Genetic polymorphisms of CYP2E1 and risk of colorectal cancer: the Fukuoka Colorectal Cancer Study.

Cytochrome P450 2E1 (CYP2E1) is involved in the metabolic activation of a wide variety of potential carcinogens, and functional polymorphisms in the CYP2E1 gene have been investigated in relation to colorectal cancer. We examined the relation of the CYP2E1 RsaI and 96-bp insertion polymorphisms to colorectal cancer risk and the interaction between these polymorphisms and some lifestyle risk factors. Subjects were 685 incident cases of colorectal cancer and 778 community controls. Statistical adjustment was made for alcohol use, body mass index, physical activity, and other factors. The RsaI c2 allele was associated with a decreased risk of rectal cancer [adjusted odds ratio for at least one c2 allele, 0.71; 95% confidence interval (95% CI), 0.53-0.95], and an increased risk of rectal cancer was observed among individuals having one or two 96-bp insertion alleles (adjusted odds ratio, 1.40; 95% CI, 1.06-1.85). Individuals with two 96-bp insertion alleles showed a 2.28-fold increase in colon cancer risk (95% CI, 1.29-4.01). The two polymorphisms were in almost complete linkage disequilibrium (D' = 0.94). A positive association between alcohol intake and colorectal cancer was observed only in individuals without RsaI c2 allele (P(trend) = 0.03) or in those without 96-bp insertion allele (P(trend) = 0.009). Colon cancer risk was increased in relation to red meat intake only in individuals having one or two 96-bp insertion alleles (P(interaction) = 0.03). The present study suggests that variation in activity and inducibility of CYP2E1, in relation to alcohol or red meat intake, contributes to the development of colorectal cancer.

Association between genetic polymorphisms of the base excision repair gene MUTYH and increased colorectal cancer risk in a Japanese population.

The MUTYH gene encodes a DNA glycosylase that can initiate the base excision repair pathway and prevent G:C > T:A transversion by excising adenine mispaired with 8-hydroxyguanine. Biallelic germline mutations of MUTYH have been shown to predict familial and sporadic multiple colorectal adenomas and carcinomas, however, whether there is an association between single nucleotide polymorphisms (SNPs) of MUTYH and sporadic colorectal cancer (CRC) risk has remained unclear. In this study we investigated four MUTYH SNPs, IVS1+11C > T, IVS6+35G > A, IVS10-2A > G, and 972G > C (Gln324His), for an association with increased CRC risk in a population-based series of 685 CRC patients and 778 control subjects from Kyushu, Japan. A statistically significant association was demonstrated between IVS1+11T and increased CRC risk (odds ratio [OR]: 1.43; 95% confidence interval [CI]: 1.012-2.030; P = 0.042) and one of the five haplotypes based on the four SNPs, the IVS1+11T - IVS6+35G - IVS10-2A - 972C (TGAC) haplotype containing IVS1+11T, was demonstrated to be associated with increased CRC risk (OR, 1.43; 95% CI, 1.005-2.029; P = 0.046). Subsite-specific analysis showed that the TGAC haplotype was statistically significantly (P = 0.013) associated with an increased risk of distal colon, but not proximal colon or rectal cancer. Furthermore, IVS1+11C > T was found to be in complete linkage disequilibrium with -280G > A and 1389G > C (Thr463Thr). The results indicated that Japanese individuals with - 280A/IVS1+11T/1389C genotypes or the TGAC haplotype are susceptible to CRC.

Calcium, dairy foods, vitamin D, and colorectal cancer risk: the Fukuoka Colorectal Cancer Study.

Epidemiologic evidence supporting a protective role of calcium and vitamin D in colorectal carcinogenesis has been accumulating in Western populations, but it is limited in Asian populations, whose intake of calcium is relatively low. We investigated the association of intakes of these nutrients with colorectal cancer risk in Japanese. Study subjects were participants of a large-scale case-control study in Fukuoka, Japan. Diet was assessed through interview regarding 148 dietary items by showing typical foods or dishes on the display of a personal computer. In a multivariate analysis adjusting for potential confounding variables, calcium intake was significantly, inversely associated with colorectal cancer risk (P for trend=0.01); the odds ratio for the highest versus lowest quintile of calcium intake was 0.64 (95% confidence interval, 0.45-0.93). Higher levels of dietary vitamin D were significantly associated with decreased risk of colorectal cancer among those who had fewer chances of sunlight exposure at work or in leisure (P for trend=0.02). A decreased risk of colorectal cancer associated with high calcium intake was observed among those who had higher levels of vitamin D intake or among those who had a greater chance of daily sunlight exposure, but not among those with medium or lower intake of vitamin D or among those with potentially decreased sunlight exposure. These results add to support for a joint action of calcium and vitamin D in the prevention of colorectal carcinogenesis.

Personality and colorectal cancer: the Fukuoka colorectal cancer study.

OBJECTIVE: Although personality factors, especially emotional suppression and loss-hopelessness, have been linked to the occurrence and progression of cancer, little is reported specifically on colorectal cancer. It has also been claimed that a 'hysterical' personality characterized by exaggerated emotional expressions, egocentricity and ambivalent connection may be protective from cancer. This community-based case-control study examined whether personality factors relevant to emotional suppression or loss-hopelessness are associated with an increased risk of colorectal cancer, and whether factors related to the hysterical personality are associated with a decreased risk. METHODS: The stress inventory (SI), a self-administered questionnaire to assess the possible disease-prone and other relevant personalities in Japanese, was completed by 497 patients with newly diagnosed colorectal cancer and 809 controls randomly selected in the Fukuoka area of Japan. RESULTS: After controlling for age, sex and residence using a logistic regression model, none of the SI scales relevant to emotional suppression ('unfulfilled needs for acceptance', 'altruism', 'rationalizing conflicts/frustrations') or loss-hopelessness ('low sense of control', 'object-dependence/loss', 'object-dependence/happiness') was related to colorectal cancer. On the other hand, two scales representing elements of the hysterical personality, 'object-dependence/ambivalence' and 'egoism' were protectively associated with risk. Additional adjustment for body-mass index and lifestyle factors did not materially change these associations. CONCLUSIONS: Although personalities relevant to the emotional suppression or loss-hopelessness may not be a risk factor for colorectal cancer in the Japanese population, ambivalent connection and egocentricity may be protective.

Colorectal polypectomy and risk of colorectal cancer by subsite: the Fukuoka Colorectal Cancer study.

BACKGROUND: Colorectal adenomas are well-established precursor lesions for colorectal cancer and removal of polyps is deemed to reduce the risk of colorectal cancer. However, benefit of colorectal polypectomy in routine practice is still uncertain. We therefore investigated subsite-specific risks of colorectal cancer in relation to history of colorectal polypectomy in a case-control study. METHODS: Both case patients and control subjects were residents aged 20-74 years in Fukuoka City and three adjacent areas. The case group comprised 840 patients undergoing surgery for a first diagnosis of colorectal cancer, while the control subjects were 833 residents who were selected in the community by two-stage random sampling. Past history of selected diseases, surgery and lifestyle factors were ascertained by in-person interview. Statistical adjustment was made for sex, 5-year age class, residence, smoking, alcohol drinking, physical activity, body mass index and parental history of colorectal cancer. RESULTS: Overall, 74 case patients (9%) and 85 control subjects (10%) reported a prior history of colorectal polyps, and 50 cases (6%) and 64 controls (8%) had a history of colorectal polypectomy. The adjusted odds ratio associated with colorectal polypectomy was 0.71 (95% confidence interval [CI] 0.48-1.06) for the overall risk of colorectal cancer. The corresponding values for cancer of the proximal colon, distal colon, and rectum were 1.68 (95% CI 0.98-2.88), 0.71 (95% CI 0.41-1.26) and 0.24 (95% CI 0.11-0.52), respectively. CONCLUSIONS: The findings indicate that colorectal polypectomy in current practice confers a decreased risk of rectal cancer and possibly of distal colon cancer.

Genetic polymorphism in cytochrome P450 7A1 and risk of colorectal cancer: the Fukuoka Colorectal Cancer Study.

Bile acids have long been implicated in the etiology of colorectal cancer, but epidemiologic evidence remains elusive. Cholesterol 7alpha-hydroxylase (CYP7A1) is the rate-limiting enzyme in the synthesis of bile acids from cholesterol in the liver, and thus may be an important determinant of bile acid production. We examined the association between the CYP7A1 A-203C polymorphism and colorectal cancer. The CYP7A1 A-203C polymorphism was determined by the PCR-RFLP method in 685 incident cases of colorectal cancer and 778 controls randomly selected from a community in the Fukuoka area, Japan. The CC genotype was slightly less frequent in the case group, and the adjusted odds ratio for the CC versus AA genotype was 0.88 (95% confidence interval, 0.65-1.20). In the analysis by subsite of the colorectum, a decreased risk associated with the CYP7A1 CC genotype was observed for proximal colon cancer, but not for either distal colon or rectal cancer. The adjusted odds ratios (95% confidence intervals) of proximal colon cancer for the CC genotype were 0.63 (0.36-1.10) compared with the AA genotype, and 0.59 (0.37-0.96) compared with the AA and AC genotypes combined. A decreased risk of proximal colon cancer in relation to the CC genotype of CYP7A1 A-203C, which probably renders less activity of the enzyme converting cholesterol to bile acids, is new evidence for the role of bile acids in colorectal carcinogenesis.

Alcohol dehydrogenase and aldehyde dehydrogenase polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study.

Alcohol dehydrogenase and aldehyde dehydrogenase are key enzymes in alcohol metabolism and therefore may be of importance to colorectal cancer development. The present case-control study was conducted to determine the influence of ADH2, ADH3 and ALDH2 polymorphisms in Fukuoka, Japan, with 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly from the study area. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for sex, age class, area, and alcohol use. Individuals with the allele 47Arg of the ADH2 polymorphism (slow metabolizers) had a statistically significant increase in risk, with an adjusted OR of 1.32 (95% CI = 1.07-1.63), compared with those having the ADH2*47His/His genotype. This association was not affected by the level of alcohol consumption. The ADH3 polymorphism showed no measurable association with the risk of colorectal cancer on either overall analysis or stratified analysis with alcohol use. The heterozygous ALDH2*487Glu/Lys genotype was not associated with an increase in the risk of colorectal cancer (adjusted OR 0.89, 95% CI = 0.71-1.13) compared with the ALDH2*487Glu/Glu genotype. Rather unexpectedly, the homozygous ALDH2*487Lys/Lys genotype was related to a statistically significantly decreased risk of colorectal cancer (adjusted OR 0.55, 95% CI = 0.33-0.93). It is unlikely that acetaldehyde metabolism determined by ALDH2 polymorphism contributes to the risk of colorectal cancer, whereas the role of ADH2 polymorphism deserves further investigation.

Meat, fish and fat intake in relation to subsite-specific risk of colorectal cancer: The Fukuoka Colorectal Cancer Study.

High intake of red meat has been associated with increased risk of colorectal cancer in Western countries. There has been much interest in the role of n-3 polyunsaturated fatty acids (PUFA) in colorectal cancer prevention, but epidemiological findings are limited and inconsistent. The objective of our study was to examine associations of meat, fish and fat intake with risk of colorectal cancer, paying particular attention to the subsite within the colorectum. Data were from the Fukuoka Colorectal Cancer Study, a population-based case-control study, covering 782 cases and 793 controls. Diet was assessed by interview, using newly developed personal-computer software for registering semiquantitative food frequencies. The intake of beef/pork, processed meat, total fat, saturated fat or n-6 PUFA showed no clear association with the overall or subsite-specific risk of colorectal cancer. There was an almost significant inverse association between n-3 PUFA and the risk of colorectal cancer; the covariate-adjusted odds ratio for the highest (median 3.94 g/day) versus lowest (median 1.99 g/day) quintile of energy-adjusted intake was 0.74 (95% confidence interval 0.52-1.06, trend P=0.050). The consumption of fish and fish products was similarly inversely related to the risk although the association was not statistically significant. These associations were more evident for distal colon cancer; adjusted odds ratio for the highest versus lowest quintile of n-3 PUFA intake was 0.56 (95% confidence interval 0.34-0.92, trend P=0.02). Our findings do not support the hypothesis that consumption of red meat increases colorectal cancer risk but do suggest that high intake of fish may decrease the risk, particularly of distal colon cancer.

Physical activity and colorectal cancer: the Fukuoka Colorectal Cancer Study.

The number of cases of colorectal cancer in Japan has increased over the past few decades, and incidence rates are now among the highest in the world. The present investigation within the Fukuoka Colorectal Cancer Study, including 778 cases and 767 controls aged 20-74 years, examined the association between physical activity and colorectal cancer risk by subsite. Employment-associated and leisure time physical activity was assessed by a questionnaire and interview. Division of sites into the proximal and distal colon, as well as the rectum, revealed clear site-dependent protective effects, with adjustment for smoking, alcohol consumption, BMI and age. In males, greater job-related physical activity was associated with significant reduction of risk in the distal colon and rectum (P = 0.047 and 0.02, respectively), whereas total and moderate or hard non-job physical activity exerted effects limited to the rectum (P = 0.01 and 0.004, respectively). In females, job-related physical activity and moderate or hard non-job physical activity was also protective, but only in the distal colon. Separate assessment of the influence of BMI 10 years previous to the study showed increase in risk with obesity in males but not in females, limited to distal colon and rectum. The results of the present study indicate that physical activity associated with work and leisure-time exerts beneficial effects in Japanese, but not on the proximal colon.

Methylenetetrahydrofolate reductase C677T and A1298C polymorphisms and colorectal cancer: the Fukuoka Colorectal Cancer Study.

Methylenetetrahydrofolate reductase (MTHFR) is a key enzyme regulating folate metabolism, which affects DNA synthesis and methylation. This study investigated the relation of MTHFR C677T and A1298C polymorphisms to colorectal cancer in a case-control study in Fukuoka, Japan. The subjects comprised 685 incident cases of histologically confirmed colorectal adenocarcinomas and 778 community controls selected randomly in the study area. The genotype was determined by the PCR-RFLP method using genomic DNA extracted from buffy coat. Alcohol use was ascertained by in-person interview. Statistical adjustment was made for gender, age class, area, and alcohol use. The MTHFR 677TT genotype was associated with a statistically significant decrease in the risk with an adjusted odds ratio of 0.69 (95% confidence interval 0.51-0.93) compared with the 677CC and 677CT combined, and the decrease was most evident in individuals with no alcohol consumption. While the A1298C polymorphism showed no measurable association with the overall risk of colorectal cancer, the 1298CC genotype was associated with a statistically significant increase in the risk when alcohol consumption was high, and was also associated with an approximately 2-fold increase in the risk of each of proximal and distal colon cancer. The findings add to evidence that individuals with the MTHFR 677TT genotype have a decreased risk of colorectal cancer in the absence of folate depletion, suggesting a protective role of folate by ensuring a sufficient thymidylate pool for DNA synthesis. Because very few individuals had the 1298CC genotype, the findings regarding the A1298C polymorphism need careful interpretation and confirmation in larger studies.