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.

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.

Trends of travel burdens to access cancer care among children with cancer: analysis of a population-based cancer registry data in Aichi, Japan.

Centralization of childhood cancer treatment in specialized hospitals is necessary for quality treatment and care, but imposes a time and cost burden for patients and their families. We investigated the 20-year trend in the patients' car travel burden to reach cancer-care hospitals in Aichi Prefecture, Japan. From the Aichi population-based cancer registry data, 1,741 cases diagnosed in 1998-2017 under 15 years of age were extracted and assigned to three treatment groups: invasive treatment (n = 697), radiotherapy (n = 371), or chemotherapy groups (n = 1,462), allowing for duplicate assignment. Their travels to access each treatment hospital were estimated and summarized as the estimated travel times (ETT), estimated travel distances (ETD), and direct distances (DD). The ETTs were compared using the Brunner-Munzel test. The average cases per year for each hospital were plotted. The annual trends during 1998-2017 on ETT, ETD, and DD were investigated using Joinpoint regression models. The ETTs were 0.38-0.45 hours on median for three periods (1998-2005, 2006-2012, and 2013-2017) in three treatment groups and increased by 0.02-0.07 hours from 2006-2012 to 2013-2017, with a statistically significant difference in the radiotherapy group (0.07 hours, P = 0.037). The average cases per year increased for the top hospital in each group, and regression model analyses showed no joinpoint on the annual median trend. In conclusion, the increases in travel times were small and not considered clinically significant, and treatment centralization was observed from 2006-2012 to 2013-2017.

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.

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.).

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.

Expansion of Cancer Risk Profile for BRCA1 and BRCA2 Pathogenic Variants.

Importance: The clinical importance of genetic testing of BRCA1 and BRCA2 in breast, ovarian, prostate, and pancreatic cancers is widely recognized. However, there is insufficient evidence to include other cancer types that are potentially associated with BRCA1 and BRCA2 in clinical management guidelines. Objective: To evaluate the association of BRCA1 and BRCA2 pathogenic variants with additional cancer types and their clinical characteristics in 100 914 individuals across 14 cancer types. Design, Setting, and Participants: This case-control analysis to identify cancer types and clinical characteristics associated with pathogenic variants in BRCA1 and BRCA2 included DNA samples and clinical information from 63 828 patients with 14 common cancer types and 37 086 controls that were sourced from a multi-institutional hospital-based registry, BioBank Japan, between April 2003 and March 2018. The data were analyzed between August 2019 and October 2021. Main Outcomes and Measures: Germline pathogenic variants in coding regions and 2 bp flanking intronic sequences in BRCA1 and BRCA2 were identified by a multiplex polymerase chain reaction-based target sequence method. Associations of (likely) pathogenic variants with each cancer type were assessed by comparing pathogenic variant carrier frequency between patients in each cancer type and controls. Results: A total of 65 108 patients (mean [SD] age at diagnosis, 64.1 [11.6] years; 27 531 [42.3%] female) and 38 153 controls (mean [SD] age at registration, 61.8 [14.6] years; 17 911 [46.9%] female) were included in this study. A total of 315 unique pathogenic variants were identified. Pathogenic variants were associated with P < 1 × 10-4 with an odds ratio (OR) of greater than 4.0 in biliary tract cancer (OR, 17.4; 95% CI, 5.8-51.9) in BRCA1, esophageal cancer (OR, 5.6; 95% CI, 2.9-11.0) in BRCA2, and gastric cancer (OR, 5.2; 95% CI, 2.6-10.5) in BRCA1, and (OR, 4.7; 95% CI, 3.1-7.1) in BRCA2 in addition to the 4 established cancer types. We also observed an association with 2 and 4 other cancer types in BRCA1 and BRCA2, respectively. Biliary tract, female breast, ovarian, and prostate cancers showed enrichment of carrier patients according to the increased number of reported cancer types in relatives. Conclusions and Relevance: The results of this large-scale registry-based case-control study suggest that pathogenic variants in BRCA1 and BRCA2 were associated with the risk of 7 cancer types. These results indicate broader clinical relevance of BRCA1 and BRCA2 genetic testing.

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.

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.

Hospital volume and 5-year survival in head and neck cancer patients in Osaka, Japan.

BACKGROUND: Few previous studies have examined the relationship between hospital volume and hazard of death for head and neck cancer patients. The purpose of this study was to examine the association between hospital volume and 5-year survival from diagnosis among head and neck cancer patients. METHODS: Using data from the population-based Osaka Cancer Registry, hospital volume was divided into three volume groups according to the number of head and neck cancer treatments identified between 2009 and 2011. We analysed the association between hospital volume and 5-year survival among 3069 patients aged 0-79 using Cox proportional hazard models, adjusting for characteristics of patients. RESULTS: Compared with head and neck cancer patients in high-hospital volume, patients treated in middle- and low-hospital volume were found to have a higher risk of death (middle-hospital volume: hazard ratio = 1.26; 95% confidence interval, 1.09-1.46, low-hospital volume: hazard ratio = 1.24; 95% confidence interval, 1.06-1.46). CONCLUSIONS: We found a significantly higher risk of hazard of death in middle- and low-hospital volume than in high-hospital volume for head and neck 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.

Body mass index and colorectal cancer risk: A Mendelian randomization study.

Traditional observational studies have reported a positive association between higher body mass index (BMI) and the risk of colorectal cancer (CRC). However, evidence from other approaches to pursue the causal relationship between BMI and CRC is sparse. A two-sample Mendelian randomization (MR) study was undertaken using 68 single nucleotide polymorphisms (SNPs) from the Japanese genome-wide association study (GWAS) and 654 SNPs from the GWAS catalogue for BMI as sets of instrumental variables. For the analysis of SNP-BMI associations, we undertook a meta-analysis with 36 303 participants in the Japanese Consortium of Genetic Epidemiology studies (J-CGE), comprising normal populations. For the analysis of SNP-CRC associations, we utilized 7636 CRC cases and 37 141 controls from five studies in Japan, and undertook a meta-analysis. Mendelian randomization analysis of inverse-variance weighted method indicated that a one-unit (kg/m2 ) increase in genetically predicted BMI was associated with an odds ratio of 1.13 (95% confidence interval, 1.06-1.20; P value <.001) for CRC using the set of 68 SNPs, and an odds ratio of 1.07 (1.03-1.11, 0.001) for CRC using the set of 654 SNPs. Sensitivity analyses robustly showed increased odds ratios for CRC for every one-unit increase in genetically predicted BMI. Our MR analyses strongly support the evidence that higher BMI influences the risk of CRC. Although Asians are generally leaner than Europeans and North Americans, avoiding higher BMI seems to be important for the prevention of CRC in Asian populations.

Hospital Surgical Volume and 3-Year Mortality in Severe Prognosis Cancers: A Population-Based Study Using Cancer Registry Data.

BACKGROUND: The impact of hospital surgical volume on long-term mortality has not been well assessed in Japan, especially for esophageal, biliary tract, and pancreatic cancer, although these three cancers need a high level of medical-technical skill. The purpose of this study was to examine associations between hospital surgical volume and 3-year mortality for these severe-prognosis cancer patients. METHODS: Patients who received curative surgery for esophageal, biliary tract, and pancreatic cancers were analyzed using the Osaka Cancer Registry data from 2006-2013. Hospital surgical volume was categorized into tertiles (high/middle/low) according to the average annual number of curative surgeries per hospital for each cancer. Three-year survivals were calculated using the Kaplan-Meier method. Hazard ratios (HRs) of 3-year mortality were calculated using Cox proportional hazard models, adjusting for patient characteristics. RESULTS: Three-year survival was higher with increased hospital surgical volume for all three cancers, but the relative importance of volume varied across sites. After adjustment for all confounding factors, HRs in middle- and low-volume hospitals were 1.34 (95% confidence interval [CI], 1.14-1.58) and 1.57 (95% CI, 1.33-1.86) for esophageal cancer; 1.39 (95% CI, 1.15-1.67) and 1.57 (95% CI, 1.30-1.89) for biliary tract cancer; 1.38 (95% CI, 1.16-1.63) and 1.90 (95% CI, 1.60-2.25) for pancreatic cancer, respectively. In particular for localized pancreatic cancer, the impact of hospital surgical volume on 3-year mortality was strong (HR 2.66; 95% CI, 1.61-4.38). CONCLUSION: We suggest that patients who require curative surgery for esophageal, biliary tract, and pancreatic cancer may benefit from referral to high-volume hospitals.

Driving to Childhood Cancer Hub Hospitals: A Study on Hospital Accessibility in Japan.

OBJECTIVE: In 2013, 15 childhood cancer hub hospitals in Japan were designated to provide quality medical treatment and care. The present study assessed hospital accessibility by investigating travel times and distances from patient residences. METHODS: A total of 37,309 residence/hospital pairs were generated using the addresses of 15 hub hospitals that were designated in 2019 and local government offices in 2014. Using the Google Directions Application Programming Interface (API), travel times and distances were calculated on the assumption that each patient would arrive by driving to the hospitals by 10 am on Wednesday, November 6, 2019. Thus, after identifying the nearest hospital for each residence and deriving adjusted estimated travel times (AETT), the data were summarized according to the regional block using weighted population descriptive statistics for children under 15 years of age in 2015. The cumulative distribution functions of the weighted mean of AETT were also plotted. RESULTS: Childhood cancer patients could access the nearest hub hospital by traveling approximately 1.78 hours (AETT, range: 0.1 to 41.8) and 91.86 km (range: 1.0 to 1438.0). Moreover, a total of 94.5% of patients had the nearest hub hospital within their own regional block. The cumulative distribution functions of AETT indicated that many children in three blocks with multiple hub hospitals have shorter travel times and better hospital accessibility than those in other blocks. CONCLUSIONS: Although feasibility is ultimately dependent on each patient's condition and situation, child cancer patients on average can likely complete hospital visits from home and return within a single day. However, this is likely not the case for children who live at considerable distances from hub hospitals. We found regional differences in travel times and distances, depending on whether a given block contained multiple hub hospitals.

Hospital volume and postoperative 5-year survival for five different cancer sites: A population-based study in Japan.

The relationship between hospital volume and patient outcome is globally known; thus, hospital volume is widely used as a quality indicator. In Japan, however, recent studies on this topic are scarce. The present study examined whether hospital surgery volume is associated with postoperative 5-year survival among cancer patients. Using the Osaka Cancer Registry, we identified a sample of 86 145 patients who were diagnosed with cancer at any of five different sites (stomach, colorectum, lung, breast and uterus) and underwent surgeries between 2007 and 2011 in Osaka. We ranked hospitals by annual surgical volume, sorted patients in descending order by hospital volume, and assigned them into quartiles (high, medium, low and very low volume). We analyzed the association between hospital volume and 5-year survival among 80 959 patients aged between 15 and 84 years using Cox proportional hazard models. Adjustments were made for characteristics of patients, type of surgery and adjuvant treatment received. The mortality hazard of patients treated at very low-volume hospitals was 1.36-1.82-fold higher than that of patients treated at high-volume hospitals. Absolute differences in adjusted survival rates between high-volume and very low-volume hospitals varied with the cancer site: 14.9 in stomach, 11.5 in colorectal, 10.8 in lung, 2.4 in breast and 3.3 in uterine cancers. Hospitals with lower surgery volumes showed higher mortality risks after cancer surgery than those with higher volumes. Monitoring site-specific surgery volumes and referring patients from low-volume to high-volume hospitals may be beneficial for improving the long-term survival of cancer patients.

Estimation of lifetime cumulative incidence and mortality risk of gastric cancer.

OBJECTIVE: To estimate cumulative incidence and mortality risk for gastric cancer by risk category. METHODS: Risk was classified into four types according to the presence/absence of Helicobacter pylori infection and chronic atrophic gastritis: in order of lowest to highest risk, Group A: H. pylori(-) and atrophic gastritis(-); Group B: H. pylori(+) and atrophic gastritis(-); Group C:H. pylori(+) and atrophic gastritis(+); and, Group D: H. pylori(-) and atrophic gastritis(+). We used vital statistics for the crude all-cause and crude gastric cancer mortality rates in 2011 and data from population-based cancer registries (the Monitoring of Cancer Incidence in Japan) for gastric cancer incidence in 2011. For relative risk and prevalence, we used the results of a meta-analysis integrating previous studies and data from the Japan Public Health Center-based Prospective Study for the Next Generation, respectively (baseline survey 2011-16). We calculated the crude incidence and mortality rates and estimated the cumulative risk using a life-table method. RESULTS: The estimated lifetime cumulative incidence risk was 11.4% for men and 5.7% for women. The estimated risk for Groups A, B, C and D was 2.4%, 10.8%, 26.7% and 35.5% for men, and 1.2%, 5.5%, 13.5% and 18.0% for women, respectively. Similarly, the estimated lifetime cumulative mortality risk was 3.9% for men and 1.8% for women. The estimated risk of mortality for Groups A, B, C and D was 0.8%, 3.6%, 9.0% and 12.0% for men, and 0.4%, 1.7%, 4.2% and 5.7% for women, respectively. CONCLUSIONS: Our results may be useful for designing individually tailored prevention programs.

Genetic polymorphisms and oral cancer.

Oral cancer, a disease associated with major morbidity and mortality, represents a significant worldwide health problem. It is clear that the major etiological factors for oral cancer are tobacco and alcohol exposure. It has been shown that metabolic activation is associated with cancer susceptibility. Various carcinogens and carcinogenic precursors, such as benzopyrene and nitrosamine, have been identified in tobacco smoke, and those are activated or detoxified by two types of metabolic enzymes, phase I and phase II. There are some polymorphisms for these enzyme genes, the functions of which are modified by the types of polymorphisms. On the other hand, there are some genes besides these enzyme genes related to cancer susceptibility. In this review, we discuss the relationships between polymorphisms concerned with oral cancer. Although there are many reports on the polymorphisms related to oral cancer, the results of these reports are controversial. Further studies are needed to evaluate the interactions between carcinogens and the genetic polymorphisms.