colorectal cancers combined (P = .07).
Additional analyses were conducted to evaluate colorectal cancer risk by the time interval between urine collection and cancer diagnosis (Table 4). Case subjects were categorized into two strata based on the median cutoff point (30 months) between urine collection and cancer diagnosis. A positive association was found both for cancer diagnosed within 30 months and for cancer diagnosed at more than 30 months after urine collection. The RRs were increased from 1.0 to 2.3, 5.4, and 7.6 with increasing PGE-M quartiles in cancer diagnosed within 30 months, whereas the RRs were increased from 1.0 to 2.9, 3.6, and 4.4 with increasing PGE-M quartiles for cases diagnosed more than 30 months. To evaluate the effect of undiagnosed subclinical colorectal cancer on observed association, we excluded cases diagnosed from the first year of follow-up. The RRs associated with urinary PGE-M increased from 1.0 to 2.8, 3.9, and 11.4 (P for trend = .070) with increasing urinary PGE-M quartiles for cases diagnosed between 13 and 30 months of follow-up. This finding suggests that the elevated baseline urinary PGE-M level among colorectal cancer patients is unlikely to be attributed to PGE-M produced by a subclinical malignancy. The associations were essentially unchanged after adjusting for other potential confounding factors, including other chronic disease conditions and the use of aspirin and herbal medicines.
Using data from a large prospective cohort study, we demonstrated, for the first time, that urinary PGE2 metabolite (PGE-M) levels were strongly associated with the subsequent risk of developing colorectal cancer in a dose-response manner. This finding is consistent with the role of COX-2 overexpression and excessive PG production in colorectal carcinogenesis, and suggests that urinary PGE-M may be a promising biomarker in the risk assessment of colorectal cancer.
The COX-2 enzyme is overexpressed in approximately 90% of colorectal adenocarcinomas and in 40% to 90% of colorectal adenomas.33-35 This enzyme catalyzes the key step in the conversion of arachidonic acid to prostaglandin H2 (PGH2). PGH2, in turn, is the substrate for several tissue-specific prostaglandin synthases that catalyze the formation of several bioactive prostanoids, including PGI2, PGE2, PGF2 It is generally accepted that the most accurate index of endogenous eicosanoid production in humans is the measurement of excreted urinary metabolites.29 The quantity of urinary PGE-M is far greater (by up to 100-fold) than the level of the major urinary metabolites of other PGs and thromboxane, suggesting that the formation of PGE2 exceeds the generation of other eicosanoids in humans.29 We have recently shown that the reductions of urinary PGE-M caused by an intake of selective COX-2 inhibitor or nonspecific COX inhibitor are similar, indicating that a significant component of PGE2 formation, and thus of total PG production in vivo, is COX-2 derived.29 In other words, urinary PGE-M is a useful biomarker for the in vivo level of COX-2 activity. Therefore, the positive association identified in our study for urinary PGE-M levels and colorectal cancer risk could reflect the upregulation of not only PGE2 but also the overall COX-2 pathway in women who subsequently developed colorectal cancer. The population-based prospective cohort study design, extremely high follow-up rates, and the fact that most participants provided a urine sample at baseline minimize the potential selection bias. Although urinary PGE-M levels can be quantified fairly accurately using the liquid chromatography/tandem mass spectrometric method we developed recently, there may be some within-person variation of this biomarker, particularly since urinary PGE-M can be modulated through NSAID use. In the SWHS cohort, however, less than 5% of women took aspirin regularly, and the positive association between urinary PGE-M and colorectal cancer was essentially unchanged after excluding women who reported regular aspirin use. Within-person variations are typically random, which tends to attenuate the association.42 Therefore, the true association between urinary PGE-M and colorectal cancer risk could be stronger than that reported in our report. Urinary PGE-M measured from urine samples collected at different time points could help reduce within-person variations. However, we are not aware of any existing cohort studies that have collected and stored multiple urine samples from a sufficient number of case subjects before cancer diagnosis for the type of investigations described in this report. As with most cohort studies, the SWHS participants were not screened for cancer at baseline. Thus, it is possible that undiagnosed asymptomatic cancer could explain part of the association observed in the early years of follow-up. The association persisted, however, after excluding cases diagnosed in the first 30 months of follow-up. Nevertheless, we are most interested in evaluating a biomarker for cancer risk and therefore a marker that is capable of identifying undiagnosed, asymptomatic cancer could be highly valuable. Some control subjects may have had undiagnosed colorectal cancers or large polyps when the urine samples were collected at baseline. On the basis of the findings of the study, participants with colorectal cancer or large polyps may have an elevated level of urinary PGE-M. The misclassification of cases into the control group would falsely increase the mean urinary PGE-M levels and attenuate the true association. This bias is unlikely to be large because colorectal cancer is still a relatively uncommon cancer in Chinese women, and thus the possibility of undiagnosed cases in the control group is likely to be very small. Furthermore, on the basis of the most recent follow-up data, no controls included in the study were found to have any cancer diagnoses. In summary, using data and urine specimens from a large population-based prospective cohort study, we identified a strong association between urinary PGE-M levels and subsequent diagnosis of colorectal cancer in women. This finding is supported by substantial evidence from in vitro and in vivo experiments indicating the important role of COX-2 and PGE2 in colorectal carcinogenesis. Our study suggests that urinary PGE-M may be a promising biomarker in the risk assessment of colorectal cancer.
The authors indicated no potential conflicts of interest
This study would not have been possible without the support of all of the study participants and research staff of the Shanghai Women's Health Study (SWHS). The SWHS is also supported in part by the Intramural Research Program of the National Institutes of Health (N02 CP1101066).
Supported by National Institutes of Health Grants No. CA70867, CA95103, GM15431, CA77839, DK48831, RR00095, and CA97386. Authors' disclosures of potential conflicts of interest and author contributions are found at the end of this article.
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Copyright © 2006 by the American Society of Clinical Oncology, Online ISSN: 1527-7755. Print ISSN: 0732-183X
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ABSTRACT
INTRODUCTION
B), proxisome proliferator-activated receptor delta (PPAR
), and the Wnt signaling pathway, may also be involved.
30 days) and time (morning or afternoon) of urine collection, interval since last meal (
, PGD2, and TXA2. Cumulative data indicate that PGE2 is one of the PGs most clearly involved in promoting colorectal carcinogenesis. PGE2 has been shown to induce cell proliferation and motility,
