A risk prediction model for head and neck cancers incorporating lifestyle factors, HPV serology and genetic markers.

Head and neck cancer is often diagnosed late and prognosis for most head and neck cancer patients remains poor. To aid early detection, we developed a risk prediction model based on demographic and lifestyle risk factors, human papillomavirus (HPV) serological markers and genetic markers. A total of 10 126 head and neck cancer cases and 5254 controls from five North American and European studies were included. HPV serostatus was determined by antibodies for HPV16 early oncoproteins (E6, E7) and regulatory early proteins (E1, E2, E4). The data were split into a training set (70%) for model development and a hold-out testing set (30%) for model performance evaluation, including discriminative ability and calibration. The risk models including demographic, lifestyle risk factors and polygenic risk score showed a reasonable predictive accuracy for head and neck cancer overall. A risk model that also included HPV serology showed substantially improved predictive accuracy for oropharyngeal cancer (AUC = 0.94, 95% CI = 0.92-0.95 in men and AUC = 0.92, 95% CI = 0.88-0.95 in women). The 5-year absolute risk estimates showed distinct trajectories by risk factor profiles. Based on the UK Biobank cohort, the risks of developing oropharyngeal cancer among 60 years old and HPV16 seropositive in the next 5 years ranged from 5.8% to 14.9% with an average of 8.1% for men, 1.3% to 4.4% with an average of 2.2% for women. Absolute risk was generally higher among individuals with heavy smoking, heavy drinking, HPV seropositivity and those with higher polygenic risk score. These risk models may be helpful for identifying people at high risk of developing head and neck cancer.

Lung Cancer Absolute Risk Models for Mortality in an Asian Population using the China Kadoorie Biobank.

BACKGROUND: Lung cancer is the leading cause of cancer mortality globally. Early detection through risk-based screening can markedly improve prognosis. However, most risk models were developed in North American cohorts of smokers, whereas less is known about risk profiles for never-smokers, which represent a growing proportion of lung cancers, particularly in Asian populations. METHODS: Based on the China Kadoorie Biobank, a population-based prospective cohort of 512 639 adults with up to 12 years of follow-up, we built Asian Lung Cancer Absolute Risk Models (ALARM) for lung cancer mortality using flexible parametric survival models, separately for never and ever-smokers, accounting for competing risks of mortality. Model performance was evaluated in a 25% hold-out test set using the time-dependent area under the curve and by comparing model-predicted and observed risks for calibration. RESULTS: Predictors assessed in the never-smoker lung cancer mortality model were demographics, body mass index, lung function, history of emphysema or bronchitis, personal or family history of cancer, passive smoking, and indoor air pollution. The ever-smoker model additionally assessed smoking history. The 5-year areas under the curve in the test set were 0.77 (95% confidence interval = 0.73 to 0.80) and 0.81 (95% confidence interval = 0.79 to 0.84) for ALARM-never-smokers and ALARM-ever smokers, respectively. The maximum 5-year risk for never and ever-smokers was 2.6% and 12.7%, respectively. CONCLUSIONS: This study is among the first to develop risk models specifically for Asian populations separately for never and ever-smokers. Our models accurately identify Asians at high risk of lung cancer death and may identify those with risks exceeding common eligibility thresholds who may benefit from screening.

Considerations of biomarker application for cancer continuum in the era of precision medicine.

Purpose of the review: The goal of this review is to highlight emerging biomarker research by the key phases of the cancer continuum and outline the methodological considerations for biomarker application. Recent findings: While biomarkers have an established role in targeted therapy and to some extent, disease monitoring, their role in early detection and survivorship remains to be elucidated. With the advent of omics technology, the discovery of biomarkers has been accelerated exponentially, therefore careful consideration to ensure an unbiased study design and robust validity is crucial. Summary: The rigor of biomarker research holds the key to the success of precision health care. The potential clinical utility and the feasibility of implementation should be central to future biomarker research study design.

Body mass index and height in relation to brain tumor risk in a Japanese population.

PURPOSE: Although height and body mass index (BMI) are reported to be positively associated with several common cancers, evidence regarding their association with brain tumor risk remains sparse, particularly in Asian populations. In this study, we analyzed the association between height and BMI and brain tumor risk in a Japanese population using a large population-based prospective cohort study. METHODS: A total of 102,925 participants (48,213 men and 54,712 women) enrolled in the Japan Public Health Center-based Prospective Study were followed from baseline, namely 1990 for cohort I and 1993 for cohort II, until 2012. Information on participants' dietary and lifestyle habits, including height and body weight, was collected through survey questionnaires administered at baseline. We used the Cox proportional hazards regression model to estimate hazard ratios and 95% confidence intervals (CIs) for brain tumor incidence, with adjustment for potential confounding variables. RESULTS: During an average follow-up of 18.1 years, 157 (70 men and 87 women) cases of brain tumor were newly diagnosed. BMI showed a statistically insignificant positive association with the risk of brain tumor. In addition, statistically significant positive trends were seen for men and meningioma, with multivariable-adjusted hazard ratios for a BMI of 27.5 to less than 40 versus 18.5 to less than 23 kg per m2 of 2.14 (95% CI = 0.99-4.59) (P = 0.03) and 1.98 (95% CI = 0.84-4.67) (P = 0.046), respectively. In contrast, height showed no clear association with brain tumor risk, overall or in subgroup analysis. CONCLUSIONS: Compared with a BMI of 18 to less than 23.5 kg per m2, a higher BMI was associated with higher risk of brain tumor, particularly in men and with meningioma.

Association between dietary sugar intake and colorectal adenoma among cancer screening examinees in Japan.

Although intake of highly sugary foods is considered to be a potential risk factor for colorectal cancer through hyperinsulinemia, the association of sugar intake and colorectal adenoma, a precursor lesion to most colorectal cancer, is poorly understood, particularly in Asian populations. We undertook a cross-sectional study in a Japanese population to investigate the association between dietary sugar intake and the prevalence of colorectal adenoma. Study subjects were selected from participants who underwent magnifying colonoscopy with dye spraying as part of a cancer screening program and who responded to a self-administered questionnaire before the colonoscopy. A total of 738 cases with colorectal adenoma and 697 controls were enrolled. Dietary intakes of glucose, fructose, galactose, sucrose, maltose, lactose, and total sugars (sum of these six mono- or disaccharides) were calculated from a food frequency questionnaire, and divided into quartiles based on the distribution among controls. Odds ratios and 95% confidence intervals of colorectal adenoma were estimated using unconditional logistic regression models, with adjustment for potential confounding factors. Total sugar intake was not significantly associated with the prevalence of colorectal adenoma (odds ratio for the highest intake group compared to reference group = 1.18; 95% confidence interval, 0.81-1.73; P for trend = .34). Furthermore, no statistically significant positive associations were observed for any of the six mono- or disaccharides. Findings were similar on additional analyses by site, size, and number of adenomas. Our findings do not support an association between high sugar intake and increased odds ratios of colorectal adenoma.

Inclusion of a gene-environment interaction between alcohol consumption and the aldehyde dehydrogenase 2 genotype in a risk prediction model for upper aerodigestive tract cancer in Japanese men.

The well-known gene-environment interaction between alcohol consumption and aldehyde dehydrogenase 2 (ALDH2) genotype in upper aerodigestive tract cancer risk may improve our ability to identify high-risk subjects. Here, we developed and validated risk prediction models for this cancer in Japanese men and evaluated whether adding the gene-environment interaction to the model improved the predictive performance. We developed two case-cohort datasets in the Japan Public Health Center-based Prospective Study: one from subjects in the baseline survey for model development (108 cases and 4049 subcohort subjects) and the second from subjects in the 5-year follow-up survey for model validation (31 cases and 1527 subcohort subjects). We developed an environmental model including age, smoking status, and alcohol consumption, and a gene-environment interaction model including age, smoking status, and the combination of alcohol consumption and the ALDH2 genotype. We found a statistically significant gene-environment interaction for alcohol consumption and the ALDH2 genotype. The c-index for the gene-environment interaction model (0.71) was slightly higher than that for the environmental model (0.67). The values of integrated discrimination improvement and net reclassification improvement for the gene-environment interaction model were also slightly higher than those for the environmental model. Goodness-of-fit tests suggested that the models were well calibrated. Results from external model validation by the 5-year follow-up survey were consistent with those from the model development by the baseline survey. The addition of a gene-environment interaction to a lifestyle-based model might improve the performance to estimate the probability of developing upper aerodigestive tract cancer for Japanese men.

Doneness preferences, meat and meat-derived heterocyclic amines intake, and N-acetyltransferase 2 polymorphisms: association with colorectal adenoma in Japanese Brazilians.

Intake of heterocyclic amines (HCAs) and other mutagenic compounds formed during cooking has been hypothesized to be responsible for the positive association observed between red meat and colorectal cancer. We evaluated whether well-done/very well-done preferences for various meat and fish items, higher intakes of meat and fish, and meat-derived and fish-derived HCA are associated with the risk of colorectal adenoma (CRA) in a Japanese-Brazilian population. We selected 302 patients with adenoma and 403 control individuals who underwent total colonoscopy between 2007 and 2013, and collected information on aspects of meat intake using a detailed questionnaire. We also estimated HCA intake of the study participants using an HCA database that matched the cooking methods of this population. Latent class analysis on the basis of response to doneness preferences for different cooking methods of commonly consumed meat and fish items identified four distinct subgroups. Compared with the subgroup characterized by a preference for rare/medium well-done cooking for most meat and fish items, the odds ratio of CRA for the well-done/very well-done preference subgroup was 1.19 (95% confidence interval: 0.51-2.75). High intake of mixed-meat dishes was suggestively associated inversely with CRA, whereas a high intake of poultry was associated positively with CRA. No clear association with intake of total or specific HCAs and no effect modification by N-acetyltransferase 2 acetylation genotype were observed. We found no statistically significant associations between meat and HCA intake and CRA. These findings do not support a positive association between meat and meat-derived HCA intake and the risk of CRA.

Association of Animal and Plant Protein Intake With All-Cause and Cause-Specific Mortality in a Japanese Cohort.

Importance: Epidemiological evidence regarding the long-term effects of higher dietary protein intake on mortality outcomes in the general population is not clear. Objective: To evaluate the associations between animal and plant protein intake and all-cause and cause-specific mortality. Design, Setting, and Participants: This prospective cohort study included 70 696 participants in the Japan Public Health Center-based Prospective Cohort who were aged 45 to 74 years and had no history of cancer, cerebrovascular disease, or ischemic heart disease at study baseline. Data were collected from January 1, 1995, through December 31, 1999, with follow-up completed December 31, 2016, during which 12 381 total deaths were documented. Dietary intake information was collected through a validated food frequency questionnaire and used to estimate protein intake in all participants. Participants were grouped into quintile categories based on their protein intake, expressed as a percentage of total energy. Data were analyzed from July 18, 2017, through April 10, 2019. Main Outcomes and Measures: Hazard ratios (HRs) and 95% CIs for all-cause and cause-specific mortality were estimated using Cox proportional hazards regression models with adjustment for potential confounding factors. Results: Among the 70 696 participants, 32 201 (45.5%) were men (mean [SD] age, 55.6 [7.6] years) and 38 495 (54.5%) were women (mean [SD] age, 55.8 [7.7] years). Intake of animal protein showed no clear association with total or cause-specific mortality. In contrast, intake of plant protein was associated with lower total mortality, with multivariable-adjusted HRs of 0.89 (95% CI, 0.83-0.95) for quintile 2; 0.88 (95% CI, 0.82-0.95) for quintile 3; 0.84 (95% CI, 0.77-0.92) for quintile 4; and 0.87 (95% CI, 0.78-0.96) for quintile 5, with quintile 1 as the reference category (P = .01 for trend). For cause-specific mortality, this association with plant protein intake was evident for cardiovascular disease (CVD)-related mortality (HRs, 0.84 [95% CI, 0.73-0.96] to 0.70 [95% CI, 0.59-0.83]; P = .002 for trend). Isocaloric substitution of 3% energy from plant protein for red meat protein was associated with lower total (HR, 0.66; 95% CI, 0.55-0.80), cancer-related (HR, 0.61; 95% CI, 0.45-0.82), and CVD-related (HR, 0.58; 95% CI, 0.39-0.86) mortality; substitution for processed meat protein was associated with lower total (HR, 0.54; 95% CI, 0.38-0.75) and cancer-related (HR, 0.50; 95% CI, 0.30-0.85) mortality. Conclusions and Relevance: In this large prospective study, higher plant protein intake was associated with lower total and CVD-related mortality. Although animal protein intake was not associated with mortality outcomes, replacement of red meat protein or processed meat protein with plant protein was associated with lower total, cancer-related, and CVD-related mortality.

Association of BMI and height with the risk of endometrial cancer, overall and by histological subtype: a population-based prospective cohort study in Japan.

Evidence on the association between BMI, height, and endometrial cancer risk, including by subtypes, among Asian populations remains limited. We evaluated the impact of BMI and height on the risk of endometrial cancer, overall and by histological subtype. We prospectively investigated 53 651 Japanese women aged 40-69 years. With an average follow-up duration of 18.6 years, 180 newly diagnosed endometrial cancers were reported, including 119 type 1 and 21 type 2. The association between BMI, height, and endometrial cancer risk was assessed using a Cox proportional hazards regression model with adjustment for potential confounders. Overweight and obesity were associated positively with the risk of endometrial cancer. Compared with BMI of 23.0-24.9 kg/m, hazard ratios (HRs) (95% confidence intervals) were 1.93 (1.17-3.16) for BMI of 27.0-29.9 kg/m and 2.37 (1.20-4.66) for BMI of at least 30.0 kg/m. On analysis by histological subtype, with each increase in BMI of 5 U, the estimated HR of type 1 endometrial cancer increased (HR=1.54, 95% confidence interval: 1.21-1.98), but HR of type 2 endometrial cancer was unaffected. There was no statistically significant association between height and endometrial cancer risk. In conclusion, the risk of endometrial cancer was elevated in women with a BMI of at least 27.0 kg/m. By histological subtype, BMI was associated with type 1, but not type 2 endometrial cancer risk among a population with a relatively low BMI compared with western populations.

Plasma C-peptide and glycated albumin and subsequent risk of cancer: From a large prospective case-cohort study in Japan.

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.

Increased Levels of Branched-Chain Amino Acid Associated With Increased Risk of Pancreatic Cancer in a Prospective Case-Control Study of a Large Cohort.

BACKGROUND & AIMS: A marker is needed to identify individuals at risk for pancreatic cancer. Increases in branched-chain amino acids (BCAAs) have been associated with pancreatic cancer. We performed a prospective case-control study to study the association between plasma BCAA levels and risk of pancreatic cancer in a large cohort. METHODS: We conducted a nested case-control study selected from 30,239 eligible participants 40-69 years old within the Japan Public Health Center-based prospective study. Over 16.4 years, 170 newly diagnosed pancreatic cancer cases were identified. Each case was matched to 2 controls by age, gender, geographic area, and fasting time at blood collection. Adjusted odds ratios (ORs) and 95% confidence intervals (CIs) for pancreatic cancer were calculated using conditional logistic regression models with adjustment for potential confounding factors. RESULTS: Increased plasma BCAA levels at baseline were associated with an increased risk of pancreatic cancer. Compared with the lowest quartile of BCAA levels, the OR in the highest quartile was 2.43 (95% CI 1.21-4.90), and the OR per 1 SD increase in BCAA levels was 1.32 (95% CI 1.05-1.67). The association was especially strong for cases with blood samples collected at least 10 years before cancer diagnosis (OR per SD 1.60, 95% CI 1.10-2.32) compared with those detected less than 10 years before diagnosis (OR per SD 1.16, 95% CI 0.86-1.57). CONCLUSIONS: In an analysis of data from the Japan Public Health Center-based prospective study, we found an association between increased plasma BCAA level and increased risk of pancreatic cancer-particularly when the increase in BCAAs was observed at least 10 years before diagnosis. These findings add to the growing body of evidence for the association between BCAA levels and pancreatic cancer risk.

Plasma 25-hydroxyvitamin D concentration and subsequent risk of total and site specific cancers in Japanese population: large case-cohort study within Japan Public Health Center-based Prospective Study cohort.

OBJECTIVE: To evaluate the association between pre-diagnostic circulating vitamin D concentration and the subsequent risk of overall and site specific cancer in a large cohort study. DESIGN: Nested case-cohort study within the Japan Public Health Center-based Prospective Study cohort. SETTING: Nine public health centre areas across Japan. PARTICIPANTS: 3301 incident cases of cancer and 4044 randomly selected subcohort participants. EXPOSURE: Plasma concentration of 25-hydroxyvitamin D measured by enzyme immunoassay. Participants were divided into quarters based on the sex and season specific distribution of 25-hydroxyvitamin D among subcohorts. Weighted Cox proportional hazard models were used to calculate the multivariable adjusted hazard ratios for overall and site specific cancer across categories of 25-hydroxyvitamin D concentration, with the lowest quarter as the reference. MAIN OUTCOME MEASURE: Incidence of overall or site specific cancer. RESULTS: Plasma 25-hydroxyvitamin D concentration was inversely associated with the risk of total cancer, with multivariable adjusted hazard ratios for the second to fourth quarters compared with the lowest quarter of 0.81 (95% confidence interval 0.70 to 0.94), 0.75 (0.65 to 0.87), and 0.78 (0.67 to 0.91), respectively (P for trend=0.001). Among the findings for cancers at specific sites, an inverse association was found for liver cancer, with corresponding hazard ratios of 0.70 (0.44 to 1.13), 0.65 (0.40 to 1.06), and 0.45 (0.26 to 0.79) (P for trend=0.006). A sensitivity analysis showed that alternately removing cases of cancer at one specific site from total cancer cases did not substantially change the overall hazard ratios. CONCLUSIONS: In this large prospective study, higher vitamin D concentration was associated with lower risk of total cancer. These findings support the hypothesis that vitamin D has protective effects against cancers at many sites.

Development of a risk prediction model for lung cancer: The Japan Public Health Center-based Prospective Study.

Although the impact of tobacco consumption on the occurrence of lung cancer is well-established, risk estimation could be improved by risk prediction models that consider various smoking habits, such as quantity, duration, and time since quitting. We constructed a risk prediction model using a population of 59 161 individuals from the Japan Public Health Center (JPHC) Study Cohort II. A parametric survival model was used to assess the impact of age, gender, and smoking-related factors (cumulative smoking intensity measured in pack-years, age at initiation, and time since cessation). Ten-year cumulative probability of lung cancer occurrence estimates were calculated with consideration of the competing risk of death from other causes. Finally, the model was externally validated using 47 501 individuals from JPHC Study Cohort I. A total of 1210 cases of lung cancer occurred during 986 408 person-years of follow-up. We found a dose-dependent effect of tobacco consumption with hazard ratios for current smokers ranging from 3.78 (2.00-7.16) for cumulative consumption ≤15 pack-years to 15.80 (9.67-25.79) for >75 pack-years. Risk decreased with time since cessation. Ten-year cumulative probability of lung cancer occurrence estimates ranged from 0.04% to 11.14% in men and 0.07% to 6.55% in women. The model showed good predictive performance regarding discrimination (cross-validated c-index = 0.793) and calibration (cross-validated χ2 = 6.60; P-value = .58). The model still showed good discrimination in the external validation population (c-index = 0.772). In conclusion, we developed a prediction model to estimate the probability of developing lung cancer based on age, gender, and tobacco consumption. This model appears useful in encouraging high-risk individuals to quit smoking and undergo increased surveillance.

Association between plasma concentrations of branched-chain amino acids and adipokines in Japanese adults without diabetes.

Previous studies have consistently reported an association between circulating levels of branched-chain amino acids (BCAAs) or adipokines and insulin resistance; however, the association between BCAA and adipokine levels remains to be clarified. In this cross-sectional study involving 678 participants (435 men) without diabetes, plasma BCAA (valine, leucine, and isoleucine), adipokine (total and high molecular weight [HMW] adiponectin, leptin, and tumor necrosis factor-α [TNF-α]) concentrations, and an updated homeostasis model assessment of insulin resistance (HOMA2-IR) were measured. The association between the concentrations of total BCAAs and adipokines was adjusted for confounding factors, including body mass index. For the lowest and highest BCAA quartiles, the adjusted geometric mean levels of HMW adiponectin were, respectively, 1.51 and 0.91 µg/mL, in men (P for trend < 0.0001); 3.61 and 2.29 µg/mL, in women (P = 0.0005). The corresponding geometric mean levels for leptin were 1681 and 2620 pg/mL, in men (P = 0.003), and 4270 and 6510 pg/mL, in women (P = 0.003). Those for HOMA2-IR were 0.89 and 1.11, in men (P < 0.0001), and 0.79 and 0.96, in women (P < 0.0001); no significant association was found with TNF-α. These results suggest significant associations between BCAA concentrations and those for adiponectin, leptin and HOMA2-IR in individuals without diabetes.

Association of plasma C-reactive protein level with the prevalence of colorectal adenoma: the Colorectal Adenoma Study in Tokyo.

Epidemiologic studies have identified a positive association between obesity and colorectal neoplasia. Adiposity induces systemic low-grade inflammation, which is commonly assessed with a sensitive biomarker, C-reactive protein (CRP). To understand the molecular mechanisms of obesity in the etiology of colorectal neoplasia, the present study was conducted in 782 adenoma cases and 738 controls who underwent total colonoscopy, and their plasma CRP level was evaluated in relation to colorectal adenoma prevalence. A logistic regression model was used to compute odds ratios (OR) and 95% confidence intervals (CI) of adenoma according to quartile of plasma CRP. Plasma CRP level was positively associated with higher adenoma prevalence in all subjects (OR 1.30; 95% CI 0.94-1.79 for the highest versus lowest quartile; P trend = 0.031). Further analysis by adenoma size and number revealed a pronounced association with a larger size (≥5 mm) and multiple numbers (≥2). These positive associations were reduced to non-significance following further adjustment for body mass index, and OR for the highest versus lowest quartile of plasma CRP became 1.12 (95% CI 0.80-1.56; P trend = 0.25) in all subjects. In conclusion, this study suggests that obesity-related systemic low-grade inflammation may play an important role in the early stages of colorectal carcinogenesis.

Alcohol consumption, genetic variants in the alcohol- and folate metabolic pathways and colorectal cancer risk: the JPHC Study.

The association between alcohol intake and colorectal cancer (CRC) may vary secondary to single nucleotide polymorphisms (SNPs) in two pathways related to alcohol intake. 375 cases of CRC were identified among 38 373 Japan Public Health Center-based prospective Study (JPHC Study) participants who had returned a baseline questionnaire, reported no diagnosis of any cancer and provided blood samples. For each case, two controls were selected on matching variables. Logistic regression models were used to determine matched Odds Ratios (OR) and 95% Confidence Intervals (CI) for the association between alcohol consumption, genetic polymorphisms of enzymes in the alcohol- and folate metabolic pathways (e.g. methylenetetrahydrofolate reductase (MTHFR) rs1801133) and CRC risk. Compared to never/occasional alcohol intake, moderate to heavy alcohol intake was associated with CRC (OR = 2.12, 95% CI, 1.34-3.36). When compared to the CC genotype, the MTHFR rs1801133 CT/TT genotype was inversely associated with CRC (OR = 0.72, 95% CI, 0.54-0.97). Never/occasional consumers of alcohol with the MTHFR rs1801133 CT/TT genotype were also at a reduced risk of CRC compared to never/occasional drinkers with the CC genotype (OR = 0.68, 95% CI, 0.47-0.98) (P for interaction = 0.27). The results indicate that the folate pathway is likely to be involved in alcohol-related CRC development.

Vitamin D Receptor Gene Polymorphism and the Risk of Colorectal Cancer: A Nested Case-Control Study.

Epidemiological and experimental evidence suggest that vitamin D is protective against the risk of colorectal cancer. Polymorphisms in the gene encoding vitamin D receptor (VDR), which mediates most of the known cellular effects of vitamin D, have been suggested to alter this association. Here, using a tag SNP approach, we comprehensively evaluated the role of common genetic variants in VDR and their interaction with plasma vitamin D levels in relation to colorectal cancer risk in Japanese populations. A total of 356 colorectal cancer cases and 709 matched control subjects were selected from the participants of the Japan Public Health Center-based Prospective Cohort Study. Among these subjects, 29 VDR single nucleotide polymorphisms (SNPs) were selected and genotyped, and plasma vitamin D concentrations were measured. Conditional logistic regression models were used to estimate odds ratios (ORs) and 95% confidence intervals (CIs) of colorectal cancer, with adjustment for potential confounding factors. Among the results, eight VDR SNPs, namely rs2254210, rs1540339, rs2107301, rs11168267, rs11574113, rs731236, rs3847987 and rs11574143, the latter 5 of which were located in the 3' region, were nominally associated with the risk of colorectal cancer (P = 0.01-0.048). Furthermore, of the above 5 3' region SNPs, the inverse associations for 3 SNPs (rs11574113, rs3847987 and rs11574143) appeared to be evident only in those with high plasma vitamin D concentration. However, neither of these direct and suggestive interaction analysis associations was significant after multiple testing adjustment. Overall, the findings of this study provide only limited support for an association between common genetic variations in VDR and colorectal cancer risk in the Japanese population.

Coffee and green tea consumption in relation to brain tumor risk in a Japanese population.

Few prospective studies have investigated the etiology of brain tumor, especially among Asian populations. Both coffee and green tea are popular beverages, but their relation with brain tumor risk, particularly with glioma, has been inconsistent in epidemiological studies. In this study, we evaluated the association between coffee and greed tea intake and brain tumor risk in a Japanese population. We evaluated a cohort of 106,324 subjects (50,438 men and 55,886 women) in the Japan Public Health Center-Based Prospective Study (JPHC Study). Subjects were followed from 1990 for Cohort I and 1993 for Cohort II until December 31, 2012. One hundred and fifty-seven (70 men and 87 women) newly diagnosed cases of brain tumor were identified during the study period. Hazard ratio (HR) and 95% confidence intervals (95%CIs) for the association between coffee or green tea consumption and brain tumor risk were assessed using a Cox proportional hazards regression model. We found a significant inverse association between coffee consumption and brain tumor risk in both total subjects (≥3 cups/day; HR = 0.47, 95%CI = 0.22-0.98) and in women (≥3 cups/day; HR = 0.24, 95%CI = 0.06-0.99), although the number of cases in the highest category was small. Furthermore, glioma risk tended to decrease with higher coffee consumption (≥3 cups/day; HR = 0.54, 95%CI = 0.16-1.80). No association was seen between green tea and brain tumor risk. In conclusion, our study suggested that coffee consumption might reduce the risk of brain tumor, including that of glioma, in the Japanese population.

Dietary heterocyclic amine intake, NAT2 genetic polymorphism, and colorectal adenoma risk: the colorectal adenoma study in Tokyo.

BACKGROUND: While several studies have provided support for a positive association between meat intake and colorectal neoplasia, the role of heterocyclic amines (HCA), which is hypothesized to underline this relation, has been less consistent. We evaluated the association of HCA intake with colorectal adenoma risk in a case-control study in a middle-aged Japanese population. METHODS: Study subjects were 738 patients with adenoma and 697 controls who underwent total colonoscopy between 2004 and 2005 and responded to self-administered lifestyle and dietary questionnaires. HCA exposure concentration was estimated from meat and fish intake based on an HCA database that was validated against 2-amino-1-methyl-6-phenylimidazo[4,5-b]pyridine (PhIP) values measured in human hair. Logistic regression models were used to estimate ORs and 95% confidence interval (CI) for the association between HCA and colorectal adenoma risk after adjusting for potential confounders. RESULTS: High intake of 2-amino-3,4-dimethylimidazo[4,5-f]quinoline (MeIQ) and total HCA was associated with an increased risk of colorectal adenoma in women but not in men. The multivariate-adjusted OR for the highest versus lowest quartile in women was 2.10 (95% CI, 1.20-3.67; Ptrend = 0.01) for MeIQ and 1.73 (95% CI, 0.99-3.01; Ptrend = 0.03) for total HCA. No clear association with PhIP or 2-amino-3,8-dimethylimidazo[4,5-f]quinoxaline (MeIQx) estimates and no effect modification by NAT2 acetylation genotype was observed. CONCLUSIONS: This study suggests that high MeIQ and total HCA estimates are positively associated with colorectal adenoma risk. IMPACT: The findings add to evidence that HCA may play a role in colorectal carcinogenesis in humans. Cancer Epidemiol Biomarkers Prev; 24(3); 613-20. ©2015 AACR.

Coffee intake and the risk of colorectal adenoma: The colorectal adenoma study in Tokyo.

Coffee is a commonly consumed beverage which contains several potential anticarcinogenic and chemopreventive compounds, and has been hypothesized to have protective effects in colorectal neoplasia. However, the limited available data on coffee consumption in relation to colorectal adenoma (CRA), a precursor lesion to most colorectal cancers, remain largely inconsistent. In this study, we evaluated the association of coffee intake with the risk of CRA in a middle-aged Japanese population. Study subjects were selected from examinees who underwent total colonoscopy as part of a cancer screening program and responded to self-administered dietary and lifestyle questionnaires. A total of 738 patients with adenoma and 697 controls were included in the study. Coffee intake was assessed with a food frequency questionnaire, and divided into quartiles based on the distribution among controls. Unconditional logistic regression models were used to estimate odds ratio (OR) and 95% confidence interval (CI) of CRA, with adjustment for potential confounding factors. High coffee consumption was associated with a reduced risk of CRA, with a multivariate-adjusted OR for the highest versus lowest quartile of coffee intake of 0.67 (95% CI = 0.48-0.93; ptrend = 0.02). The inverse association of coffee intake was limited to proximal (OR = 0.64; 95%CI = 0.44-0.95; ptrend = 0.04) and distal colon adenoma (OR = 0.62; 95%CI = 0.39-0.99; ptrend = 0.06), and appeared to be more evident with small (OR = 0.68; 95%CI = 0.49-0.96; ptrend = 0.04) and single adenomas (OR = 0.65; 95%CI = 0.44-0.95; ptrend = 0.02). Green tea intake was not found to be associated with CRA risk. This study provides support for the protective effect of coffee drinking on colon adenomas, a precursor of colon cancer.