Decreased Risk Of Colorectal Cancer Research Articles

Abstract 4820: Habitual intake of total flavonoids and flavonoid subclasses and risk of colorectal cancer in men and women.

Abstract Background: Flavonoids inhibit the growth of colon cancer cells in vitro. In a recent randomized controlled trial, the Polyp Prevention Trial, a higher intake of one sub-class, flavonols, was significantly associated with a 76% reduced risk of recurrent advanced adenoma. Cohort studies that have examined the association between flavonoid intake and risk of colorectal cancer (CRC) have yielded inconsistent results, but most previous studies only evaluated habitual intake of a limited number of subclasses and there is growing evidence for differential effects depending on subtle difference in structure between the sub-classes Objective: To examine whether higher habitual dietary intake of total flavonoids and their subclasses (flavanones, anthocyanins, flavan-3-ols, flavonols, flavones and polymers) are associated with lower risk of CRC. Methods: Using data from validated food frequency questionnaires administered every four years and an updated USDA flavonoid food composition database flavonoid intakes were calculated for 73,666 participants from the Nurses’ Health Study I, and for 32,059 participants from the Health Professionals Follow-up Study. Results: During 16 years of follow-up, 1,405 colorectal cancer cases (652 in men, 753 in women) were identified. Intakes of total flavonoids and subclasses were not associated with risk of CRC (hazard ratios (95% confidence interval) multivariable adjusted for age, smoking before age 30, family history of colorectal cancer, history of endoscopy, aspirin use, body mass index, physical activity, postmenopausal hormone use in women, alcohol consumption, intake of total energy, calcium and vitamin D; highest vs. lowest quintile: total flavonoids, men: 0.97 (0.75-1.26), women: 1.00 (0.80-1.26); flavonols, men: 0.98 (0.76-1.26), women: 1.21 (0.96-1.52); flavones, men: 0.86 (0.67-1.11), women: 0.90 (0.72-1.13); flavanones, men: 0.98 (0.75-1.28), women: 1.00 (0.80-1.26); flavan-3-ols, men: 1.00 (0.78-1.29), women: 0.96 (0.76-1.21); anthocyanins, men: 0.89 (0.69-1.15), women: 1.25 (0.98-1.60); polymers, men: 0.92 (0.71-1.18), women: 0.88 (0.69-1.11)). Conclusion: Our findings do not provide support for the hypothesis that a higher intake of flavonoids or any specific sub-class decrease risk of CRC. Citation Format: Katharina Nimptsch, Xuehong Zhang, Edward Giovannucci, Aedin Cassidy, Éilis J. O'Reilly, Tobias Pischon, Eric B. Rimm, Jennifer Lin, Walter C. Willett, Charles S. Fuchs, Kana Wu. Habitual intake of total flavonoids and flavonoid subclasses and risk of colorectal cancer in men and women. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 4820. doi:10.1158/1538-7445.AM2013-4820

The effect of copy number variation in the phase II detoxification genes UGT2B17 and UGT2B28 on colorectal cancer risk

Genetic polymorphisms in combination with the Western-style diet, physical inactivity, smoking, excessive alcohol consumption, and obesity have been hypothesized to affect colorectal cancer (CRC) risk. Metabolizers of environmental carcinogenic and endogenous compounds affecting CRC risk include the phase II detoxification UDP-glucuronosyltransferase (UGT) enzymes UGT2B17 and UGT2B28, which are 2 of the most commonly deleted genes in the genome. To study the effect of UGT2B17 and UGT2B28 copy number variation (CNV) on CRC risk, 665 Caucasian CRC cases and 621 Caucasian controls were genotyped who had completed extensive demographics and lifestyle questionnaires. A significant association between the UGT2B17 deletion genotype (0/0) and decreased CRC risk was found when the entire population was analyzed (P = .044). Stratification by sex yielded a decreased risk (P = .020) in men with the UGT2B17 deletion (0/0), but no association was observed in women (P = .724). A significant association between UGT2B17 (0/0) and decreased risk for rectal (P = .0065) but not colon cancer was found. No significant association was found between UGT2B28 CNV and CRC risk. The UGT2B17 deletion genotype (0/0) was associated with a decreased CRC risk in a Caucasian population. After sex stratification, the association was observed in men but not in women, which is consistent with previous findings that men have higher UGT2B17 expression and activity than women. Because UGT2B17 metabolizes certain nonsteroidal anti-inflammatory drugs and flavonoids with antioxidative properties, individuals with a gene deletion may have higher levels of these protective dietary components.

The mTOR Pathway and the Role of Energy Balance Throughout Life in Colorectal Cancer Etiology and Prognosis: Unravelling Mechanisms Through a Multidimensional Molecular Epidemiologic Approach

Timing of exposure to lifestyle factors that influence energy balance may differentially affect colorectal cancer (CRC) risk and prognosis. Caloric restriction in youth and short stature, as markers of early-life exposures, have shown to decrease CRC risk, whereas large body size and low physical activity levels in adulthood are established risk factors for CRC. Regarding prognosis, overweight, sarcopenia, and their co-occurrence (sarcopenic obesity) may negatively influence the health and quality of life of CRC survivors. There is mechanistic support for disruption of the mammalian target of rapamycin (mTOR) pathway as an underlying mechanism possibly driving these associations, because mTOR integrates signals from growth factors, nutrients, mutagens, and hormones to induce cell proliferation, resistance to apoptosis, and autophagy. However, epidemiologic evidence connecting mTOR to energy-balance-related CRC throughout the lifespan is scarce. This perspective proposes how multidimensional molecular epidemiologic studies can shed light on the etiology and prognosis of energy-balance-related CRC.

Systematic Review and Meta-Analysis of the Relationship between EPHX1 Polymorphisms and Colorectal Cancer Risk

BackgroundMicrosomal epoxide hydrolase (EPHX1) plays an important role in both the activation and detoxification of PAHs, which are carcinogens found in cooked meat and tobacco smoking. Polymorphisms at exons 3 and 4 of the EPHX1 gene have been reported to be associated with variations in EPHX1 activity. The aim of this study is to quantitatively summarize the relationship between EPHX1 polymorphisms and colorectal cancer (CRC) risk.MethodsTwo investigators independently searched the Medline, Embase, CNKI, and Chinese Biomedicine Databases for studies published before June 2012. Summary odds ratios (ORs) and 95% confidence intervals (CIs) for EPHX1 Tyr113His (rs1051740) and His139Arg (rs2234922) polymorphisms and CRC were calculated in a fixed-effects model and a random-effects model when appropriate.ResultsThis meta-analysis yielded 14 case-control studies, which included 13 studies for Tyr113His (6395 cases and 7893 controls) and 13 studies for His139Arg polymorphisms (5375 cases and 6962 controls). Overall, the pooled results indicated that EPHX1 Tyr113His polymorphism was not associated with CRC risk; while the His139Arg polymorphism was significantly associated with decreased CRC risk (Arg/His vs. His/His, OR = 0.90, 95%CI = 0.83–0.98; dominant model, OR = 0.92, 95%CI = 0.85–0.99). The statistically significant association between EPHX1 His139Arg polymorphism and CRC was observed among Caucasians and population-based case-control studies. This association showed little heterogeneity and remained consistently strong when analyses were limited to studies in which genotype frequencies were in Hardy–Weinberg equilibrium, or limited to studies with matched controls. When cumulative meta-analyses of the two associations were conducted by studies’ publication time, the results were persistent and robust.ConclusionThis meta-analysis suggests that EPHX1 Tyr113His polymorphism may be not associated with CRC development; while the EPHX1 His139Arg polymorphism may have a potential protective effect on CRC.

Quantitative assessment of the association between MTHFR C677T polymorphism and colorectal cancer risk in East Asians

A great number of studies regarding the association between MTHFR C677T polymorphism and risk of colorectal cancer (CRC) in East Asians were published, but the results were inconsistent. Thus, a meta-analysis was performed to investigate the association. PubMed, Embase, and CBM databases were searched for eligible publications. Pooled odds ratios (ORs) with 95 % confidence intervals (95 % CIs) were calculated using random or fixed effect models. Finally, 24 case-control studies with a total of 7,230 CRC cases and 9,285 controls were included. Meta-analyses of a total of 24 studies showed there was a statistically significant association between MTHFR C677T polymorphism and decreased CRC risk in East Asians under four genetic models (T versus C, OR = 0.92, 95 % CI 0.85-0.99; TT versus CC, OR = 0.80, 95 % CI 0.69-0.94; TT versus CT/CC, OR = 0.82, 95 % CI 0.71-0.95; TT/CT versus CC, OR = 0.92, 95 % CI 0.86-0.98). The cumulative meta-analyses for the allele contrast (T versus C), homozygote (TT versus CC), dominant (TT/CT versus CC), and recessive (TT versus CT/CC) models all showed a trend of more obvious association as information accumulated by year. Subgroup analyses by country further identified this association in Korea and Japan. This meta-analysis suggests that MTHFR C677T polymorphism is associated with decreased risk of colorectal cancer in East Asians, and MTHFR 677T variant has a protective effect on colorectal cancer.

Subsite-specific colorectal cancer risk in the colorectal endoscopy era

Colorectal endoscopy (sigmoidoscopy and colonoscopy) is thought to reduce colorectal cancer (CRC) risk. Since the 1980s, its use has increased in the United States, which may be a reason for decreasing CRC incidence rates. To investigate the plausibility of a contribution of colorectal endoscopy use to the decrease in CRC risk. Descriptive analysis of temporal trends. U.S. population from 1978 to 2007. Using incidence data from the Surveillance, Epidemiology and End Results Program, we assessed the subsite-specific cumulative risk of CRC developing until age 79 years. The cumulative risk of proximal CRC remained relatively stable over the observation period, varying between 2.09% (95% CI, 2.06%-2.11%) and 2.66% (95% CI,2.62%-2.69%) for men and between 1.90% (95% CI, 1.88%-1.93%) and 2.24% (95% CI, 2.21%-2.27%) for women. By contrast, the cumulative risk of distal CRC decreased from 4.68% (95% CI, 4.64%-4.73%) to 3.03% (95% CI, 3.00%-3.06%) for men and from 3.15% (95% CI, 3.11%-3.18%) to 1.93% (95% CI, 1.91%-1.95%) for women, which was largely attributable to the reduced cumulative risk of cancer in the sigmoid colon. The observed pattern was restricted to the population aged 50 to 79 years, whereas the magnitude of the decrease was greater for older age groups and similar across stages. The study is based on aggregated registry data only; therefore, no inferences about causal effects can be drawn. The results show a major reduction of CRC risk, particularly in the sigmoid colon. Increased use of colorectal endoscopy in the population aged 50 years and older along with environmental factors may have contributed to the decreasing risk.

Genetic variants within ultraconserved elements and susceptibility to right- and left-sided colorectal adenocarcinoma

We investigated whether single nucleotide polymorphisms within ultraconserved elements (UCEs) are associated with susceptibility to overall colorectal cancer (CRC) and susceptibility to tumor site-specific CRC. The study included 787 CRC patients and 551 healthy controls. The study comprised of a training set (520 cases and 341 controls) and a replication set (267 cases and 210 controls). We observed associations in rs7849 and rs1399685 with CRC risk. For example, a dose-dependent trend (per-allele odds ratio (OR), 0.78; 95% confidence interval (CI), 0.63-1.00; P for trend = 0.05) associated with the variant allele of rs7849 in the training set. The significant trend toward a decrease in CRC risk was confirmed in the replication set (per-allele OR, 0.72; 95% CI, 0.52-0.99; P for trend = 0.044). When stratified by tumor location, for left-sided CRC (LCRC) risk, significant association was observed for the variant-containing genotypes of rs1399685 (OR, 1.77; 95% CI, 1.02-3.06) and the risk was replicated in the replication population (OR, 2.04; 95% CI, 1.02-4.07). The variant genotypes of rs9784100 and rs7849 conferred decreased risk but the associations were not replicated. Three right-sided CRC (RCRC) susceptibility loci were identified in rs6124509, rs4243289 and rs12218935 but none of the loci was replicated. Joint effects and potential higher order gene-gene interactions among significant variants further categorized patients into different risk groups. Our results strongly suggest that several genetic variants in the UCEs may contribute to CRC susceptibility, individually and jointly, and that different genetic etiology may be involved in RCRC and LCRC.

Impact of colonoscopic screening in male and female Lynch syndrome carriers with an MSH2 mutation

The lifetime risk of developing colorectal cancer (CRC) in Lynch syndrome (LS) carriers is very high. To determine the impact of colonoscopic screening in 54 male and 98 female MSH2 mutation carriers, outcomes were compared with 94 males and 76 females who were not screened. CRC incidence and survival in the screened group were compared to that expected, derived from the non-screened group. To correct for survivor bias, controls were matched for age at entry into screening and also for gender. In males, median age to CRC was 58 years, whereas expected was 47 years (p = 0.000), and median survival was 66 years vs 62 years (p = 0.034). In screened females, median age to CRC was 79 years compared to 57 years in the non-screened group (p = 0.000), and median survival was 80 years compared with expected of 63 years (p = 0.001). Twenty percent of males and 7% of females developed an interval CRC within 2 years of previous colonoscopy. Although colonoscopic screening was associated with decreased CRC risk and better survival, CRCs continued to occur. CRC development may be further reduced by decreasing the screening interval to 1 year and improving quality of colonoscopy.

E-cadherin (CDH1) gene promoter polymorphism and the risk of colorectal cancer

Published data on the relationship between E-cadherin (CDH1) gene promoter polymorphisms and colorectal cancer (CRC) risk are inconclusive. To derive a more precise estimation of the relationship, a meta-analysis was carried out. In this meta-analysis, we evaluated reported studies of associations between polymorphisms of CDH1 gene promoter -160 C > A and -347 G > GA site, and CRC risk using fixed-effects model and random-effects model. We found decreased CRC risk among subjects carrying CDH1 -160AA (odds ratio [OR] = 0.86, 95 percent confidence interval [95% CI]: 0.75-0.98) and CA + AA (OR = 0.92, 95% CI: 0.87-0.98), using 4,652/4,428 cases/controls and 7,866/7,689 cases/controls from ten studies, respectively. We found a protective effect of the CDH1 -160CA + AA polymorphisms for CRC in distal site tumor population and population-based control in stratified analysis. We found a protective effect of the CDH1 -160AA and CA + AA polymorphisms for CRC in European and American population (OR = 0.87, 95% CI: 0.76-0.99 and OR = 0.91, 95% CI: 0.85-0.98, respectively). We observed that the CDH1 -347 G/GA + GA/GA carrier had an increased risk of CRC, the summary OR was 1.33 (95% CI: 1.08-1.62). Data indicated that certain CDH1 gene promoter -160 C > A and -347 G > GA variants might affect the susceptibility of CRC. Recommendations for further studies include pooling of individual data to facilitate evaluation of multigenic effects and detailed analysis of effect modification by environmental and lifestyle factors.

Yogurt consumption and risk of colorectal cancer in the Italian European prospective investigation into cancer and nutrition cohort

Fermented dairy products like yogurt have been suggested to protect against colorectal cancer (CRC). We conducted a prospective study on 45,241 (14,178 men; 31,063 women) volunteers of the EPIC-Italy cohort who completed a dietary questionnaire including specific questions on yogurt intake. During 12 years of follow-up, 289 volunteers were diagnosed with CRC. Hazard ratios (HRs) for the disease and 95% confidence intervals (CIs) were estimated by Cox proportional hazard models, stratified by dietary questionnaire and adjusted for energy intake and other potential confounders. Yogurt intake was inversely associated with CRC risk. For the energy-adjusted model, HR for CRC in the highest versus lowest tertile of yogurt intake was 0.62 (95% CI, 0.46-0.83). In the full model adjusted for energy, simple sugar, calcium, fiber, animal fat, alcohol and red meat intake, as well as body mass index, smoking, education and physical activity, HR was 0.65 (95% CI, 0.48-0.89) in the highest versus lowest tertile. The protective effect of yogurt was evident in the entire cohort, but was stronger in men, although there was no interaction of sex with the yogurt-CRC association (p(interaction) 0.20, fully adjusted model). In our prospective study, high yogurt intake was significantly associated with decreased CRC risk, suggesting that yogurt should be part of a diet to prevent the disease. Investigation of larger cohorts is necessary to reveal any residual confounding of the association of yogurt intake with CRC risk.

P1-507 Polymorphisms in genes related to sex steroid transport and signalling modulate menopausal hormone therapy effect on risk of colorectal cancer

IntroductionMenopausal hormone therapy (MHT) has been associated with reduced colorectal cancer (CRC) risk. Since the underlying biological mechanisms of MHT effects on CRC are unknown, we investigated whether single nucleotide...

The effect of estrogen vs. combined estrogen‐progestogen therapy on the risk of colorectal cancer

Studies suggest that estrogen therapy (ET) and combined estrogen-progestogen therapy (EPT) may have different associations with colorectal cancer (CRC) risk, but data are conflicting. Prior meta-analyses did not distinguish between ET and EPT. We conducted a meta-analysis to summarize the relative risks (RR) of CRC due to ET versus EPT among peri- or postmenopausal women. From a total of 2,661 articles, four randomized controlled trials, eight cohort and eight case-control studies were included. Variables assessed included study characteristics, duration and recency of menopausal hormone therapy (HT) use, method of assessment of HT use, outcome definition and its ascertainment method. RRs were synthesized by random-effects models. We found that EPT ever use was associated with a decreased risk of CRC (RR 0.74, 95% CI 0.68-0.81), and so was ET ever use (RR 0.79, 95% CI 0.69-0.91). While current use of ET was associated with a significantly reduced risk of CRC (RR 0.70, 95% CI 0.57-0.85), former use was not (RR 0.86, 95%CI 0.67-1.11). Recency did not significantly modify the association between EPT and CRC risk. EPT former use was associated with a lower RR of CRC compared to ET former use (p = 0.008) but no such difference was observed between EPT and ET current use (p = 0.12). Overall, we found consistent evidence supporting the association between EPT and CRC risk reduction, regardless of recency. While literature for the association between ET and CRC risk is heterogeneous, our analyses suggest only current use of ET is associated with a decreased CRC risk.

Abstract 2994: Constitutional telomere length correlates with colorectal cancer (CRC), but varies by age of cancer onset

Abstract Introduction: Short constitutional telomere length is associated with aging and cancer, but the correlation of telomere length and age at diagnosis of CRC has not been evaluated. Methods: We measured telomere length using quantitative PCR of peripheral blood leukocyte DNA in 1026 individuals diagnosed with MSS CRC who were ≤60 years of age and were chemo-radiotherapy naïve at the time of blood draw. We compared telomere length with 1972 unrelated healthy controls who were frequency matched for gender and age at time of blood collection. We used constructed percentiles of telomere length using the data from the controls. Results: Overall, regardless of cancer status, there was a weak negative correlation of telomere length with age such that as age increased telomere length decreased (Pearson correlation coefficient =−0.1, p< 0.0001); and men had shorter telomeres than women (p=0.0002). The odds ratio (OR) for MSS CRC increased with longer telomere length (OR 1.62 [CI: 1.31-1.99] for those with telomere lengths in the 90th percentile compared to those with telomere lengths in the 50th percentile. In multivariate analysis with adjustment for gender, BMI, smoking, alcohol, and diabetes, telomere length remained an independent risk factor for CRC (p< 0.001), with interaction between telomere length and age (≤50, longer telomeres increased CRC risk; > 50 years old, increasing telomere length associated with decreased CRC risk). Risk was higher for MSS CRC ≤50 years for patients with telomere lengths in the 90th percentile compared to those in the 50th percentile (OR 2.31; CI:1.65-3.23). For subjects diagnosed 50-60 yrs, longer telomere length was associated with lower risk of CRC, and shorter telomere length was associated with the development of CRC (OR 1.22 for telomere lengths in the 10th percentile compared to those in the 50th percentile (OR 1.22:CI; 1.05-1.43). Conclusion: Telomere dynamics appear to influence MSS CRC risk and may differ on the basis of age of cancer diagnosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 2994. doi:10.1158/1538-7445.AM2011-2994

Abstract A59: Prospective analysis of the association between use of statins or other lipid-lowering agents and colorectal cancer risk

Abstract Background: Experimental and epidemiologic data suggest that 3-hydroxy-3-methylglutaryl coenzyme A inhibitors (statins) have antitumor activity against colorectal cancer (CRC). We utilized data from the population-based Women's Health Initiative (WHI) cohort to assess whether statins are associated with a decreased risk of CRC. Methods: The study population included 159,219 postmenopausal women ages 50-79 at baseline, in which 2,000 cases of CRC were identified over an average of 10.7 (2.9) years of follow-up. All cases of CRC were confirmed by review of medical records and pathology reports. Participants were asked to bring all current medications to their screening interviews and clinic staff entered information on statin use and other lipid lowering medications into the WHI database. Self- and interviewer-administered questionnaires were used to collect information on other CRC risk factors. Cox proportional hazards regression was used to calculate hazard ratios (HRs) with 95% confidence intervals (CIs). Analyses investigated the association of any statin use, type of statin, statin potency, and duration of use with CRC. Statistical tests were two-sided. Results: Statins were used by 12,030 (7.6%) women in the cohort. The annualized rate of CRC was 0.13% among statin users and 0.12% among nonusers. The multivariable adjusted HR for statin users compared with nonusers was 0.99 (95% CI=0.83 to 1.20, p=0.95). There was no trend in risk of CRC by duration of statin use, with HR = 0.91 (95% CI=0.66 to 1.27) for < 1 years of use, HR = 1.28 (95% CI=0.97 to 1.68) for 1- < 3 years of use, and HR =0.79 (95% CI=0.56 to 1.11) for > 3 years of use. There was no relationship between type of statin use, statin potency (low, medium and high), or use of other lipid-lowering medications and CRC risk. In addition there was no relationship between statin use and tumor location (proximal, distal and rectal), or clinical features (tumor stage, grade or histology). Conclusions: Statin use was not associated with a decrease in CRC risk in the WHI cohort. Citation Information: Cancer Prev Res 2010;3(12 Suppl):A59.

Effect of aspirin and NSAIDs on risk and survival from colorectal cancer

BackgroundPrevious studies have shown that aspirin and other non-steroidal anti-inflammatory drugs (NSAIDs) lower colorectal cancer (CRC) risk. However, the lowest effective NSAID dose, treatment duration, and effects on survival are...

A Candidate Gene Study of Folate-Associated One Carbon Metabolism Genes and Colorectal Cancer Risk

Folate-associated one-carbon metabolism (FOCM) may play an important role in colorectal carcinogenesis. Variation in FOCM genes may explain some of the underlying risk of colorectal cancer. This study utilized data from 1,805 population-based colorectal cancer cases and 2,878 matched sibling controls from the Colon Cancer Family Registry. We used a comprehensive haplotype tagging single nucleotide polymorphism (tagSNP) approach to select 395 tagSNPs in 15 genes involved in folate and vitamin B(12) metabolism. Genotyping was done using the Illumina GoldenGate or Sequenom platforms. Risk factor and dietary data were collected using self-completed questionnaires. Microsatellite instability (MSI) status was determined using standard techniques, and tumor subsite was obtained from pathology reports. The association between SNPs and colorectal cancer was assessed using conditional logistic regression with sibships as the matching factor and assuming a log additive or codominant model. In the log additive model, two linked (r(2) = 0.99) tagSNPs in the DHFR gene (rs1677693 and rs1643659) were associated with a significant decrease in colorectal cancer risk after correction for multiple testing (odds ratio, 0.87; 95% confidence interval, 0.71-0.94; P = 0.029; and odds ratio, 0.87; 95% confidence interval, 0.71-0.95; P = 0.034 for rs1677693 and rs1643659, respectively). These two linked (r(2) = 0.99) tagSNPs and one tagSNP in the MTR gene (rs4659744) were significantly associated with reduced colorectal cancer risk only among individuals not using multivitamin supplements. Overall, we found only moderate evidence that genetic variation in 15 folate pathway genes may affect colorectal cancer risk except in non-multivitamin users. This study suggests that multivitamin supplement use may modify the association between folate pathway genes and colorectal cancer risk in a post-folic-acid-supplemented population.

The effect of opposed versus unopposed hormone replacement therapy (HRT) on the risk of colorectal cancer (CRC).

3619 Background: Separate studies suggest that estrogen alone (E) versus estrogen plus progesterone (EP) may have different effects on CRC risk, but data are conflicting. Prior meta-analyses did not address the role of opposed versus unopposed HRT specifically. We conducted a meta-analysis to summarize the relative risks (RR) of CRC due to E versus EP. Methods: From a total of 2,317 articles identified from PubMed and EMBASE, 5 randomized controlled trials (RCTs) and 13 observational studies were eligible for analyses. We considered these variables: study year/size/design/population, duration and recency of HRT use, method of exposure assessment, and outcome definition and ascertainment. RR were synthesized by random-effects models. Results: E was associated with a marginally significant decreased risk of CRC (RR 0.88, 95% CI 0.78-1.00). Adding progesterone significantly strengthened this association (RR 0.74, 0.67-0.82, p value for the difference between E and EP = 0.01). We found significant heterogeneity for E, but not for EP studies. Several factors were predictive of lower RR in the E arm and can potentially explain the heterogeneity, including current use, case-control design, and HRT exposure assessed by self-report (see Table). Recency was less important for the association between EP and CRC risk. Conclusions: There is consistent evidence supporting the association between EP and CRC risk reduction. While literature for the effect of E on CRC risk is inconclusive, our analyses suggest only current use of E is associated with a decreased CRC risk. HRT Variable Subgroups No. Pooled estimates Heterogeneity p values Meta-regression p values HRT E 12 0.88 (0.78-1.00) 0.003 0.01 EP 16 0.74 (0.67-0.82) 0.58 E Design RCT 1 1.08 (0.75-1.55) N/A <0.01 Cohort 4 0.99 (0.81-1.2) 0.14 <0.01 Case-control 6 0.76 (0.62-0.92) 0.01 Ref Recency Current user 3 0.73 (0.54-0.98) 0.03 <0.01 Former user 3 0.93 (0.62-1.41) 0.04 HRT assessed by self-report Yes 6 0.78 (0.63-0.97) 0.001 0.03 No 6 0.96 (0.84-1.09) 0.22 EP Design RCT 4 0.73 (0.57-0.94) 0.49 0.78 Cohort 5 0.76 (0.64-0.9) 0.33 0.85 Case-control 6 0.74 (0.63-0.87) 0.75 Ref Recency Current user 3 0.77 (0.57-1.04) 0.38 0.47 Former user 3 0.64 (0.46-0.89) 0.99 No significant financial relationships to disclose.

Plasma Folate, Related Genetic Variants, and Colorectal Cancer Risk in EPIC

A potential dual role of folate in colorectal cancer (CRC) is currently subject to debate. We investigate the associations between plasma folate, several relevant folate-related polymorphisms, and CRC risk within the large European Prospective Investigation into Cancer and Nutrition cohort. In this nested case-control study, 1,367 incident CRC cases were matched to 2,325 controls for study center, age, and sex. Risk ratios (RR) were estimated with conditional logistic regression and adjusted for smoking, education, physical activity, and intake of alcohol and fiber. Overall analyses did not reveal associations of plasma folate with CRC. The RR (95% confidence interval; Ptrend) for the fifth versus the first quintile of folate status was 0.94 (0.74-1.20; 0.44). The polymorphisms MTHFR677C-->T, MTHFR1298A-->C, MTR2756A-->G, MTRR66A-->G, and MTHFD11958G-->A were not associated with CRC risk. However, in individuals with the lowest plasma folate concentrations, the MTHFR 677TT genotype showed a statistically nonsignificant increased CRC risk [RR (95% CI; Ptrend) TT versus CC=1.39 (0.87-2.21); 0.12], whereas those with the highest folate concentrations showed a nonsignificant decreased CRC risk [RR TT versus CC=0.74 (0.39-1.37); 0.34]. The SLC19A180G-->A showed a positive association with CRC risk [RR AA versus GG 1.30 (1.06-1.59); <0.01]. This large European prospective multicenter study did not show an association of CRC risk with plasma folate status nor with MTHFR polymorphisms. Findings of the present study tend to weaken the evidence that folate plays an important role in CRC carcinogenesis. However, larger sample sizes are needed to adequately address potential gene-environment interactions.

Ornithine decarboxylase G316A genotype and colorectal cancer risk

Ornithine decarboxylase (ODC) is a modifier of adenomatous polyposis coli-dependent tumourigenesis. The G316 > A polymorphism in intron 1 of the ODC gene lies between two myc-binding domains and alters the expression of the gene to affect polyamine metabolism. This variant may be associated with recurrence of colorectal adenoma. We examined whether this variant also modified the susceptibility to sporadic colorectal cancer (CRC). The G316 > A variant was analysed in a large (n = 754) CRC case-controlled series of hospital patient volunteers (n = 627) in the Czech Republic, and the relationship with cancer risk was estimated by conditional logistic regression. After adjusting for age and sex, G316 > A was associated with no decrease in CRC risk for either heterozygotes [odds ratio 0.98, 95% confidence interval (CI) 0.77-1.23] or rare allele homozygotes (odds ratio 0.92, 95% CI 0.61-1.37). The G316 > A functional variant in the ODC gene is unlikely to make much impact on reducing CRC risk regardless of the reduction in risk found for the recurrence of colorectal adenoma.

Abstract 4374: Plant stanols induce the formation of intestinal adenomas and activate ERK1 signaling in the ApcMin/+ mouse

Abstract Introduction The incidence of colorectal cancer (CRC) has been increasing in many Western countries for several decades. Diet rich in plant foods is known to decrease CRC risk, whereas high intake of fat and cholesterol is associated with an increased risk. Plant sterols have been shown to inhibit colon cancer cell growth in vitro (Awad et al. 1996, Choi et al. 2003). The ApcMin/+ mouse carries a heterozygous germ line mutation in the Apc tumour suppressor gene. The homologous gene is mutated in patients with hereditary colon cancer (FAP, familial adenomatosis polyposis). In the ApcMin/+ mouse, the loss of heterozygosity in Apc allele activates the Wnt/Tcf-pathway which leads to accumulation of β-catenin in the cytosol and its translocation to the cell nucleus. β-Catenin acts as a transcription factor for several genes (e.g. cyclin D1, c-myc) and enhances cell proliferation. ApcMin/+ mice develop dozens of adenomas in the small intestine. The aim of this study was to investigate the effect of plant stanol feeding on adenoma formation and cell signaling in ApcMin/+ mice. The sterol composition of the intestinal mucosa was also analyzed. Materials and methods ApcMin/+ mice were fed either a 0.8% (w/w) plant stanol diet (n=14) or a control diet without plant stanols (n=14). Plant stanols were added to the experimental diet in the form of freeze-dried products with plant stanol ester enrichment. The level of cyclin D1, phosphorylated and total ERK1/2 (extracellular signal regulated kinase) were analyzed from the normal appearing intestinal mucosa by Western blot. Cholesterol, plant sterols (sitosterol, campesterol) and stanols (sitostanol, campestanol) were isolated from the intestinal mucosa by direct saponification method and analyzed by gas chromatography. Results The number of small intestinal adenomas was significantly increased by plant stanol feeding (p=0.002). Plant stanols induced adenoma formation by over 60% compared to the control group. No difference in the size of intestinal adenomas was seen. Plant stanol feeding increased the level of activated ERK1 (the ratio of phosphorylated p44 to total p44) and nuclear cyclin D1 in the intestinal mucosa (p=0.024 and p=0.038, respectively). The level of mucosal cholesterol was not affected by plant stanol feeding; however, the level of sitosterol and campesterol were decreased (p&amp;lt;0.001 for both) and sitostanol and campestanol increased (p&amp;lt;0.001 for both) in the intestinal mucosa of plant stanol fed ApcMin/+ mice. The number of intestinal adenomas and the level of mucosal plant sterols appear to have a negative correlation (rs=-0.517; p=0.007). References Awad et al. Anticancer Res 1996;16:2797-2804. Choi et al. Int J Oncol 2003;23:1657-62. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 4374.