Search

Although alcohol consumption is reported to increase the incidence of breast cancer in European studies, evidence for an association between alcohol and breast cancer in Asian populations is insufficient. We conducted a pooled analysis of eight large-scale population-based prospective cohort studies in Japan to evaluate the association between alcohol (both frequency and amount) and breast cancer risk with categorization by menopausal status at baseline and at diagnosis. Estimated hazard ratios (HR) and 95% confidence intervals were calculated in the individual cohorts and combined using random-effects models. Among 158 164 subjects with 2 369 252 person-years of follow-up, 2208 breast cancer cases were newly diagnosed. Alcohol consumption had a significant association with a higher risk of breast cancer in both women who were premenopausal at baseline (regular drinker compared to nondrinker: HR 1.37, 1.04-1.81, ≥23 g/d compared to 0 g/d: HR 1.74, 1.25-2.43, P for trend per frequency category: P = .017) and those who were premenopausal at diagnosis (≥23 g/d compared to 0 g/d: HR 1.89, 1.04-3.43, P for trend per frequency category: P = .032). In contrast, no significant association was seen in women who were postmenopausal at baseline or at diagnosis, despite a substantial number of subjects and long follow-up period. Our results revealed that frequent and high alcohol consumption are both risk factors for Asian premenopausal breast cancer, similarly to previous studies in Western countries. The lack of a clear association in postmenopausal women in our study warrants larger investigation in Asia.

Family history (FH) of cancer is an important factor of increased risk of several cancers. Although the association between FH of cancer and concordant cancer risk has been reported in many previous epidemiological studies, no comprehensive prospective study with adjustment for lifestyle habits has evaluated the association of FH of cancer and concordant cancer risk. We investigated the association between FH of cancer and concordant cancer risk in a Japanese population-based prospective study, initiated in 1990 for cohort I and in 1993 for cohort II. We analyzed data on 103,707 eligible subjects without a history of cancer who responded to a self-administered questionnaire including FH of cancer at baseline. Study subjects were followed through 2012 and analyzed using multivariable-adjusted Cox proportional hazards regression models. During 1,802,581 person-years of follow-up, a total of 16,336 newly diagnosed cancers were identified. Any site (Hazard ratios = 1.11 (95% confidence interval = 1.07-1.15]), esophagus (2.11 [1.00-4.45]), stomach (1.36 [1.19-1.55]), liver (1.69 [1.10-2.61]), pancreas (2.63 [1.45-4.79]), lung (1.51 [1.14-2.00]), uterus (1.93 [1.06-3.51]) and bladder cancers (6.06 [2.49-14.74]) with FH of the concordant cancer were associated with an increased risk compared to those without FH. Our findings suggest that having FH of cancer is associated with an increased risk of several concordant cancer incidences in an Asian population. Enquiring about FH of several types of cancer may be important in identifying groups at high-risk of those cancers.

Ovarian cancer is the eighth most common cancer in women worldwide and incidence rates vary markedly by world region. This study provides a comprehensive overview of ovarian cancer incidence trends globally, examining the influence of birth cohort and period of diagnosis on changing risk. We presented current patterns and trends of ovarian cancer incidence until 2012 using data from successive volumes of Cancer Incidence in Five Contents. The incidence of ovarian cancer is highest in northern and eastern European countries, and in northern America. Declining trends were observed in most countries with the exception of a few central and eastern Asian countries. Marked declines were seen in Europe and North America for women aged 50–74 where rates have declined up to 2.4% (95% CI: −3.9, ‒0.9) annually in Denmark over the last decade. Additionally, declines in the incidence rate ratio (IRR) were observed for generations born after the 1930s, with an additional strong period effect seen around 2000 in United States and Denmark. In contrast, IRRs increased among younger generations born after the 1950s in Japan and Belarus. Overall, the favourable trends in ovarian cancer incidence is likely due to the increase use of oral contraceptive pills, and changes in the prevalence of other reproductive risk and protective factors for ovarian cancer over the years studied. Changes in disease classifications and cancer registry practices may also partially contribute to the variation in ovarian cancer incidence rates. Thus, continuous cancer surveillance is essential to detect the shifting patterns of ovarian cancer.

Earlier cohort studies using conventional regression models have consistently shown an increased cancer risk among individuals with type 2 diabetes. However, reverse causality and residual confounding due to common risk factors could exist, and it remains unclear whether diabetes per se contributes to cancer development. Mendelian randomization analyses might clarify the true association between diabetes and cancer risk. We conducted a case–cohort study with 10,536 subcohort subjects and 3,541 newly diagnosed cancer cases derived from 32,949 eligible participants aged 40–69 years within the Japan Public Health Center‐based Prospective Study. With 29 known type 2 diabetes susceptibility variants, we used an inverse variance‐weighted method to estimate hazard ratios for the associations of diabetes with risks of total and site‐specific cancers. The hazard ratios of cancer per doubling of the probability of diabetes were 1.03 (95% confidence interval [CI], 0.92–1.15) overall, 1.08 (95% CI: 0.73–1.59) for the pancreas, 0.80 (95% CI: 0.57–1.14) for the liver and 0.90 (95% CI: 0.74–1.10) for the colorectum. Additional analyses, using publicly available large‐scale genome‐wide association study data on colorectal cancer in Japan, resulted in a narrower CI (hazard ratio: 1.00; 95% CI: 0.93–1.07). In this prospective Mendelian randomization study with a large number of incident cancer cases, we found no strong evidence to support associations between diabetes and overall and site‐specific cancer risks. Our findings suggest that there is little evidence to support the genetic role of type 2 diabetes in cancer development in the Japanese population., What's new? While type 2 diabetes is implicated in cancer development, the two conditions share multiple risk factors, raising questions about the actual contribution of diabetes to cancer risk. Here, a Mendelian randomization (MR) analysis was used to clarify the relationship between diabetes and cancer in a Japanese cohort. Based on data for 32,949 individuals, including 3,541 incident cancer cases, MR analysis revealed no strong genetic evidence supporting a link between diabetes and cancer risk, including site‐specific and overall risk. This finding was confirmed by investigation of data from a genome‐wide association study of colorectal cancer from the BioBank Japan Project.

Oxidative stress and chronic inflammation are potential pathogenic factors of pancreatic cancer. Although fruits and vegetables are abundant in antioxidants and anti-inflammatory constituents, the reported associations between fruit and vegetable intake and pancreatic cancer risk have been inconsistent. Here, we investigated the association between fruit and vegetable intake and pancreatic cancer risk as part of the Japan Public Health Center-based Prospective Study. The analysis included 90,185 participants who responded to a medical and lifestyle questionnaire during 1995-1998. Associations between fruit and vegetable intake and pancreatic cancer risk were evaluated with Cox proportional hazards models. Additional analyses were stratified by smoking status and body mass index. During follow-up (median duration, 16.9 years), 577 participants were diagnosed with pancreatic cancer. In multivariate-adjusted models, pancreatic cancer risk was inversely associated with total fruit intake (highest vs. lowest intake quartile; hazard ratio [HR]: 0.74, 95% confidence interval [CI]: 0.57-0.95, p-trend: 0.116) and positively associated with total vegetable intake (HR: 1.30, 95% CI: 1.01-1.66, p-trend: 0.151). For total fruit intake, the inverse association with pancreatic cancer risk was more apparent in never smokers (HR: 0.67, 95% CI: 0.47-0.97, p-trend: 0.034). For total vegetable intake, the positive association was statistically significant in ever smokers (HR: 1.49, 95% CI: 1.01-2.19, p-trend: 0.043) and statistically nonsignificant in never smokers. In summary, total fruit intake and total vegetable intake had inverse and positive associations, respectively, with pancreatic cancer risk. Vegetable intake may correlate with increased risk partly because of the influence of smoking on vegetable intake.

To elucidate the individual impacts of insulin and blood glucose on cancer risk, we investigated the association of plasma C-peptide, a surrogated marker of insulin and glycated albumin (GA), a more stable marker of blood glucose, with all-site and site-specific cancer risk by mutually accounting for their confounding effects. The study was prospectively conducted with nearly 4,000 cancer cases arising in our population-based cohort of 33,736 subjects who answered the baseline questionnaire and supplied blood samples. After exclusion of subjects with apparent DM, analysis was done in 3,036 cancer cases and 3,667 subcohort subjects. Among men and women combined, highest levels of C-peptide were statistically significantly associated with an increased risk of all-site [Hazard ratio (HR): 1.21; 95% confidence interval: 1.02-1.42], colon [1.73; 1.20-2.47], liver [3.23; 1.76-5.91], kidney, renal pelvis and ureter cancers [2.47; 1.07-5.69], compared to the respective lowest levels, after adjustment for GA levels. Among these C-peptide-related cancers, colon and liver cancers also showed an increased risk associated with elevated GA levels independently of C-peptide levels. The corresponding HRs for colon and liver cancers compared to the highest and lowest GA levels were 1.43 [1.02-2.00] and 2.02 [1.15-3.55], respectively. Effect modification by gender was only evident for the association between C-peptide and colon cancer (p for interaction = 0.04). Higher insulin levels, independently of higher blood glucose levels, may be relevant to DM-related carcinogenesis for several cancer sites. Examination of circulating insulin levels is a plausible option in evaluating cancer risk even in individuals who have not developed DM.

Associations of coffee and tea consumption with lung cancer risk have been inconsistent, and most lung cancer cases investigated were smokers. Included in this study were over 1.1 million participants from 17 prospective cohorts. Cox regression analyses were conducted to estimate hazard ratios (HRs) and 95% confidence intervals (CIs). Potential effect modifications by sex, smoking, race, cancer subtype and coffee type were assessed. After a median 8.6 years of follow-up, 20 280 incident lung cancer cases were identified. Compared with non-coffee and non-tea consumption, HRs (95% CIs) associated with exclusive coffee drinkers (≥2 cups/day) among current, former and never smokers were 1.30 (1.15–1.47), 1.49 (1.27–1.74) and 1.35 (1.15–1.58), respectively. Corresponding HRs for exclusive tea drinkers (≥2 cups/day) were 1.16 (1.02–1.32), 1.10 (0.92–1.32) and 1.37 (1.17–1.61). In general, the coffee and tea associations did not differ significantly by sex, race or histologic subtype. Our findings suggest that higher consumption of coffee or tea is associated with increased lung cancer risk. However, these findings should not be assumed to be causal because of the likelihood of residual confounding by smoking, including passive smoking, and change of coffee and tea consumption after study enrolment.

Coffee is a rich source of bioactive compounds that have potential anticarcinogenic effects. However, it remains unclear whether coffee drinking is associated with colorectal cancer. Also, despite different etiological factors involved in gut physiology, few studies have investigated this association by anatomical site of the lesion. To address these issues, this study examined the association between coffee drinking and colorectal cancer in a pooled analysis from 8 cohort studies conducted in Japan. Among 320,322 participants followed up for 4,503,274 person-years, 6,711 incident colorectal cancer cases were identified. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using the random effects model. Coffee drinking was not materially associated with colorectal cancer risk in men or women (pooled HR 0.92, 95% CI 0.82-1.03 in men and pooled HR 0.90, 95% CI 0.76-1.07 in women). Analysis by subsite showed a lower risk of colon cancer among female drinkers of ≥3 cups coffee/day (pooled HR 0.80, 95% CI 0.64-0.99). There was no such association in men. Coffee drinking was not associated with risk of rectal cancer in men or women. Results were virtually the same among never smokers except for an increased risk of rectal cancer associated with frequent coffee consumption. Coffee drinking may be associated with lower risk of colon cancer in Japanese women.

While many epidemiological studies have studied the association between lung cancer risk and fruits and vegetable consumption (the major sources of antioxidant vitamins), only a few have investigated the direct association with antioxidants in consideration of cancer subtypes and smoking status. Here, we examined the association between consumption of antioxidant vitamins and lung cancer risk in one of the largest prospective cohort studies in Japan. We investigated the association of dietary antioxidant vitamins intake, namely retinol, vitamin C, vitamin E, α-carotene, and β-carotene and subsequent incidence of lung cancer among 38,207 men and 41,498 women in the Japan Public Health Center-based prospective study. Cox proportional hazard regression was performed with adjustment for potential confounders and by strata of cancer subtypes and smoking status. Antioxidant and other dietary intakes were assessed using a food frequency questionnaire (FFQ). During 1,233,096 person-years of follow-up between 1995 and 2013, a total of 1,690 lung cancer cases were newly diagnosed. In a multivariate regression model, while higher retinol intake was positively associated with overall lung cancer risk in men (HR 1.26; 95% CI 1.05-1.51; ptrend = 0.003), the estimates were more evident with small cell carcinoma (HR 1.92; 95% CI 1.13-3.24; ptrend

Although coffee and green tea are suggested to reduce the risk of some types of cancers, only a few epidemiological studies have investigated their effect on the risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here, we investigated the association of coffee and green tea consumption and the risk of AML and MDS in a large-scale population-based cohort study in Japan. A total of 95,807 Japanese subjects (45,937 men and 49,870 women; age 40-69 years at baseline) were followed to the end of 2012, for an average of 18 years. Hazard ratios (HRs) and 95% confidence intervals (95%CIs) for the association between coffee and green tea consumption at baseline and the risk of AML and MDS were assessed using a Cox proportional hazards model with adjustment for potential confounders. During 1,751.956 person-years, we identified 85 AML cases and 70 MDS cases. Our findings showed no significant association between coffee consumption and the risk of AML, or between green tea consumption and the risk of AML or MDS. In contrast, we observed a decreasing dose-response relationship between coffee consumption and the risk of MDS among men (almost none: reference, 1-4 times/week: HR=0.83, 95% CI: 0.43–1.62; ≥1cups/day: HR=0.47, 0.22-0.99, p for trend=0.049). Stratified analysis by smoking status suggested that the observed relative risk for AML and MDS of coffee drinkers relative to non-coffee drinkers might be due to residual confounding by smoking. These findings deserve further investigation in future studies. This article is protected by copyright. All rights reserved.

The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population-based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95915 subjects (45649 men and 50266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70-1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450, >450 g/week of pure ethanol compared with non- and occasional drinkers, respectively, indicating an inverted U-shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (P for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted. This article is protected by copyright. All rights reserved.

Previous epidemiological studies evaluated endogenous sex hormone levels and colorectal cancer (CRC) risk have yielded inconsistent results. Also, it is unknown if consumption of dietary isoflavones may influence the endogenous sex hormones and CRC relationships. We conducted a nested case-control study within the JPHC Study Cohort II wherein 11,644 women provided blood samples at the 5-year follow-up survey. We selected two matched controls for each case from the cohort (185 CRC cases and 361 controls). Multivariable conditional logistic regression was used to estimate odds ratios (ORs), 95% confidence intervals (CIs) for the association between circulating sex hormone levels and CRC risk. Comparing extreme tertiles, circulating testosterone levels were positively associated with CRC risk (OR = 2.10, 95% CI = 1.11-3.99, p for trend = 0.03). Levels of estradiol, SHBG, and progesterone were not associated with CRC risk. In a subgroup analysis by dietary isoflavone intake, SHBG levels were positively associated with CRC risk among those with low total isoflavone intake (p for trend = 0.03), with a statistically nonsignificant inverse association among those with high total isoflavone intake (p for trend = 0.22; p for interaction = 0.002). Endogenous levels of testosterone were positively associated with CRC among postmenopausal women. The association of endogenous SHBG with CRC development may be altered by the level of dietary isoflavone intake.

Cytochrome P450 (CYP) 1A1 and glutathione S-transferases (GST) M1 and T1 are major enzymes in the carcinogen metabolizing pathway. We examined the association between single nucleotide polymorphisms (SNPs) of CYP1A1 (rs4646421, rs4646422 and rs1048943), GSTM1 and GSTT1 and gastric cancer risk in Japan. This is a nested case-control study (457 cases and 457 matched controls) of our population-based cohort involving 36,745 subjects who answered a baseline questionnaire and supplied blood samples. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression models. We found that CYP1A1 (rs4646422) variant allele was associated with a statistically significant increased risk of gastric cancer compared with the homozygous wild-type genotype (OR = 1.65; 95% CI = 1.17-2.32). GSTM1 null, GSTT1 null and GSTM1/T1 both or either null genotypes were associated with increased risk, but not statistically significantly. Combination of the CYP1A1 (rs4646422) variant allele and GSTM1/T1 both or either null genotypes was associated with a statistically significant increased risk compared with the combination of the CYP1A1 homozygous wild-type genotype and the GSTM1/T1 both active genotypes. In addition, compared with CYP1A1 (rs4646422) homozygous wild-type genotypes in those who were never-smokers, CYP1A1 variant alleles in those who smoked ≥30 pack-years were associated with an increased risk; neither gene-gene nor gene-environment interactions were significant. The CYP1A1 (rs4646422) polymorphism might be involved in gastric carcinogenesis among the Japanese population.

Reports relating meat intake to prostate cancer risk are inconsistent. Associations between these dietary factors and prostate cancer were examined in a consortium of 15 cohort studies. During follow-up, 52,683 incident prostate cancer cases, including 4,924 advanced cases, were identified among 842,149 men. Cox proportional hazard models were used to calculate study-specific relative risks (RR) and then pooled using random effects models. Results do not support a substantial effect of total red, unprocessed red and processed meat for all prostate cancer outcomes, except for a modest positive association for tumors identified as advanced stage at diagnosis (advanced(r)). For seafood, no substantial effect was observed for prostate cancer regardless of stage or grade. Poultry intake was inversely associated with risk of advanced and fatal cancers (pooled multivariable RR [MVRR], 95% confidence interval, comparing ≥ 45 vs.

Previous studies have reported associations between diabetes and cancer risk. However, specific association of hemoglobin A1c (HbA1c) levels with cancer risk remains inconclusive. We followed 29,629 individuals (11,336 men; 18,293 women) aged 46–80 years who participated in the Japan Public Health Center‐based prospective study who had HbA1c measurements available and were cancer‐free at baseline. Cancer incidence was assessed by systemic surveys. We estimated hazard ratios (HRs) for cancer risk with adjustment for age sex, geographic area, body mass index, smoking status, physical activity, alcohol, coffee, vegetable and total energy consumption, and history of cardiovascular disease. After a median follow‐up of 8.5 years, 1,955 individuals had developed cancer. Higher HbA1c levels within both the non‐diabetic and diabetic ranges in individuals without known diabetes were associated with overall cancer risk. Compared with individuals without known diabetes and HbA1c levels of 5.0–5.4%, the HRs for all cancers were 1.27 (95% confidence interval, 1.07–1.52); 1.01 (0.90–1.14); 1.28 (1.09–1.49); and 1.43 (1.14–1.80) for individuals without known diabetes and HbA1c levels, What's new? Diabetes and cancer share a positive association, yet the relationship between cancer risk and the most reliable blood glucose marker, hemoglobin A1c (HbA1c), remains unclear. This large‐scale prospective study with strictly standardized HbA1c values in a Japanese population, which was cancer‐free at baseline, shows that elevated HbA1c levels are significantly associated with risk for all reported cancer sites in both sexes, independent of potential confounding factors. The findings support the idea that glycemic control is key to cancer prevention in both diabetic and nondiabetic individuals with high HbA1c levels.

To elucidate the individual impacts of insulin and blood glucose on cancer risk, we investigated the association of plasma C-peptide, a surrogated marker of insulin and glycated albumin (GA), a more stable marker of blood glucose, with all-site and site-specific cancer risk by mutually accounting for their confounding effects. The study was prospectively conducted with nearly 4,000 cancer cases arising in our population-based cohort of 33,736 subjects who answered the baseline questionnaire and supplied blood samples. After exclusion of subjects with apparent DM, analysis was done in 3,036 cancer cases and 3,667 subcohort subjects. Among men and women combined, highest levels of C-peptide were statistically significantly associated with an increased risk of all-site [Hazard ratio (HR): 1.21; 95% confidence interval: 1.02-1.42], colon [1.73; 1.20-2.47], liver [3.23; 1.76-5.91], kidney, renal pelvis and ureter cancers [2.47; 1.07-5.69], compared to the respective lowest levels, after adjustment for GA levels. Among these C-peptide-related cancers, colon and liver cancers also showed an increased risk associated with elevated GA levels independently of C-peptide levels. The corresponding HRs for colon and liver cancers compared to the highest and lowest GA levels were 1.43 [1.02-2.00] and 2.02 [1.15-3.55], respectively. Effect modification by gender was only evident for the association between C-peptide and colon cancer (p for interaction = 0.04). Higher insulin levels, independently of higher blood glucose levels, may be relevant to DM-related carcinogenesis for several cancer sites. Examination of circulating insulin levels is a plausible option in evaluating cancer risk even in individuals who have not developed DM.

Limited and inconsistent studies exist on the association between the intake of fish, n - 3 polyunsaturated fatty acids (PUFA) and n - 6 PUFA and breast cancer. Fish and n - 3 PUFA support various body functions and are thought to reduce the carcinogenesis risk while n - 6 PUFA may have a positive association with cancer risk. We examined the association between intake of fish, n - 3 PUFA [including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA)] and n - 6 PUFA and breast cancer with subanalyses on estrogen (ER) and progesterone receptor (PR) status. We investigated 38,234 Japanese women aged 45-74 years from the Japan Public Health Center-based prospective study (JPHC study), and during 14.1 years of follow-up time, 556 breast cancer cases were newly diagnosed. Breast cancer risk was not associated with the intake of total fish, n - 3 PUFA and n - 6 PUFA when analyzed in totality through multivariable Cox proportional hazards regression models with age as the time scale. Intake of total n - 6 was positively associated with the development of ER+PR+ tumors [multivariable-adjusted HR Q4 vs. Q1 = 2.94 (95% CI: 1.26-6.89; ptrend = 0.02)]. Intake of EPA was associated with a decreased breast cancer risk for ER+PR+ tumors [multivariable-adjusted HR Q2 vs. Q1 = 0.47 (95% CI: 0.25-0.89; ptrend =0.47)]. While the overall association between the intake of total fish, n - 3 PUFA and n - 6 PUFA and breast cancer risk is null, for ER+PR+ tumors, a positive association was seen between n - 6 intake and breast cancer, and a marginally significant inverse association was observed for EPA intake.

Coffee is a rich source of bioactive compounds that have potential anticarcinogenic effects. However, it remains unclear whether coffee drinking is associated with colorectal cancer. Also, despite different etiological factors involved in gut physiology, few studies have investigated this association by anatomical site of the lesion. To address these issues, this study examined the association between coffee drinking and colorectal cancer in a pooled analysis from 8 cohort studies conducted in Japan. Among 320,322 participants followed up for 4,503,274 person-years, 6,711 incident colorectal cancer cases were identified. Study-specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using Cox proportional hazards models and then pooled using the random effects model. Coffee drinking was not materially associated with colorectal cancer risk in men or women (pooled HR 0.92, 95% CI 0.82-1.03 in men and pooled HR 0.90, 95% CI 0.76-1.07 in women). Analysis by subsite showed a lower risk of colon cancer among female drinkers of ≥3 cups coffee/day (pooled HR 0.80, 95% CI 0.64-0.99). There was no such association in men. Coffee drinking was not associated with risk of rectal cancer in men or women. Results were virtually the same among never smokers except for an increased risk of rectal cancer associated with frequent coffee consumption. Coffee drinking may be associated with lower risk of colon cancer in Japanese women.

While many epidemiological studies have studied the association between lung cancer risk and fruits and vegetable consumption (the major sources of antioxidant vitamins), only a few have investigated the direct association with antioxidants in consideration of cancer subtypes and smoking status. Here, we examined the association between consumption of antioxidant vitamins and lung cancer risk in one of the largest prospective cohort studies in Japan. We investigated the association of dietary antioxidant vitamins intake, namely retinol, vitamin C, vitamin E, α-carotene, and β-carotene and subsequent incidence of lung cancer among 38,207 men and 41,498 women in the Japan Public Health Center-based prospective study. Cox proportional hazard regression was performed with adjustment for potential confounders and by strata of cancer subtypes and smoking status. Antioxidant and other dietary intakes were assessed using a food frequency questionnaire (FFQ). During 1,233,096 person-years of follow-up between 1995 and 2013, a total of 1,690 lung cancer cases were newly diagnosed. In a multivariate regression model, while higher retinol intake was positively associated with overall lung cancer risk in men (HR 1.26; 95% CI 1.05-1.51; p

Although coffee and green tea are suggested to reduce the risk of some types of cancers, only a few epidemiological studies have investigated their effect on the risk of acute myeloid leukemia (AML) and myelodysplastic syndromes (MDS). Here, we investigated the association of coffee and green tea consumption and the risk of AML and MDS in a large-scale population-based cohort study in Japan. A total of 95,807 Japanese subjects (45,937 men and 49,870 women; age 40-69 years at baseline) were followed to the end of 2012, for an average of 18 years. Hazard ratios (HRs) and 95% confidence intervals (95% CIs) for the association between coffee and green tea consumption at baseline and the risk of AML and MDS were assessed using a Cox proportional hazards model with adjustment for potential confounders. During 1,751.956 person-years, we identified 85 AML cases and 70 MDS cases. Our findings showed no significant association between coffee consumption and the risk of AML, or between green tea consumption and the risk of AML or MDS. In contrast, we observed a decreasing dose-response relationship between coffee consumption and the risk of MDS among men (almost none: reference, 1-4 times/week: HR = 0.83, 95% CI: 0.43-1.62; ≥1cups/day: HR = 0.47, 0.22-0.99, p for trend = 0.049). Stratified analysis by smoking status suggested that the observed relative risk for AML and MDS of coffee drinkers relative to non-coffee drinkers might be due to residual confounding by smoking. These findings deserve further investigation in future studies.

The association between alcohol consumption and bladder cancer risk has been insufficiently investigated in East Asian populations, who frequently have the inactive enzyme for metabolizing acetaldehyde. Given that acetaldehyde associated with alcohol consumption is assessed as a carcinogen, consideration of differences in acetaldehyde exposure would aid accuracy in assessing the bladder cancer risk associated with alcohol consumption. Here, we conducted a population-based cohort study in Japan to examine this association, including information on the flushing response as a surrogate marker of the capacity of acetaldehyde metabolism. Hazard ratios (HR) and 95% confidence intervals (CI) were estimated using multivariate Cox proportional hazard models. During follow up from 1990 through 2012 for the 95,915 subjects (45,649 men and 50,266 women, aged 40-69 years), 354 men and 110 women were newly diagnosed with bladder cancer. No significant association between alcohol consumption and bladder cancer risk was observed in the overall analysis. Among male flushers, HRs were 1.04 (95% CI 0.70-1.54), 1.67 (1.16-2.42), 1.02 (0.62-1.67) and 0.63 (0.33-1.20) for alcohol consumption of 1-150, 151-300, 301-450,450 g/week of pure ethanol compared with non-drinkers and occasional drinkers, respectively, indicating an inverted U-shaped association between alcohol consumption and bladder cancer risk. In contrast, no significant association was identified among male non-flushers. The marginally significant interaction between alcohol consumption and the flushing response (p for interaction = 0.083) may support our hypothesis that acetaldehyde derived from alcohol consumption is associated with bladder cancer risk. A prospective study considering polymorphisms of genes involved in acetaldehyde metabolism is warranted.

To date, the association between diabetes mellitus (DM) and gastric cancer has been controversial, including the underlying mechanism. We investigated the association between plasma diabetic biomarkers (insulin, C-peptide, and blood glucose) and gastric cancer risk. In addition, homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) were calculated. A total of 36,745 subjects aged 40-69 years in the Japan Public Health Center-based prospective study (JPHC) who returned the baseline questionnaire and provided blood samples were followed from 1990 to 2004. In the present analysis, 477 cases and 477 matched controls were used. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) for developing gastric cancer were calculated using conditional logistic regression models. Plasma insulin was positively associated with increased risk of gastric cancer; compared to tertile 1, ORs were 1.69 (95% CI = 1.11-2.59) and 2.01 (1.19-3.38) for tertiles 2 and 3, respectively (p for trend = 0.009). In men, C-peptide was also positively associated with a significant risk; corresponding ORs were 1.42 (0.85-2.38) and 1.91 (1.03-3.54), respectively (p for trend = 0.04). These findings were confirmed for blood samples from the fasting group (≥8 hr after a meal). Higher HOMA-IR was also associated with increased risk, whereas no association was observed for blood glucose. Our findings suggest that Japanese population with higher insulin and C-peptide levels derived from insulin resistance have an elevated risk of gastric cancer.

Although alcohol and smoking have not been established as risk factors for prostate cancer, they are important risk factors for other human cancers and potentially major avoidable factors. Alcohol drinkers and smokers might be less likely to get screening, which might lead to attenuation of the positive association. Here, we investigated the association of alcohol drinking and smoking and prostate cancer according to stage, as well as prostate cancer detected by subjective symptoms, in a large prospective study among Japanese men. The Japan Public Health Center-based prospective study (JPHC study) was established in 1990 for Cohort I and in 1993 for Cohort II. Subjects were 48,218 men aged 40–69 years who completed a questionnaire, which included their alcohol and smoking habits at baseline, and who were followed until the end of 2010. During 16 years of follow-up, 913 men were newly diagnosed with prostate cancer; of whom 248 had advanced cases, 635 were organ-localized and 30 were of an undetermined stage. Alcohol consumption was dose-dependently associated with advanced prostate cancer [nondrinkers: reference, 0–150 g/week: hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 0.83–1.82; 150–300 g/week: HR = 1.51, 95% CI = 1.04–2.19; ≥300 g/week: HR = 1.41, 95% CI = 0.97–2.05, p for trend = 0.02]. The positive association was not substantially changed among cancers detected by subjective symptoms. Smoking was inversely associated with prostate cancer among total subjects, but tended to increase the risk of advanced prostate cancer detected by subjective symptoms. In conclusion, abstinence from alcohol and prohibition of smoking might be important factors in the prevention of advanced prostate cancer.

Cytochrome P450 (CYP) 1A1 and glutathione S-transferases (GST) M1 and T1 are major enzymes in the carcinogen metabolizing pathway. We examined the association between single nucleotide polymorphisms (SNPs) of CYP1A1 (rs4646421, rs4646422 and rs1048943), GSTM1 and GSTT1 and gastric cancer risk in Japan. This is a nested case-control study (457 cases and 457 matched controls) of our population-based cohort involving 36,745 subjects who answered a baseline questionnaire and supplied blood samples. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) were calculated using conditional logistic regression models. We found that CYP1A1 (rs4646422) variant allele was associated with a statistically significant increased risk of gastric cancer compared with the homozygous wild-type genotype (OR = 1.65; 95% CI = 1.17-2.32). GSTM1 null, GSTT1 null and GSTM1/T1 both or either null genotypes were associated with increased risk, but not statistically significantly. Combination of the CYP1A1 (rs4646422) variant allele and GSTM1/T1 both or either null genotypes was associated with a statistically significant increased risk compared with the combination of the CYP1A1 homozygous wild-type genotype and the GSTM1/T1 both active genotypes. In addition, compared with CYP1A1 (rs4646422) homozygous wild-type genotypes in those who were never-smokers, CYP1A1 variant alleles in those who smoked ≥30 pack-years were associated with an increased risk; neither gene-gene nor gene-environment interactions were significant. The CYP1A1 (rs4646422) polymorphism might be involved in gastric carcinogenesis among the Japanese population.

Because studies of the association between alcohol intake and the risk of primary liver cancer use varying cut-off points to classify alcohol intake, it is difficult to precisely quantify this association by meta-analysis of published data. Furthermore, there are limited data for women in prospective studies of the dose-specific relation of alcohol intake and the risk of primary liver cancer. We analyzed original data from 4 population-based prospective cohort studies encompassing 174,719 participants (89,863 men and 84,856 women). After adjustment for a common set of variables, we used Cox proportional hazards regression to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of primary liver cancer incidence according to alcohol intake. We conducted a meta-analysis of the HRs derived from each study. During 1,964,136 person-years of follow-up, 804 primary liver cancer cases (605 men and 199 women) were identified. In male drinkers, the multivariate-adjusted HRs (95% CI) for alcohol intakes of 0.1-22.9, 23.0-45.9, 46.0-68.9, 69.0-91.9 and ≥92.0 g/day, as compared to occasional drinkers, were 0.88 (0.57-1.36), 1.06 (0.70-1.62), 1.07 (0.69-1.66), 1.76 (1.08-2.87) and 1.66 (0.98-2.82), respectively (p for trend = 0.015). In women, we observed a significantly increased risk among those who drank ≥23.0 g/day, as compared to occasional drinkers (HR: 3.60; 95% CI: 1.22-10.66). This pooled analysis of data from large prospective studies in Japan indicates that avoidance of (1) heavy alcohol drinking (≥69.0 g alcohol/day) in men and (2) moderate drinking (≥23.0 g alcohol/day) in women may reduce the risk of primary liver cancer.

Few prospective studies have investigated the association between BMI at age 20 years (BMI20y) and breast cancer risk with consideration to estrogen/progesterone receptor status (ER/PR). We evaluated the association between BMI20y and ER/PR-defined breast cancer risk among 41,594 women in the population-based Japan Public Health Center-based Prospective Study. Anthropometric factors were assessed using self-reported questionnaires. Relative risks (RRs) were estimated by Cox proportional hazards regression models. Through to the end of 2006, 452 breast cancer cases were identified. We observed a statistically significant inverse association between BMI20y and breast cancer incidence [multivariable-adjusted RR for each 5-unit increment 0.75 (95%CI=0.61-0.92)], which was not modified by menopausal or recent BMI status. In contrast, recent BMI and subsequent BMI gain were not associated with increased risk among premenopausal women, but were substantially associated with increased risk among postmenopausal women [corresponding RR(recent BMI)=1.31 (95%CI=1.07-1.59); RR(subsequent BMI gain)=1.32 (95%CI=1.09-1.60)]. In subanalyses by receptor status (∼50% of cases), the observed inverse association of BMI20y with risk was consistent with the result for ER-PR- [0.49 (95%CI=0.27-0.88)], while the observed positive associations of BMI gain with postmenopausal breast cancer risk appeared to be confined to ER+PR+ tumors [corresponding RR(for subsequent BMI gain)=2.24 (95%CI=1.50-3.34)]. Low BMI at age 20 years was substantially associated with an increased risk of breast cancer. In contrast, high recent BMI and subsequent BMI gain from age 20 were associated with increased risk of postmenopausal ER+PR+ tumors.

Epidemiological studies have evaluated whether the impact of alcohol intake on breast cancer risk is modified by use of exogenous estrogens, folate intake, body weight and smoking status, but results have been inconsistent. Further, effect modification by intake of isoflavones and alcohol-induced facial flushing, which are prevalent in Asian populations, have not been investigated. We investigated the association between alcohol intake and breast cancer risk and whether the association is modified by these factors among 50,757 premenopausal and postmenopausal women (aged 40-69 years) in the population-based Japan Public Health Center-based Prospective Study. Alcohol consumption and other related factors were assessed using self-reported questionnaires. Through to the end of 2006, 572 patients were identified. Relative risks (RRs) and 95% confidence intervals (CIs) were estimated by hazard ratios derived from Cox proportional hazards regression models. Compared with never-drinkers, regular alcohol drinkers (>150 g of ethanol/week) had a higher risk of the development of breast cancer; the multivariable-adjusted RRs were 1.75 (95% CI = 1.16-2.65; p(trend) = 0.035) for overall, 1.78 (95% CI = 1.09-2.90) for premenopausal and 1.21 (95% CI = 0.53-2.75) for postmenopausal women. There was no statistical evidence for effect modification by menopausal status, use of exogenous estrogens, intakes of isoflavone and folate, body weight, alcohol-induced facial flushing or smoking (All p(interactions) > or = 0.15). Excessive alcohol intake was associated with an increase in the risk of breast cancer in this population. There was no statistical evidence for effect modification.

An inverse association between serum total cholesterol and cancer mortality cast a controversy for cause or result of low cholesterol on cancer risk. Therefore, we examined a total of 33,368 Japanese men and women aged 40-69 years, who were free of prior diagnosis of cancer and cardiovascular disease, undertook serum total cholesterol measurement and completed a food frequency questionnaire between 1990 and 1994. They were followed to ascertain incident total and major sites of cancer until the end of 2004 to examine sex-specific associations between cholesterol and cancer risk by incident time, stage and virus infection. After 412,714 person-years of follow-up, 2,728 incident cancers were documented. Serum total cholesterol levels were inversely associated with risk of total cancer in men, with strong inverse associations with stomach cancer in men and liver cancer in both sexes. After exclusion for first 3-year incident cases and advanced cases with metastasis, the inverse association diminished for total and stomach cancers but remained for liver cancer. The multivariable hazard ratios (95% CI) for serum total cholesterol

Although smoking is a major cause of lung cancer, the proportion of lung cancer cases among Japanese women who never smoked is high. As the prevalence of smoking in Japan is relatively high in men but low in women, the development of lung cancer in non-smoking Japanese women may be significantly impacted by passive smoking. We conducted a population-based prospective study established in 1990 for Cohort I and in 1993 for Cohort II. The study population was defined as all residents aged 40-69 years at the baseline survey. 28,414 lifelong non-smoking women provided baseline information on exposure to tobacco smoke from their husband, at the workplace and during childhood. Over 13 years of follow-up, 109 women were newly diagnosed with lung cancer, of whom 82 developed adenocarcinoma. Compared with women married to never smokers, hazard ratio (HR) [95% confidence interval (CI)] for all lung cancer incidence in women who lived with a smoking husband was 1.34 (95% CI 0.81-2.21). An association was clearly identified for adenocarcinoma (HR 2.03, 95% CI 1.07-3.86), for which dose-response relationships were seen for both the intensity (p for trend = 0.02) and amount (p for trend = 0.03) of the husband's smoking. Passive smoking at the workplace also increased the risk of lung cancer (HR 1.32, 95% CI 0.85-2.04). Moreover, a higher risk of adenocarcinoma was seen for combined husband and workplace exposure (HR 1.93, 95% CI 0.88-4.23). These findings confirm that passive smoking is a risk factor for lung cancer, especially for adenocarcinoma among Japanese women.

Gastric cancer is a particularly important issue in Japan, where incidence rates are among the highest observed. In this work, we provide a risk prediction model allowing the estimation of the 10-year cumulative probability of gastric cancer occurrence. The study population consisted of 19,028 individuals from the Japanese Public Health Center cohort II who were followed-up from 1993 to 2009. A parametric survival model was used to assess the impact on the probability of gastric cancer of clinical and lifestyle-related risk factors in combination with serum anti-Helicobacter pylori antibody titres and pepsinogen I and pepsinogen II levels. Based on the resulting model, cumulative probability estimates were calculated and a simple risk scoring system was developed. A total of 412 cases of gastric cancer occurred during 270,854 person-years of follow-up. The final model included (besides the biological markers) age, gender, smoking status, family history of gastric cancer and consumption of highly salted food. The developed prediction model showed good predictive performance in terms of discrimination (optimism-corrected c-index: 0.768) and calibration (Nam and d'Agostino's χ(2) test: 14.78; p values = 0.06). Estimates of the 10-year probability of gastric cancer occurrence ranged from 0.04% (0.02, 0.1) to 14.87% (8.96, 24.14) for men and from 0.03% (0.02, 0.07) to 4.91% (2.71, 8.81) for women. In conclusion, we developed a risk prediction model for gastric cancer that combines clinical and biological markers. It might prompt individuals to modify their lifestyle habits, attend regular check-up visits or participate in screening programmes.

Limited and inconsistent studies exist on the association between the intake of fish, n - 3 polyunsaturated fatty acids (PUFA) and n - 6 PUFA and breast cancer. Fish and n - 3 PUFA support various body functions and are thought to reduce the carcinogenesis risk while n - 6 PUFA may have a positive association with cancer risk. We examined the association between intake of fish, n - 3 PUFA [including eicosapentaenoic acid (EPA), docosahexaenoic acid (DHA), docosapentaenoic acid (DPA) and alpha-linolenic acid (ALA)] and n - 6 PUFA and breast cancer with subanalyses on estrogen (ER) and progesterone receptor (PR) status. We investigated 38,234 Japanese women aged 45-74 years from the Japan Public Health Center-based prospective study (JPHC study), and during 14.1 years of follow-up time, 556 breast cancer cases were newly diagnosed. Breast cancer risk was not associated with the intake of total fish, n - 3 PUFA and n - 6 PUFA when analyzed in totality through multivariable Cox proportional hazards regression models with age as the time scale. Intake of total n - 6 was positively associated with the development of ER+PR+ tumors [multivariable-adjusted HR Q4 vs. Q1 = 2.94 (95% CI: 1.26-6.89; ptrend = 0.02)]. Intake of EPA was associated with a decreased breast cancer risk for ER+PR+ tumors [multivariable-adjusted HR Q2 vs. Q1 = 0.47 (95% CI: 0.25-0.89; ptrend =0.47)]. While the overall association between the intake of total fish, n - 3 PUFA and n - 6 PUFA and breast cancer risk is null, for ER+PR+ tumors, a positive association was seen between n - 6 intake and breast cancer, and a marginally significant inverse association was observed for EPA intake.

Although a link between female hormonal factors and the risk of lung cancer has been suggested, few studies have examined this association in detail. We investigated the associations between reproductive factors, hormone use and the risk of lung cancer in a population-based prospective study. Self-administered questionnaires were distributed to 44,677 lifelong never-smoking women in 1990-1994 to assess menstrual and reproductive factors and hormone use. After 8-12 years of follow-up, 153 lung cancer cases were diagnosed. Relative risk (RR) and 95% confidence intervals (CI) were calculated using the Cox proportional hazards model. Age at menopause, age at menarche, number of children, age at first live birth, breast feeding and use of hormones were not associated with a risk of lung cancer, either overall or among postmenopausal women or women with natural menopause. Compared to women with both late age at menarche (or =16) and early age at menopause (or =50), those with either early age at menarche or late age at menopause had a2-fold, significant increase in the risk of lung cancer. Induced menopausal women with experience of hormone replacement therapy had a significantly elevated risk compared to naturally menopausal women without female hormone use, with an RR of 2.40 (95% CI 1.07-5.40). These findings suggest that both endogenous and extraneous estrogen may be involved in the etiology of lung cancer.

To clarify whether reproductive factors have an impact on gastric cancer in Japanese females, a case-control study was conducted using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), Japan. The study subjects included 365 postmenopausal women with gastric cancer and 1,825 age-class frequency-matched noncancer outpatients presenting at Aichi Cancer Center in 1988-1998. Cases were further divided with regard to the anatomic subsite (upper third, middle third, lower third) and histologic subtypes (differentiated, nondifferentiated) and the association was evaluated using odds ratios (ORs) estimated by the logistic regression model, adjusting for potential confounding factors. A high body weight and corresponding body mass index at age 20 moderately increased the risk of gastric cancer, especially for middle third and nondifferentiated cancers. Risk fluctuation with early or late age at menarche and menopause and total duration of fertility was not consistent. Individuals with a high age at first parity tended to show decreased risk of cancer, irrespective of their subsite or histologic subtype. The ORs were decreased with a short average period of breastfeeding, especially for upper third and nondifferentiated cancers. From these results, however, it appears that height, weight, menstrual and reproductive factors have less impact on gastric cancer than environmental factors such as smoking and dietary habits or family history of gastric cancer.

To date, the association between diabetes mellitus (DM) and gastric cancer has been controversial, including the underlying mechanism. We investigated the association between plasma diabetic biomarkers (insulin, C-peptide, and blood glucose) and gastric cancer risk. In addition, homeostasis model assessment of insulin resistance (HOMA-IR) and homeostasis model assessment of β-cell function (HOMA-β) were calculated. A total of 36,745 subjects aged 40-69 years in the Japan Public Health Center-based prospective study (JPHC) who returned the baseline questionnaire and provided blood samples were followed from 1990 to 2004. In the present analysis, 477 cases and 477 matched controls were used. The odds ratios (ORs) and their corresponding 95% confidence intervals (CIs) for developing gastric cancer were calculated using conditional logistic regression models. Plasma insulin was positively associated with increased risk of gastric cancer; compared to tertile 1, ORs were 1.69 (95% CI = 1.11-2.59) and 2.01 (1.19-3.38) for tertiles 2 and 3, respectively (p for trend = 0.009). In men, C-peptide was also positively associated with a significant risk; corresponding ORs were 1.42 (0.85-2.38) and 1.91 (1.03-3.54), respectively (p for trend = 0.04). These findings were confirmed for blood samples from the fasting group (≥8 hr after a meal). Higher HOMA-IR was also associated with increased risk, whereas no association was observed for blood glucose. Our findings suggest that Japanese population with higher insulin and C-peptide levels derived from insulin resistance have an elevated risk of gastric cancer.

With the use of data from the hospital-based epidemiologic research program at Aichi Cancer Center (HERPACC), the effect of body size on the risk of breast cancer was evaluated among Japanese women, who are generally leaner than white women. In total, 1,359 breast-cancer cases were included, and 24,207 women, confirmed as free of cancer, were recruited as a reference group. Odds ratios (OR) and 95% confidence intervals (95% CI) were determined by multiple-logistic regression analysis. Separate analyses were performed for pre- and post-menopausal women. Furthermore, stratification by decade of age was done to evaluate the effect of body size on the development of breast cancer. The results obtained from the present study were as follows. (1) Current body-mass index (BMI) was positively associated with postmenopausal breast cancer (OR 2.08, 95% CI 1.49-2.92 for highest quintile vs. lowest), although higher BMI did not affect the risk in pre-menopausal women. (2) Estimates of risk were below unity for BMI at around age 20 in post-menopausal women. (3) After stratifying BMI at around age 20, gaining BMI in later life was positively associated with increased risk, regardless of BMI in early life. These findings suggest that avoidance of marked weight gain during adult life, especially after natural menopause and/or after age 60, may reduce the risk of breast cancer.

Although alcohol and smoking have not been established as risk factors for prostate cancer, they are important risk factors for other human cancers and potentially major avoidable factors. Alcohol drinkers and smokers might be less likely to get screening, which might lead to attenuation of the positive association. Here, we investigated the association of alcohol drinking and smoking and prostate cancer according to stage, as well as prostate cancer detected by subjective symptoms, in a large prospective study among Japanese men. The Japan Public Health Center-based prospective study (JPHC study) was established in 1990 for Cohort I and in 1993 for Cohort II. Subjects were 48,218 men aged 40-69 years who completed a questionnaire, which included their alcohol and smoking habits at baseline, and who were followed until the end of 2010. During 16 years of follow-up, 913 men were newly diagnosed with prostate cancer; of whom 248 had advanced cases, 635 were organ-localized and 30 were of an undetermined stage. Alcohol consumption was dose-dependently associated with advanced prostate cancer [nondrinkers: reference, 0-150 g/week: hazard ratio (HR) = 1.23, 95% confidence interval (CI) = 0.83-1.82; 150-300 g/week: HR = 1.51, 95% CI = 1.04-2.19; ≥ 300 g/week: HR = 1.41, 95% CI = 0.97-2.05, p for trend = 0.02]. The positive association was not substantially changed among cancers detected by subjective symptoms. Smoking was inversely associated with prostate cancer among total subjects, but tended to increase the risk of advanced prostate cancer detected by subjective symptoms. In conclusion, abstinence from alcohol and prohibition of smoking might be important factors in the prevention of advanced prostate cancer.

To date, epidemiologic studies investigating intake of n-3 and n-6 polyunsaturated fatty acids and risk of colorectal cancer are limited, and results remain inconsistent. This is the first prospective study to show the association by subsite (proximal colon, distal colon, rectum). To clarify the role of n-3 and n-6 polyunsaturated fatty acids intake in colon carcinogenesis, we conducted a large, population-based prospective study, characterized by high fish consumption and a wide range of n-3 polyunsaturated fatty acids intakes. Subjects were followed from response to a lifestyle questionnaire in 1995-1999 through 2006. During 827,833 person-years of follow-up (average 9.3 years), we identified 1,268 new colorectal cancer cases (521 colon and 253 rectal for men; 350 colon and 144 rectal for women). Compared to the lowest quintile, the relative risk and 95% confidence interval of developing cancer among the fifth quintile of marine n-3 polyunsaturated fatty acids intake were 0.60 and 0.31-1.14, respectively (p for trend = 0.04) in the colon in women and 0.35 and 0.14-0.88 (p for trend = 0.05) and 1.82 and 0.79-4.20 (p for trend = 0.16) in the proximal and distal colon, respectively, in men. For rectal cancer, the dose response for marine n-3 polyunsaturated fatty acids s was unclear; rather, we observed U-shaped associations in men and women. We found no evidence that n-6 polyunsaturated fatty acids increases or the n-3/n-6 ratio decreases the risk of colorectal cancer. Our results suggest that intake of marine n-3 polyunsaturated fatty acids may be inversely related to the risk of cancer in the proximal site of the large bowel.

The incidence of hepatocellular carcinoma (HCC) is much higher in men than in women. Several experiment and epidemiological studies have suggested that estrogen might play an inhibitory role in the development of HCC. Because isoflavones have a similar structure as 17beta-estradiol and appear to have an anti-estrogenic effect in women and estrogenic effect in men, we hypothesized that the effect of isoflavones on HCC differs by sex. We investigated the association between isoflavones (genistein and daidzein) and soy products and HCC in Japan in a population-based prospective study in 19,998 Japanese (7,215 men and 12,783 women) aged 40-69 years. During 11.8 years of follow-up, 101 subjects (69 men and 32 women) were newly diagnosed with HCC. Case patients were grouped according to consumption of isoflavones and soy products and stratified by hepatitis virus infection. Hazard ratios (HRs) and 95% confidence intervals (CIs) for HCC were calculated by Cox proportional-hazards modeling. In women, genistein and daidzein were dose-dependently associated with an increased risk of HCC, with multivariable HRs for the highest versus lowest tertile of 3.19 (95%CI = 1.13-9.00, p(trend) = 0.03) and 3.90 (95% CI = 1.30-11.69, p(trend) = 0.01), respectively. No association between isoflavones and HCC was observed in men. These results persisted when analysis was restricted to subjects positive for either or both hepatitis C and B virus. In conclusion, isoflavone consumption may be associated with an increased risk of HCC in women. Women with hepatitis virus infection may be advised to abstain from isoflavone consumption. Further studies are warranted to confirm these findings.

Coffee has been proposed to decrease the circulating insulin and estrogen levels, which are related to the development of endometrial cancer. However, few studies have prospectively assessed the association between coffee consumption and endometrial cancer. We conducted a population-based prospective cohort study in 53,724 Japanese women aged 40-69 years with no history of cancer at baseline in 1990-1994. We used Cox proportional hazards regression analysis to estimate the hazard ratio (HR) and 95% confidence interval (CI) of endometrial cancer incidence in relation to coffee consumption. All reported p values are 2-tailed. During the 15-year follow-up period, we documented 117 cases of endometrial cancer. Coffee consumption was significantly associated with a decreased risk of endometrial cancer. After adjustment for age, study area, body mass index, menopausal status, age at menopause for postmenopausal women, parity, use of exogenous female hormones, smoking status and by consumption of green vegetables, beef, pork and green tea, the multivariate HRs (95% CI) of endometrial cancer in women who drank coffee/=2 days/week, 3-4 days/week, 1-2 cups/day and/=3 cups/day were 1.00, 0.97 (0.56-1.68), 0.61 (0.39-0.97) and 0.38 (0.16-0.91), respectively (p for trend = 0.007). In contrast, green tea consumption was not significantly associated with a reduced risk of endometrial cancer (p for trend = 0.22). The inverse association between coffee consumption and risk of endometrial cancer was consistently observed in subgroup analyses stratified by potential confounders. Coffee consumption may be associated with a decreased risk of endometrial cancer.

Epidemiological studies have consistently demonstrated a decrease in the risk of esophageal squamous cell carcinoma (SCC) associated with higher fruit and vegetable intake, although the association has been examined predominantly in case-control studies. Here, we conducted a population-based prospective cohort study among middle-aged Japanese men. Lifestyle characteristics were investigated using a self-administered questionnaire, which included a validated food frequency questionnaire with 138 food and beverage items. We followed a total of 38,790 men aged 45-74 years. A Cox proportional hazards model was used to estimate the hazard ratios (HRs) and 95% confidence intervals (95% CIs) for esophageal SCC, with adjustment for potential confounders. During 297,651 person-years of follow-up, a total of 116 men were newly diagnosed with esophageal SCC. An increase in consumption of total fruit and vegetables by 100 grams per day (g/day) was associated with an 11% decrease in the incidence of esophageal SCC (95% CI: 1-21%). In particular, a higher intake of cruciferous vegetables was associated with a significant decrease in risk (HR per 100 g/day: 0.44; 95% CI: 0.23-0.82). Stratified analyses revealed that the beneficial effect of fruits and vegetables was not able to completely offset the harmful effect of tobacco and alcohol. Our findings provide further evidence for the protective role of fruits and vegetables in the development of esophageal SCC. To effectively reduce the burden of this disease, however, priority should be placed on smoking and drinking cessation. Finally, cruciferous vegetables deserve further investigation as foods possibly effective in the prevention of esophageal SCC.

We prospectively examined the association between coffee consumption and the risk of developing colorectal cancer in a large population-based cohort study (the JPHC Study) of Japanese men and women. Data were analyzed from a population-based cohort of 96,162 subjects (46,023 men and 50,139 women). A total of 1,163 incident colorectal cancers were identified during the follow-up period, including 763 cases of colon cancer and 400 of rectal cancer. We observed a significant inverse association between coffee consumption and the risk of developing invasive colon cancer among women. Compared with those who almost never consumed coffee, women who regularly consumed 3 or more cups of coffee per day had a RR of 0.44 (95% CI = 0.19-1.04; p for trend = 0.04) after adjustment for potential confounding factors. However, no significant association was found for rectal cancer in women. In men, no significant decrease was observed in any colorectal cancer site. Further, additional analyses on the association of green tea consumption with colorectal cancer risk found no significant association in men or women. These findings suggest that coffee consumption may lower the risk of colon cancer among Japanese women.

The physical inactivity and obesity involved in hyperglycemia and hyperinsulinemia is supposed to lead to an increased bioavailability of insulin-like growth factor-I (IGF-I). The carcinogenic effect of IGF-I may be influenced by IGF binding proteins. We investigated the association between plasma levels of C-peptide, a surrogate biomarker of insulin, IGFBP-1, IGF-I or IGFBP-3, and the risk of colorectal cancer in a nested case-control study. During an 11.5-year follow-up, 375 newly diagnosed colorectal cancers were identified in a cohort of 38,373 adults who had returned the baseline questionnaire and provided blood samples. Two matched-controls for each case were selected from the cohort. The odds ratio (OR) of colorectal cancer for plasma levels of each protein was estimated using the conditional logistic regression model adjusted for potential confounding factors. We observed a statistically significant association of plasma C-peptide with colorectal cancer only in men. The ORs were 1.0, 2.3, 2.8 and 3.2 along with quartiles (p trend, 0.0072). The association was stronger in colon cancer (p trend, 0.025) than in rectal cancer (p trend, 0.24). Other peptides were not associated with the risk in either men or women. The results did not change when repeatedly analyzed by tumor invasion levels, tumor sites or follow-up periods. In conclusion, a higher plasma C-peptide may indicate a subsequent risk of colorectal cancer in Japanese men.

Results on the association of dietary fiber intake with colorectal cancer risk were inconsistent among previous large prospective studies, but studies in non-Western populations are lacking. Consequently, the authors investigated the association between dietary fiber intake and the subsequent risk of colorectal cancer in a prospective cohort study of a Japanese population. Dietary fiber intake was estimated from food-frequency questionnaires comprising 44 or 52 items at the baseline survey and 138 food items at a 5-year follow-up survey. The authors identified 907 cases of colorectal adenocarcinoma diagnosed pathologically in 86,412 subjects during a 10-year follow-up from the baseline survey. After the 5-year follow-up survey, 522 cases were identified in 78,326 subjects during a 5.8-year follow-up. The authors estimated the multivariate-adjusted hazard ratios of colorectal cancer for dietary fiber intake using Cox's proportional hazards model. The authors found no statistically significant association between dietary fiber intake and colorectal cancer in analyses using data either from the baseline survey or from the 5-year follow-up survey. However, the risk of only the lowest quintile was high, compared with the second to the fifth quintiles. Furthermore, the lowest subtertile in the lowest quintile was associated with an increased risk in women (hazard ratio(Sub1 vs. Q5), 2.3; 95% confidence interval, 1.0-5.2). In conclusion, although a minor effect cannot be ruled out, the results did not support a hypothesis of a dose-dependent protective effect of dietary fiber intake against colorectal cancer.

We prospectively investigated the association between gastric cancer screening and subsequent risk of gastric cancer in a large-scale population-based prospective cohort study, with a 13-year follow-up in Japan. Data were analyzed from a population-based cohort of 42,150 (20,326 men and 21,824 women) subjects. Approximately 36% of subjects reported that they had undergone screening photofluorography during the preceding 12 months, and were regarded as the screened group. A total of 179 gastric cancer deaths and 636 incident gastric cancers were identified during the follow-up period. We observed a 2-fold decrease in gastric cancer mortality in screened versus unscreened subjects (RR = 0.52; 95% CI = 0.36-0.74). The extent of the reduction in mortality for gastric cancer was greater than in death from all causes excluding gastric cancer (RR = 0.71; 95% CI = 0.65-0.78). A significant decrease in the incidence of advanced gastric cancer was observed in screened subjects (RR = 0.75; 95% CI = 0.58-0.96), although the overall incidence rate did not differ significantly between the screened and unscreened subjects (RR = 1.06; 95% CI = 0.90-1.25). In age-stratified analyses, a significant reduction in gastric cancer mortality was seen in screened subjects aged 40-49 years at baseline, compared with a lesser reduction in screened subjects aged 50-59 (RR = 0.30, 95% CI = 0.13-0.72; and RR = 0.60, 95% CI = 0.40-0.88, respectively). These findings suggest that gastric cancer screening may be associated with a reduced risk of mortality from gastric cancer.

To find specific risk factors of gastric cancer (GC) independent of GC family history (GCFH), 2 studies were conducted using the database of the Hospital-based Epidemiological Research Program at Aichi Cancer Center: (i) a comparison of lifestyles between non-cancer cases with positive and negative GCFH status and (ii) a case-reference investigation of subjects with and without GCFH, treated separately. The first showed no significant variation of GCFH status with regard to smoking, drinking and most food habits. Multivariate analyses in the case-referent studies revealed odds ratios (ORs) for GC associated with habitual smoking of 2.78 (95% CI 1.22–6.28) for those with and 2.74 (95% CI 1.76–4.26) for those without GCFH. In individuals with GCFH, an independently lowered OR (0.52, 95% CI 0.27–0.99) was evident for frequent consumption of raw vegetables, whereas the opposite was noted for pickled vegetables (2.39, 95% CI 1.28–4.45). No statistically significant interaction was found between GCFH and selected lifestyle items. In conclusion, our results suggest a limited influence of GCFH on risk factors for GC. Int. J. Cancer 86:421–424, 2000. © 2000 Wiley-Liss, Inc.

A comparative case-referent study was conducted using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC), with the aim of clarifying whether histologic subtypes of gastric cancer exhibit different risk-factor patterns of habitual smoking. Our study comprised 995 histologically confirmed gastric-cancer cases [460 differentiated (intestinal type), 527 non-differentiated (diffuse type) and 8 unclassified], identified via hospital cancer registry and surgical records, and 43,846 non-cancer outpatients at Aichi Cancer Center Hospital over the years 1988-1995. Odds ratios (ORs) were estimated by gender using logistic regression and adjusted for potential confounding factors. In males, a significantly increased OR of gastric cancer was observed for habitual smokers, and this was higher in the differentiated type than the non-differentiated type and in younger than in older age groups. Risk patterns were less clear in females. Our results suggest that habitual smoking is associated more likely with the differentiated type of gastric cancer, particularly in younger cases.

To investigate the association between atrophic gastritis and gastric cancer and to identify the risk and protective factors for the progression of atrophic gastritis to cancer, we conducted a prospective study on 5,373 subjects with neither cancer nor resected stomach who underwent gastroscopic examination and completed a life-style questionnaire. After an average of 6 years of follow-up, 69 gastric-cancer cases were identified, 65 from the subjects without atrophic gastritis and 4 from the subjects without atrophic gastritis. The presence of atrophic gastritis increased the risk of gastric cancer 2.19-fold, the risk trend increasing with the degree and the extension of atrophy [relative risk (RR) 1.60 for mild atrophy and 2.85 for moderate and severe atrophy]. Among the subjects with atrophic gastritis, family history of gastric cancer (RR 2.27) and a preference for spicy food (RR 1.84) increased the risk and self-administered meal controls, such as portion reduction (RR 0.44) reduction of salty food (RR 0.56) and the change to the consumption of easily digested food (RR 0.57) decreased the risk of gastric cancer. The results of this study suggest that atrophic gastritis increases the risk of gastric cancer but that dietary modification prevents the progression from atrophic gastritis to gastric cancer, regardless of pre-cancerous lesions.

To clarify the effects of life-style on gastric cancer by subsite focusing on the proximal part (cardia and fundus) and the distal part (pyloric antrum), a case-control study was conducted at the Aichi Cancer Center in Nagoya, Japan from 1988-1991. This study compared 668 histologically confirmed gastric cancer cases [123 cardia, 218 middle (body), 256 antrum, and 71 unclassified] with 668 controls using a common questionnaire about life-styles as related to smoking, drinking, dietary habits and frequency of food intake. Controls were selected from among outpatients of the same hospital. Controls free of cancer and other specific diseases were matched with cases for sex, age (within 2 years), and time of hospital visit (within 2 months). A Western-style breakfast decreased the risk of antrum cancer, while consumption of greasy food increased the risk of cardia cancer. Fresh vegetables decreased the risk of cancer in both cardia and antrum. Habitual smoking is associated with increased risk of gastric cancer and it is more prominent in cardia cancer, especially in those who are drinkers. Results obtained from this study suggest that risk factors and relative risks of gastric cancer varied by subsite to a considerable degree. Furthermore, the joint effect of smoking and drinking may play an important role in the development of gastric cancer, especially of cardia cancer.