Overview of the Japan Collaborative Cohort Study for Evaluation of Cancer (JACC).

Starting in the late 1980s a major collaborative effort has been carried out in Japan to increase knowledge about factors contributing to mortality from cancer and circulatory disease. This Japan Collaborative Cohort Study (JACC Study) is sponsored by the Ministry of Education, Science, Sports and Culture of Japan (Monbukagakusho) and has contributions from 45 areas of the country. With Drs Kunio Aoki and Yoshiyuki Ohno as leading figures in this endeavour, the cohort now covers more than 100,000 participants enrolled at various centers located from Hokkaido in the North to Kyushu in the South. To collect epidemiological information at baseline, a self-administered questionnaire was used. Follow-up up was to 2003 in the majority of cases and a total of 17,404 deaths were registered, the five commonest sites of cancer development being the lung, stomach, liver, pancreas and colon in men, and the stomach, lung, liver, colon and pancreas in women.

Risk factors for multiple myeloma: evidence from the Japan Collaborative Cohort (JACC) study.

This study assessed the association of multiple myeloma (MM) with age, body mass index (BMI, kg/m(2)), physical activity, occupational history, and medical history for a Japanese cohort of 46,157 men and 63,541 women aged 40-79 years followed during 1988-2003 years. Cox proportional hazard model was mainly used to estimate the age and sex adjusted hazard ratio (HR) of MM including 95% confidence interval (CI) for both sexes. Same model, adjusted for age, was also used for each sex. In total, 98 MM deaths (men=49 and women=49) was observed for both sexes. Higher age groups (60-69 and 70-79 years) experienced significantly higher unadjusted HR of MM than the age group of 40-49 years. Men revealed significantly higher age-adjusted MM than women (HR=1.5; 95% CI=1.0-2.2). For both sexes, higher BMI of >or=30 kg/m(2)) (HR=2.8; 95% CI=1.0-7.7), walking <or=30 minutes/day (HR=2.0; 95% CI=1.2-3.4), worried about personal relationship in working place (HR=2.3; 95% CI=1.3-4.2), restricted own pace in working place (HR=1.9; 95% CI=1.0-3.4), and history of peptic ulcer (HR=1.7; 95% CI=1.0-2.7) significantly increased age and sex adjusted MM risk. Some of the above-mentioned significant associations became insignificant for age adjusted sex specific analyses. However, these findings should be validated by further epidemiologic studies in Japan before generalization.

A population-based follow-up study on mortality from cancer or cardiovascular disease and serum carotenoids, retinol and tocopherols in Japanese inhabitants.

OBJECTIVE: Observational epidemiologic studies have shown that a high intake of dietary and high serum levels of carotenoids are associated with a reduced risk of mortality from cancer and cardiovascular disease. To investigate whether high serum levels of carotenoids can reduce mortality rates, a population-based follow-up study was conducted among Japanese inhabitants. MATERIALS AND METHODS: Three thousand two hundred and fifty-four subjects (1,260 males and 1,994 females) aged from 39 to 85 years who had attended health check-up programs from 1989 to 1995 were recruited from the Japanese population. Serum levels of carotenoids, retinol and tocopherols were separately determined by high-performance liquid chromatography. Hazard ratios for serum values of carotenoids, retinol and tocopherols were estimated by Cox's proportional hazard model after adjusting for sex, age, and other confounding factors. RESULTS: During the 11.7-year follow-up period, 140 deaths (86 males and 54 females) from cancer of all sites were identified among the cohort subjects, including 41 from lung , 17 from stomach , 16 from colorectal and 12 from liver cancer, as well as 89 deaths from cardiovascular disease, including 45 from heart disease and 37 from stroke. High serum values of carotenoids including xanthophylls were apparently associated with low hazard ratios for mortality rates of cancer of all sites or of cardiovascular disease. High serum values of beta-carotene, total carotene, provitamin A and total carotenoid for colorectal cancer or stroke also appeared to be related to low hazard ratios. Those of retinol and tocopherols were not associated with any reduction in risk of mortality from cancer or cardiovascular disease. CONCLUSIONS: Our follow-up study demonstrated that a typical Japanese diet related to elevating serum levels of carotenoids with provitamin A activity may significantly reduce risk of mortality from cancer of certain sites or cardiovascular disease, especially colorectal cancer or stroke, while high serum levels of some xanthophylls, retinol and tocopherols do not.

Site-specific cancer risk due to diabetes mellitus history: evidence from the Japan Collaborative Cohort (JACC) Study.

The study examined the association of diabetes mellitus (DM) history with total and common site-specific cancers using a large cohort of 23,378 men and 33,503 women, extracted from 127,477 healthy participants of the JACC Study who were aged 40-79 years and living in 24 municipalities in Japan. At enrollment during 1988-90, each subject completed a self-administered questionnaire including items for age, sex, body mass index (BMI), smoking, drinking, past history of DM and cancer. Adjusting for age, BMI, smoking, and drinking in the Cox's proportional hazard model, incidence rate ratios (IRR) with 95% confidence intervals (95%CIs) were estimated for both sexes. During the follow-up period, total cancers and site-specific cancers were identified. A history of DM was reported by 7.5% of men and 4.6% of women. DM significantly increased the risk of liver cancer for both men (IRR=2.30; 95%CI=1.47-3.59) and women (IRR=2.70; 95%CI=1.20-6.05). Significant increased and reduced risk due to DM for men were also found for non-Hodgkin lymphoma (IRR=2.77; 95%CI=1.04-7.38) and stomach cancer (IRR=0.67; 95%CI=0.46-0.99) respectively. For females, a reduced risk of stomach cancer due to DM (IRR=0.49; 95%CI=0.23-1.04) was also revealed. Since a history of DM here demonstrated significant associations with some site-specific cancers, their relationships should be studied further in Japan for validation.

Lack of an association between serum level of transforming growth factor beta -1 and stomach cancer risk in the JACC study.

Alterations in the serum concentration of transforming growth factor beta-1 (TGFbeta1) have been observed in gastric cancer patients. No study, however, has ever examined the association between the serum TGFbeta1 level and stomach cancer prospectively. We conducted a prospective, nested case-control analysis among apparently healthy men and women who were followed for up to 8 years in the JACC Study to assess whether serum level of total TGFbeta1 is associated with a subsequent risk of stomach cancer. The concentration of serum TGFbeta1 in previously collected blood samples was analyzed by ELISA for 209 individuals in whom a diagnosis of stomach cancer was documented, and for 409 controls matched with them for gender, age and study area. Baseline blood levels of TGFbeta1 were not related to the risk of stomach cancer in either men or women, a finding unchanged even after adjustment for potential confounders. The multivariate-adjusted odds ratio of stomach cancer in men and women was 1.10 (95% CI, 0.82 to 1.48) and 1.09 (95% CI, 0.80 to 1.48), respectively, for each increase of 1 SD in the TGFbeta1 value. In conclusion, serum TGFbeta1 levels were not associated with increased risks of subsequent stomach cancer.gene A52C polymorphism related to the metabolism of long-chain fatty acids and oxidized LDL in the etiology of colorectal cancer.

Precise definition of anonymization in genetic polymorphism studies.

Anonymization is an essential tool to protect privacy of participants in epidemiological studies. This paper classifies types of anonymization in genetic polymorphism studies, providing precise definitions. They are: 1) unlinkable anonymization at enrollment without a participant list; 2) unlinkable anonymization before genotyping with a participant list; 3) linkable anonymization; 4) unlinkable anonymization for outsiders; and 5) linkable anonymization for outsiders. The classification in view of accessibility to a table including genotype data with directly identifiable data such as names is important; if such tables exist, staff may obtain genotype information about participants. The first three modes are defined here as anonymization unaccessible to genotype data with directly identifiable information for research staff. Anonymization with a key code held by participants is possible with any of the above anonymization modes, by which participants can access to their own genotypes through telephone or internet. A guideline issued on March 29, 2001 with collaboration of three Ministries in Japan defines "anonymization in a linkable fashion" and "anonymization in an unlinkable fashion", "for the purpose of preventing the personal information from being divulged externally in violation of law, the present guidelines or a research protocol", but the contents are not clear in practice. The proposed definitions will be useful when we describe and discuss the preferable mode of anonymization for a given polymorphism study.

No association of the mitochondrial genotype (Mt5178A/C) with six cancers in a Japanese population.

To examine an association between the mitochondrial DNA (mt5178) genotype and various cancers, we genotyped 1120 non-cancer controls and 930 cancer cases including esophageal, stomach, colorectal, lung, breast and malignant lymphoma in a sample of Japanese patients. The mt5178A/C was genotyped by the polymerase chain reaction with confronting two-pair primers (PCR-CTPP). The frequency of mt5178A/C within the non-cancer and cancer groups, and age distribution of subjects with mt5178A and C were investigated. Odd ratios (ORs) of the mt5178A and C genotypes were also examined. The frequency of mt5178A was 39.1% in non-cancer subjects while frequencies in those having cancer included 39.0% in breast, 37.4% in colorectal, 45.1% in esophageal, 38.0% in lung, 41.5% in malignant lymphoma, and 38.8% in stomach cancer. There was no significant difference in the frequency of the mt5178 genotype among the six types of cancer studied. There was also no significant difference in the frequency of the mt5178 genotype between non-cancer and cancer subjects regardless of total age with the exception that ages 40-49 years (the frequency of the mt5178A was higher in cancer subjects). There was a significant interaction term between age and the mt5178 genotype in older (age>=60) lung cancer patients. The cumulative frequency of mt5178C increased more markedly than that of mt5178A after age 40 in non-cancer subjects, and after age 50 in cancer subjects ORs of the genotype were not significant for all cancers combined or for any individual site of cancer. In the present study, the mt5178 genotype seems to have no association with any of the cancers examined here. But an interaction term between the mt5178 genotype and aging on cancer was suggested with the Japanese population under study.

Relationship between obesity and serum markers of oxidative stress and inflammation in Japanese.

The present study was conducted to assess the relationship between obesity and serum levels of C-reactive protein (CRP), carotenoids, oxidized LDL (oxLDL), oxidized LDL antibodies (oLAB), and leptin in Japanese residents. The subjects were 158 males and 158 females aged 40-79 years, and living in Hokkaido, Japan, who attended a health examination screening. Serum levels of CRP, oxLDL, oLAB, and leptin were measured by enzyme-linked immunosorbent assay (ELISA) and serum carotenoid levels were measured by high-performance liquid chromatography (HPLC). Body mass index (BMI) was calculated as body weight (kg) divided by height (m) squared and obesity was defined as BMI of 25 or more (kg/m2). Serum levels of CRP and leptin were significantly higher in the obese group than in their non-obese counterparts in both genders. Serum levels of beta-carotene and beta-cryptoxanthin were lower in the obese individuals, especially in females. While values for oxLDL and oLAB did not significantly vary. BMI was positively correlated with log-transformed serum levels of CRP and leptin in both genders (males: r=0.231, p<0.05; females: r=0.305, p<0.001). In females, moreover, BMI was negatively correlated with log-transformed serum levels of beta-carotene, zeaxanthin/lutein, and beta-cryptoxanthin (r=-0.244, p<0.01; r=-0.200, p<0.05; r=-0.207, p<0.01, respectively). Significantly higher odds ratios (ORs) for high serum levels of CRP (males: OR=2.12; females: OR=3.96) and leptin (males: OR=3.83; females: OR=9.07) were observed in obese versus non-obese men and women, after adjusting for various confounding factors. Significantly lower adjusted odds ratios for high serum levels of alpha- and beta-carotenes (males: OR=0.23, 0.33; females: OR=0.35, 0.39, respectively) were also observed in the obese as compared to the non-obese group. In conclusion, obesity is highly associated with states of oxidative stress and low-grade inflammation in Japanese residents, suggesting that these latter might play an important role in the association between a high BMI and certain cancers as well as coronary heart disease (CHD).

Triplex polymerase chain reactions with confronting two-pair primers (PCR-CTPP) for NQO1 C609T, GSTM1 and GSTT1 polymorphisms: a convenient genotyping method.

The polymerase chain reaction with confronting two-pair primers (PCR-CTPP) is a time-saving and inexpensive genotyping method, which is applicable for most single nucleotide polymorphisms (SNPs). To date, we have established PCR-CTPP conditions for tens of SNPs, including duplex genotyping. This paper introduces triplex PCR-CTPP to simultaneously genotype three functional polymorphisms of carcinogen-detoxifying enzymes, NQO1 C609T, GSTM1 null, and GSTT1 null, all of which are reported to have a significant association with smoking-related cancers. We applied this method for 241 non-cancer patients to demonstrate the performance. Among the subjects, the genotype frequency of NQO1 C609T was 35.7% for CC, 44.4% for CT and 19.9% for TT. The null type frequencies of GSTM1 and GSTT1 were 53.4% and 44.0%, respectively. Their distributions were similar to those reported for Japanese by other studies. This is the first paper reporting the success of triplex PCR-CTPP. The polymorphisms applied are useful examples, which could be adopted not only for research purposes, but also for risk assessment of individuals exposed to carcinogenic substances, such as smokers. This convenient genotyping approach has advantages for application in cancer prevention, especially in the Asian Pacific region.