Association between consumption of small fish and all-cause mortality among Japanese: the Japan Multi-Institutional Collaborative Cohort Study.

OBJECTIVE: Although small fish are an important source of micronutrients, the relationship between their intake and mortality remains unclear. This study aimed to clarify the association between intake of small fish and all-cause and cause-specific mortality. DESIGN: We used the data from a cohort study in Japan. The frequency of the intake of small fish was assessed using a validated food frequency questionnaire. The hazard ratios (HRs) and 95% confidence intervals (CIs) for all-cause and cause-specific mortality according to the frequency of the intake of small fish by sex were estimated using a Cox proportional hazard model with adjustments for covariates. SETTING: The Japan Multi-Institutional Collaborative Cohort (J-MICC) Study. PARTICIPANTS: A total of 80,802 participants (34,555 males and 46,247 females), aged 35-69 years. RESULTS: During a mean follow-up of 9.0 years, we identified 2,482 deaths including 1,495 cancer-related deaths. The intake of small fish was statistically significantly and inversely associated with the risk of all-cause and cancer mortality in females. The multivariable-adjusted HRs (95% CIs) in females for all-cause mortality according to the intake were 0.68 (0.55-0.85) for intakes 1-3 times/month, 0.72 (0.57-0.90) for 1-2 times/week, and 0.69 (0.54-0.88) for ≥3 times/week, compared with the rare intake. The corresponding HRs (95% CIs) in females for cancer mortality were 0.72 (0.54-0.96), 0.71 (0.53-0.96), and 0.64 (0.46-0.89), respectively. No statistically significant association was observed in males. CONCLUSIONS: Intake of small fish may reduce the risk of all-cause and cancer mortality in Japanese females.

Active and passive smoking and breast cancer in Japan: a pooled analysis of nine population-based cohort studies.

BACKGROUND: Epidemiological studies have shown inconsistent results regarding the link between smoking and breast cancer risk, despite the biological plausibility of a positive association. METHODS: Participants were 166 611 women from nine prospective cohort studies in Japan which launched in 1984-1994 and followed for 8-22 years. Information on smoking and secondhand smoke was obtained through self-administered baseline questionnaires. Breast cancer was defined as code C50 according to the International Classification of Diseases for Oncology, 3rd Edition or the International Classification of Diseases, 10th Revision. After adjusting for several potential confounders, relative risks for breast cancer were calculated in the individual studies according to the current or previous status of active and passive smoking using Cox regression, followed by a summary estimate of hazard ratios using random-effects meta-analyses. RESULTS: Of the 60 441 participants who reported being premenopausal and 106 170 who reported being postmenopausal at baseline, 897 and 1168 developed breast cancer during follow-up, respectively. Compared with never smokers, current smokers had a higher risk of developing breast cancer before the age of 50 years. In addition, ever smokers who started smoking at 30 years of age or younger, or who started smoking before first childbirth, had a higher risk of developing breast cancer before the age of 50 years. No association between adulthood or childhood exposure to secondhand smoke and breast cancer was observed. CONCLUSION: Smoking may increase the risk of premenopausal breast cancer, and smoking earlier in life might be especially harmful. The impact of secondhand smoke needs further investigation.

Genetic architecture of alcohol consumption identified by a genotype-stratified GWAS and impact on esophageal cancer risk in Japanese people.

An East Asian-specific variant on aldehyde dehydrogenase 2 (ALDH2 rs671, G>A) is the major genetic determinant of alcohol consumption. We performed an rs671 genotype-stratified genome-wide association study meta-analysis of alcohol consumption in 175,672 Japanese individuals to explore gene-gene interactions with rs671 behind drinking behavior. The analysis identified three genome-wide significant loci (GCKR, KLB, and ADH1B) in wild-type homozygotes and six (GCKR, ADH1B, ALDH1B1, ALDH1A1, ALDH2, and GOT2) in heterozygotes, with five showing genome-wide significant interaction with rs671. Genetic correlation analyses revealed ancestry-specific genetic architecture in heterozygotes. Of the discovered loci, four (GCKR, ADH1B, ALDH1A1, and ALDH2) were suggested to interact with rs671 in the risk of esophageal cancer, a representative alcohol-related disease. Our results identify the genotype-specific genetic architecture of alcohol consumption and reveal its potential impact on alcohol-related disease risk.

Obesity is associated with biliary tract cancer mortality and incidence: A pooled analysis of 21 cohort studies in the Asia Cohort Consortium.

Body fatness is considered a probable risk factor for biliary tract cancer (BTC), whereas cholelithiasis is an established factor. Nevertheless, although obesity is an established risk factor for cholelithiasis, previous studies of the association of body mass index (BMI) and BTC did not take the effect of cholelithiasis fully into account. To better understand the effect of BMI on BTC, we conducted a pooled analysis using population-based cohort studies in Asians. In total, 905 530 subjects from 21 cohort studies participating in the Asia Cohort Consortium were included. BMI was categorized into four groups: underweight (<18.5 kg/m2 ); normal (18.5-22.9 kg/m2 ); overweight (23-24.9 kg/m2 ); and obese (25+ kg/m2 ). The association between BMI and BTC incidence and mortality was assessed using hazard ratios (HR) and 95% confidence intervals (CIs) by Cox regression models with shared frailty. Mediation analysis was used to decompose the association into a direct and an indirect (mediated) effect. Compared to normal BMI, high BMI was associated with BTC mortality (HR 1.19 [CI 1.02-1.38] for males, HR 1.30 [1.14-1.49] for females). Cholelithiasis had significant interaction with BMI on BTC risk. BMI was associated with BTC risk directly and through cholelithiasis in females, whereas the association was unclear in males. When cholelithiasis was present, BMI was not associated with BTC death in either males or females. BMI was associated with BTC death among females without cholelithiasis. This study suggests BMI is associated with BTC mortality in Asians. Cholelithiasis appears to contribute to the association; and moreover, obesity appears to increase BTC risk without cholelithiasis.

Seven-plus hours of daily sedentary time and the subsequent risk of breast cancer: Japan Multi-Institutional Collaborative Cohort Study.

This study aimed to investigate the association between daily sedentary time and the risk of breast cancer (BC) in a large Japanese population. The participants were 36,023 women aged 35-69 years from the Japan Multi-Institutional Collaborative Cohort Study. Cox proportional hazards analysis was used to estimate adjusted hazard ratios (HRs) and 95% confidence intervals (CIs) for BC incidence in relation to time spent sedentarily (categorical variables: <7 and ≥7 hours/day [h/d]). Additionally, the associations of BC incidence to the joint effect of sedentary time with each component of physical activity, such as leisure-time metabolic equivalents (METs), frequency of leisure-time physical activity, and daily walking time, were examined. During 315,189 person-years of follow-up, 554 incident cases of BC were identified. When compared to participants who spent <7 h/d sedentary, those who spent ≥7 h/d sedentary have a significantly higher risk of BC (HR, 1.36; 95% CI, 1.07-1.71). The corresponding HRs among participants who spent ≥7 h/d sedentary with more physical activity, such as ≥1 h/d for leisure-time METs, ≥3 days/week of leisure-time physical activity, and ≥1 h/d of daily walking were 1.58 (95% CI, 1.11-2.25), 1.77 (95% CI, 1.20-2.61), and 1.42 (95% CI, 1.10-1.83), respectively, compared with those who spent <7 h/d sedentary. This study found that spending ≥7 h/d of sedentary time is associated with the risk of BC. Neither leisure-time physical activity nor walking had a BC-preventive effect in those with ≥7 h/d of sedentary time.

Subsite-specific trends in mid- and long-term survival for head and neck cancer patients in Japan: A population-based study.

Advances in diagnostic techniques and treatment modalities have impacted head and neck cancer (HNC) prognosis, but their effects on subsite-specific prognosis remain unclear. This study aimed to assess subsite-specific trends in mid- and long-term survival for HNC patients diagnosed from 1993 to 2011 using data from population-based cancer registries in Japan. We estimated the net survival (NS) for HNC by subsite using data from 13 prefectural population-based cancer registries in Japan. Changes in survival over time were assessed by multivariate excess hazard model of mortality. In total, 68,312 HNC patients were included in this analysis. We observed an overall improvement in 5-year NS for HNC patients in Japan. However, survival varied among subsites of HNC, with some, such as naso-, oro- and hypopharyngeal cancers, showing significant improvement in both 5- and 10-year NS, whereas others such as laryngeal cancer showed only a slight improvement in 5-year NS and no significant change in 10-year NS after adjustment for age, sex and stage. In conclusion, the study provides insights into changing HNC survival by site at the population level in Japan. Although advances in diagnostic techniques and treatment modalities have improved survival, these improvements are not shared equally among subsites.

Mediation analysis unveils a carcinogenic effect of ADH1B rs1229984 through mechanisms other than change in drinking intensity: oesophageal cancer case-control study.

BACKGROUND: Ingested alcohol is predominantly oxidized to acetaldehyde by alcohol dehydrogenase 1B (ADH1B), and acetaldehyde is further oxidized to acetate mainly by aldehyde dehydrogenase 2 (ALDH2). Although alcohol consumption is a convincing risk factor for oesophageal cancer, the role of ADH1B rs1229984 (His48Arg), the single-nucleotide polymorphism associated with slow alcohol metabolism, in oesophageal cancer development is unclear. Because this single-nucleotide polymorphism is associated with both increased risk of oesophageal cancer and drinking intensity, its association with oesophageal cancer might operate either through a direct pathway independently of drinking intensity, via an indirect pathway mediated by drinking intensity, or both. METHODS: To disentangle these different pathways, we applied a mediation analysis to an oesophageal cancer case-control study (600 cases and 865 controls) by defining the ADH1B Arg allele and alcohol consumption as exposure and mediator, respectively, and decomposed the total-effect odds ratio of the ADH1B Arg allele into direct- and indirect-effect odds ratio. RESULTS: The ADH1B Arg allele was associated with oesophageal cancer risk through pathways other than change in drinking intensity (direct-effect odds ratio, 2.03; 95% confidence interval, 1.41-2.92), in addition to the indirect pathway mediated by drinking intensity (indirect-effect odds ratio, 1.27; 95% confidence interval, 1.05-1.53). Further analyses by stratifying genotypes of ALDH2 rs671 (Glu504Lys), the functional single-nucleotide polymorphism that strongly attenuates the enzymatic activity, showed significant direct-effect odds ratio within each stratum. CONCLUSIONS: These results indicate that ADH1B Arg allele contributes to oesophageal cancer risk by slowing alcohol breakdown, in addition to its effect on the amount of alcohol consumed.

Comparison of the loci associated with HbA1c and blood glucose levels identified by a genome-wide association study in the Japanese population.

Aims: Hemoglobin A1c (HbA1c) levels are widely employed to diagnose diabetes. However, estimates of the heritability of HbA1c and glucose levels are different. Therefore, we explored HbA1c- and blood glucose-associated loci in a non-diabetic Japanese population. Methods: We conducted a two-stage genome-wide association study (GWAS) on variants associated with HbA1c and blood glucose levels in a Japanese population. In the initial stage, data of 4911 participants of the Japan Multi-Institutional Collaborative Cohort (J-MICC) were subjected to discovery analysis. In the second stage, two datasets from the Tohoku Medical Megabank project, with 8175 and 40,519 participants, were used for the replication study. Association of the imputed variants with HbA1c and blood glucose levels was determined via linear regression analyses adjusted for age, sex, body mass index (BMI), smoking, and genetic principal components (PC1-PC10). Moreover, we performed a BMI-stratified GWAS on HbA1c levels in the J-MICC. The discovery analysis and BMI-stratified GWAS results were validated with re-analyses of normalized HbA1c levels adjusted for site in addition to the above, and blood glucose adjusted for fasting time as an additional covariate. Results: Genetic variants associated with HbA1c levels were identified in KCNQ1 and TMC6. None of the genetic variants associated with blood glucose levels in the discovery analysis were replicated. Association of rs2299620 in KCNQ1 with HbA1c levels showed heterogeneity between individuals with BMI ≥ 25 kg/m2 and BMI < 25 kg/m2. Conclusions: The variant rs2299620 in KCNQ1 might affect HbA1c levels differentially based on BMI grouping in the Japanese population. Supplementary Information: The online version contains supplementary material available at 10.1007/s13340-023-00618-0.

Body mass index and esophageal and gastric cancer: A pooled analysis of 10 population-based cohort studies in Japan.

The effect of body mass index (BMI) on esophageal and gastric carcinogenesis might be heterogeneous, depending on subtype or subsite. However, findings from prospective evaluations of BMI associated with these cancers among Asian populations have been inconsistent and limited, especially for esophageal adenocarcinoma and gastric cardia cancer. We performed a pooled analysis of 10 population-based cohort studies to examine this association in 394,247 Japanese individuals. We used Cox proportional hazards regression to estimate study-specific hazard ratios (HRs) and 95% confidence intervals (CIs), then pooled these estimates to calculate summary HRs with a random effects model. During 5,750,107 person-years of follow-up, 1569 esophageal cancer (1038 squamous cell carcinoma and 86 adenocarcinoma) and 11,095 gastric (728 cardia and 5620 noncardia) cancer incident cases were identified. An inverse association was observed between BMI and esophageal squamous cell carcinoma (HR per 5-kg/m2 increase 0.57, 95% CI 0.50-0.65), whereas a positive association was seen in gastric cardia cancer (HR 1.15, 95% CI 1.00-1.32). A nonsignificant and significant positive association for overweight or obese (BMI ≥25 kg/m2 ) relative to BMI <25 kg/m2 was observed with esophageal adenocarcinoma (HR 1.32, 95% CI 0.80-2.17) and gastric cardia cancer (HR 1.24, 95% CI 1.05-1.46), respectively. No clear association with BMI was found for gastric noncardia cancer. This prospective study-the largest in an Asian country-provides a comprehensive quantitative estimate of the association of BMI with upper gastrointestinal cancer and confirms the subtype- or subsite-specific carcinogenic impact of BMI in a Japanese population.

Investigating the association between glycaemic traits and colorectal cancer in the Japanese population using Mendelian randomisation.

Observational studies suggest that abnormal glucose metabolism and insulin resistance contribute to colorectal cancer; however, the causal association remains unknown, particularly in Asian populations. A two-sample Mendelian randomisation analysis was performed to determine the causal association between genetic variants associated with elevated fasting glucose, haemoglobin A1c (HbA1c), and fasting C-peptide and colorectal cancer risk. In the single nucleotide polymorphism (SNP)-exposure analysis, we meta-analysed study-level genome-wide associations of fasting glucose (~ 17,289 individuals), HbA1c (~ 52,802 individuals), and fasting C-peptide (1,666 individuals) levels from the Japanese Consortium of Genetic Epidemiology studies. The odds ratios of colorectal cancer were 1.01 (95% confidence interval [CI], 0.99-1.04, P = 0.34) for fasting glucose (per 1 mg/dL increment), 1.02 (95% CI, 0.60-1.73, P = 0.95) for HbA1c (per 1% increment), and 1.47 (95% CI, 0.97-2.24, P = 0.06) for fasting C-peptide (per 1 log increment). Sensitivity analyses, including Mendelian randomisation-Egger and weighted-median approaches, revealed no significant association between glycaemic characteristics and colorectal cancer (P > 0.20). In this study, genetically predicted glycaemic characteristics were not significantly related to colorectal cancer risk. The potential association between insulin resistance and colorectal cancer should be validated in further studies.

Helicobacter pylori, Homologous-Recombination Genes, and Gastric Cancer.

BACKGROUND: Helicobacter pylori infection is a well-known risk factor for gastric cancer. However, the contribution of germline pathogenic variants in cancer-predisposing genes and their effect, when combined with H. pylori infection, on the risk of gastric cancer has not been widely evaluated. METHODS: We evaluated the association between germline pathogenic variants in 27 cancer-predisposing genes and the risk of gastric cancer in a sample of 10,426 patients with gastric cancer and 38,153 controls from BioBank Japan. We also assessed the combined effect of pathogenic variants and H. pylori infection status on the risk of gastric cancer and calculated the cumulative risk in 1433 patients with gastric cancer and 5997 controls from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). RESULTS: Germline pathogenic variants in nine genes (APC, ATM, BRCA1, BRCA2, CDH1, MLH1, MSH2, MSH6, and PALB2) were associated with the risk of gastric cancer. We found an interaction between H. pylori infection and pathogenic variants in homologous-recombination genes with respect to the risk of gastric cancer in the sample from HERPACC (relative excess risk due to the interaction, 16.01; 95% confidence interval [CI], 2.22 to 29.81; P = 0.02). At 85 years of age, persons with H. pylori infection and a pathogenic variant had a higher cumulative risk of gastric cancer than noncarriers infected with H. pylori (45.5% [95% CI, 20.7 to 62.6] vs. 14.4% [95% CI, 12.2 to 16.6]). CONCLUSIONS: H. pylori infection modified the risk of gastric cancer associated with germline pathogenic variants in homologous-recombination genes. (Funded by the Japan Agency for Medical Research and Development and others.).

Association of 25-hydroxyvitamin D with risk of overall and colorectal cancer among Japanese using a Mendelian randomization approach.

The association between vitamin D and total and colorectal cancer risk was inconsistent in observational studies. We conducted Mendelian randomization approach in which the effect of confounding might be reduced. 110 single nucleotide polymorphisms (SNPs) associated with 25-hydroxyvitamin D concentrations were systematically selected according to the "GWAS Catalog" from all ethnic populations. For the SNP-vitamin D concentration association, 3978 individuals from two Japanese cohorts were included. Regarding SNP-total and colorectal cancer association, 4543 cancer cases and 14,224 controls and 7936 colorectal cancer cases and 38,042 controls, respectively were included from the Japanese Consortium of Genetic Epidemiology and other studies in Japan. There was no significant association between the genetically predicted plasma 25-hydroxyvitamin D concentration and total or colorectal cancer in any of the MR analyses. Odds ratios per doubling in vitamin D concentration were 0.83 (95% confidence interval [CI] 0.63-1.09) for total cancer and 1.00 (95% CI 0.80-1.24) for colorectal cancer in inverse variance weighted method, 0.83 (95% CI 0.57-1.19) for total cancer and 1.01 (95% CI 0.75-1.37) for colorectal cancer in MR-Egger method. Consistent with previous MR analyses among European ancestries, there was no significant association identified between 25-hydroxyvitamin D levels and total or colorectal cancer among Asians.

Changes in survival of patients with non-small cell lung cancer in Japan: An interrupted time series study.

The epidermal growth factor receptor tyrosine kinase inhibitors (EGFR-TKIs) gefitinib and erlotinib were approved for metastatic or relapsed non-small cell lung cancer (NSCLC) in Japan in 2002 and 2007, respectively. EGFR mutation testing was also approved in 2007. Although clinical trials showed efficacy in NSCLC patients harboring activating EGFR mutations, these effects have rarely been reported in real-world practice. We evaluated changes in survival in NSCLC patients following introduction of these agents and EGFR mutation testing by extracting patients diagnosed with NSCLC from 1993 through 2011 from six prefectural population-based cancer registries in Japan. Relative survival (RS) was calculated by sex, histological subtype, and cancer stage. We conducted interrupted time series analysis to assess survival changes following introduction of EGFR-TKIs and EGFR mutation testing. 120,068 patients with NSCLC were analyzed. One- and three-year RS gradually increased in overall NSCLC for men and women. For adenocarcinoma, among men, slopes of 1- and 3-year RS increased steeply in patients diagnosed from 2007 through 2011; among women, significant level increases were seen in 1-year RS in patients diagnosed in 2002 (4.55% [95% confidence interval: 1.76-7.33]) and 2007 (3.40% [1.27-5.52]). These significant level increases were particularly obvious in women with adenocarcinoma at an advanced stage. Our results suggest that recent improvements in survival in men and women with adenocarcinoma are due at least partly to introduction of EGFR-TKIs into real-world practice, and to prescription based on appropriate patient selection following introduction of EGFR mutation testing into real-world practice in Japan.

Impact of socioeconomic status and sibling number on the prevalence of Helicobacter pylori infection: a cross-sectional study in a Japanese population.

Helicobacter pylori infection is a significant risk factor for gastric cancer. The infection is acquired mainly in early childhood and is influenced by environmental factors, including socioeconomic status and sibling number. However, the impact of socioeconomic status and sibling number on Helicobacter pylori infection has not been well studied in Japan. We conducted a cross-sectional study to evaluate the impact of socioeconomic status, represented by education level, and sibling number on the prevalence of Helicobacter pylori infection among 3,423 non-cancer subjects who visited Aichi Cancer Center between 2005 and 2013. We calculated odds ratios (ORs) and 95% confidence intervals (CIs) using a logistic regression model adjusted for potential confounding variables. Of the 3,423 subjects, 1,459 (42.6%) were Helicobacter pylori-positive. The prevalence of Helicobacter pylori infection linearly decreased with increasing socioeconomic status [ORs (95% CIs) of moderate and high socioeconomic status relative to low socioeconomic status of 0.67 (0.53-0.84) and 0.43 (0.34-0.54), respectively; P trend=9.7×10-17]. In contrast, the prevalence of Helicobacter pylori infection linearly increased with increasing sibling number [ORs (95% CIs) of SN 3-4 and ≥5 relative to sibling number ≤2 of 1.74 (1.47-2.06) and 2.54 (2.12-3.04), respectively; P trend=1.2×10-24]. This study showed that socioeconomic status and sibling number were significantly associated with the prevalence of Helicobacter pylori infection.

Blood Lipids and the Risk of Colorectal Cancer: Mendelian Randomization Analyses in the Japanese Consortium of Genetic Epidemiology Studies.

The associations between blood lipids, including total cholesterol (TC), high-density lipoprotein cholesterol (HDL-C), triglycerides, and low-density lipoprotein cholesterol (LDL-C), and colorectal cancer risk are controversial. We evaluated potential causal relationships between blood lipids and colorectal cancer risk. Using the baseline data from the Japanese Consortium of Genetic Epidemiology studies, we estimated the single-nucleotide polymorphism (SNP)-exposure associations (n = 34,546 for TC, n = 50,290 for HDL-C, n = 51,307 for triglycerides, and n = 30,305 for LDL-C). We also estimated the SNP-outcome associations in another Japanese dataset (n = 7,936 colorectal cancer cases and n = 38,042 controls). We conducted Mendelian randomization (MR) analyses for the association between each blood lipid type and the risk of colorectal cancer using an inverse variance-weighted method. The total variances explained by the selected SNPs in TC (68 SNPs), HDL-C (50 SNPs), log-transformed triglycerides (26 SNPs), and LDL-C (35 SNPs) were 7.0%, 10.0%, 6.2%, and 5.7%, respectively. The odds ratios for colorectal cancer were 1.15 [95% confidence interval (CI), 1.01-1.32] per 1 standard deviation (SD; 33.3 mg/dL) increase in TC, 1.11 (95% CI, 0.98-1.26) per 1 SD (15.4 mg/dL) increase in HDL-C, 1.06 (95% CI, 0.90-1.26) per 1 SD (0.5 log-mg/dL) increase in log-transformed triglycerides, and 1.17 (95% CI, 0.91-1.50) per 1 SD (29.6 mg/dL) increase in LDL-C. Sensitivity analyses consistently suggested the positive association between TC and colorectal cancer, whereas results of each lipid component were inconsistent. In conclusion, this large MR study of a Japanese population showed a potentially causal association between high TC and colorectal cancer risk, although the association between each lipid component and colorectal cancer remained inconclusive. PREVENTION RELEVANCE: In this large MR analysis of a Japanese population, a positive association was found between genetically predicted high total cholesterol (TC) levels and an increased risk of colorectal cancer. Therefore, lowering TC levels by lifestyle modifications or medications may be justified for the purpose of preventing colorectal cancer.

Association between germline pathogenic variants and breast cancer risk in Japanese women: The HERPACC study.

Approximately 5%-10% of breast cancers are hereditary, caused by germline pathogenic variants (GPVs) in breast cancer predisposition genes. To date, most studies of the prevalence of GPVs and risk of breast cancer for each gene based on cases and noncancer controls have been conducted in Europe and the United States, and little information from Japanese populations is available. Furthermore, no studies considered confounding by established environmental factors and single-nucleotide polymorphisms (SNPs) identified in genome-wide association studies (GWAS) together in GPV evaluation. To evaluate the association between GPVs in nine established breast cancer predisposition genes including BRCA1/2 and breast cancer risk in Japanese women comprehensively, we conducted a case-control study within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (629 cases and 1153 controls). The associations between GPVs and the risk of breast cancer were assessed by odds ratios (OR) and 95% confidence intervals (CI) using logistic regression models adjusted for potential confounders. A total of 25 GPVs were detected among all cases (4.0%: 95% CI: 2.6-5.9), whereas four individuals carried GPVs in all controls (0.4%). The OR for breast cancer by all GPVs and by GPVs in BRCA1/2 was 12.2 (4.4-34.0, p = 1.74E-06) and 16.0 (4.2-60.9, p = 5.03E-0.5), respectively. A potential confounding with GPVs was observed for the GWAS-identified SNPs, whereas not for established environmental risk factors. In conclusion, GPVs increase the risk of breast cancer in Japanese women regardless of environmental factors and GWAS-identified SNPs. Future studies investigating interactions with environment and SNPs are warranted.

New insights into the genetic contribution of ALDH2 rs671 in pancreatic carcinogenesis: Evaluation by mediation analysis.

A functional variant on ALDH2 rs671 (G>A) confers a protective effect against alcohol-induced carcinogenesis through an indirect pathway mediated by decreased alcohol consumption. Conversely, this variant also contributes to the accumulation of carcinogenic agents, resulting in a direct carcinogenic effect. This study aimed to separately quantify these two opposing effects of the rs671 A allele on pancreatic cancer risk and explore the impact of the rs671 A allele and alcohol consumption on pancreatic carcinogenesis. We included 426 cases and 1456 age- and sex-matched controls. Odds ratio (OR) and 95% confidence interval (CI) for alcohol consumption were estimated using a conditional logistic regression model. By defining rs671 A allele and alcohol consumption as exposure and mediator, respectively, we used mediation analysis to decompose the total-effect OR of the rs671 A allele into direct- and indirect-effect ORs. Alcohol consumption (10 g/d) was associated with pancreatic cancer risk (OR, 1.05; 95% CI, 1.01-1.10), but tests for interaction between the rs671 A allele and alcohol consumption were nonsignificant, indicating that the effect of alcohol consumption did not vary by genotype. Mediation analysis showed that the nonsignificant total effect (OR, 1.15; 95% CI, 0.92-1.44) can be decomposed into the carcinogenic direct (OR, 1.34; 95% CI, 1.04-1.72) and protective indirect effect (OR, 0.86; 95% CI, 0.77-0.95). This study supports the association between alcohol consumption and pancreatic cancer risk and indicates the potential contribution of the rs671 A allele to pancreatic carcinogenesis through impaired metabolism of known or unknown ALDH2 substrates.

Circulating immune- and inflammation-related biomarkers and early-stage noncardia gastric cancer risk.

BACKGROUND: In Helicobacter pylori-driven gastric cancer, mucosal colonization induces chronic inflammation that may variably progress to cancer. Prospective studies of circulating inflammation-related proteins have suggested weak associations with gastric cancer risk. To assess potential utility as a screening tool in clinical settings, we examined circulating levels of a wide range of key inflammation molecules for associations with early-stage gastric cancer. METHODS: We used pretreatment EDTA plasma from 239 individuals with early-stage noncardia gastric cancer (203 stage I and 36 stage II) and 256 age-frequency-matched H. pylori-seropositive cancer-free controls within the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Levels of 92 biomarkers were measured by proximity extension assays using Olink's Proseek Immuno-oncology Panel. Odds ratios (ORs) for association with gastric cancer risk were calculated for quantiles (two to four categories) of each biomarker from unconditional logistic regression models, adjusted for age, sex, smoking and alcohol consumption. Two-sided P values <0.05 were considered as significant. The false discovery rate (FDR) was used to correct for multiple comparisons. RESULTS: Of 83 evaluable biomarkers, lower levels of TNFRSF12A (per quartile OR, 0.82; nominal P-trend = 0.02) and ADGRG1 (per quartile OR, 0.84; nominal P-trend = 0.03) were associated with early-stage gastric cancer but were not statistically significant after FDR correction. CONCLUSION: Our study did not identify any inflammation-related biomarkers that may be useful for early disease detection. To date, this is the first assessment of circulating inflammation-related proteins in early-stage gastric cancer. Given the complex inflammation processes preceding malignant transformation, further investigation of other biomarkers is warranted.

Risk Prediction for Gastric Cancer Using GWAS-Identifie Polymorphisms, Helicobacter pylori Infection and Lifestyle-Related Risk Factors in a Japanese Population.

BACKGROUND: As part of our efforts to develop practical intervention applications for cancer prevention, we investigated a risk prediction model for gastric cancer based on genetic, biological, and lifestyle-related risk factors. METHODS: We conducted two independent age- and sex-matched case-control studies, the first for model derivation (696 cases and 1392 controls) and the second (795 and 795) for external validation. Using the derivation study data, we developed a prediction model by fitting a conditional logistic regression model using the predictors age, ABCD classification defined by H. pylori infection and gastric atrophy, smoking, alcohol consumption, fruit and vegetable intake, and 3 GWAS-identified polymorphisms. Performance was assessed with regard to discrimination (area under the curve (AUC)) and calibration (calibration plots and Hosmer-Lemeshow test). RESULTS: A combination of selected GWAS-identified polymorphisms and the other predictors provided high discriminatory accuracy and good calibration in both the derivation and validation studies, with AUCs of 0.77 (95% confidence intervals: 0.75-0.79) and 0.78 (0.77-0.81), respectively. The calibration plots of both studies stayed close to the ideal calibration line. In the validation study, the environmental model (nongenetic model) was significantly more discriminative than the inclusive model, with an AUC value of 0.80 (0.77-0.82). CONCLUSION: The contribution of genetic factors to risk prediction was limited, and the ABCD classification (H. pylori infection-related factor) contributes most to risk prediction of gastric cancer.

A Personal Breast Cancer Risk Stratification Model Using Common Variants and Environmental Risk Factors in Japanese Females.

Personalized approaches to prevention based on genetic risk models have been anticipated, and many models for the prediction of individual breast cancer risk have been developed. However, few studies have evaluated personalized risk using both genetic and environmental factors. We developed a risk model using genetic and environmental risk factors using 1319 breast cancer cases and 2094 controls from three case-control studies in Japan. Risk groups were defined based on the number of risk alleles for 14 breast cancer susceptibility loci, namely low (0-10 alleles), moderate (11-16) and high (17+). Environmental risk factors were collected using a self-administered questionnaire and implemented with harmonization. Odds ratio (OR) and C-statistics, calculated using a logistic regression model, were used to evaluate breast cancer susceptibility and model performance. Respective breast cancer ORs in the moderate- and high-risk groups were 1.69 (95% confidence interval, 1.39-2.04) and 3.27 (2.46-4.34) compared with the low-risk group. The C-statistic for the environmental model of 0.616 (0.596-0.636) was significantly improved by combination with the genetic model, to 0.659 (0.640-0.678). This combined genetic and environmental risk model may be suitable for the stratification of individuals by breast cancer risk. New approaches to breast cancer prevention using the model are warranted.