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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.

A functional variant on ALDH2 rs671 (GA) 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.

The association between alcohol intake and stomach cancer risk remains controversial. We undertook a pooled analysis of data from six large‐scale Japanese cohort studies with 256 478 participants on this topic. Alcohol intake as ethanol was estimated using a validated questionnaire. The participants were followed for incidence of stomach cancer. We calculated study‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) for stomach cancer according to alcohol intake using a Cox regression model. Summary HRs were estimated by pooling the study‐specific HRs using a random‐effects model. During 4 265 551 person‐years of follow‐up, 8586 stomach cancer cases were identified. In men, the multivariate‐adjusted HRs (95% CIs) of stomach cancer were 1.00 (0.87‐1.15) for occasional drinkers, and 1.00 (0.91‐1.11) for, Alcohol intake increased stomach cancer risk in men, and heavy drinkers showed a greater point estimate of risk for proximal cancer than for distal cancer.

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, Traditional observational studies reported a positive association between higher body mass index (BMI) and colorectal cancer (CRC) risk. However, these studies suffer from biases such as reverse causality and confounding. This Mendelian randomization study consistently showed that the genetically predicted higher BMI was associated with an increased risk of CRC in Japanese populations.

Red meat and processed meat have been suggested to increase risk of colorectal cancer (CRC), especially colon cancer. However, it remains unclear whether these associations differ according to meat subtypes or colon subsites. The present study addressed this issue by undertaking a pooled analysis of large population‐based cohort studies in Japan: 5 studies comprising 232 403 participants (5694 CRC cases) for analysis based on frequency of meat intake, and 2 studies comprising 123 635 participants (3550 CRC cases) for analysis based on intake quantity. Study‐specific hazard ratios (HRs) and 95% confidence intervals (CIs) were estimated using the Cox proportional hazards model and then pooled using the random effect model. Comparing the highest vs lowest quartile, beef intake was associated with an increased risk of colon cancer in women (pooled HR 1.20; 95% CI, 1.01‐1.44) and distal colon cancer (DCC) risk in men (pooled HR 1.30; 95% CI, 1.05‐1.61). Frequent intake of pork was associated with an increased risk of distal colon cancer in women (pooled HR 1.44; 95% CI, 1.10‐1.87) for “3 times/wk or more” vs “less than 1 time/wk”. Frequent intake of processed red meat was associated with an increased risk of colon cancer in women (pooled HR 1.39; 95% CI, 0.97‐2.00; P trend = .04) for “almost every day” vs “less than 1 time/wk”. No association was observed for chicken consumption. The present findings support that intake of beef, pork (women only), and processed red meat (women only) might be associated with a higher risk of colon (distal colon) cancer in Japanese.

Despite treatment guidelines recommending observation for men with low-risk prostate cancer with life expectancy

Alcohol consumption is an established risk factor, and also a potential prognostic factor, for squamous cell carcinoma of the head and neck (HNSCC). However, little is known about whether the prognostic impact of alcohol consumption differs by treatment method. We evaluated the association between alcohol drinking and survival by treatment method to the primary site in 427 patients with HNSCC treated between 2005 and 2013 at Aichi Cancer Center Central Hospital (Nagoya, Japan). The impact of alcohol on prognosis was measured by multivariable Cox regression analysis adjusted for established prognostic factors. Among all HNSCC patients, the overall survival rate was significantly poorer with increased levels of alcohol consumption in multivariable analysis (trend P = 0.038). Stratification by treatment method and primary site revealed that the impact of drinking was heterogeneous. Among laryngopharyngeal cancer (laryngeal, oropharyngeal, and hypopharyngeal cancer) patients receiving radiotherapy (n = 141), a significant dose–response relationship was observed (trend P = 0.034). In contrast, among laryngopharyngeal cancer patients treated with surgery (n = 80), no obvious impact of alcohol was observed. This heterogeneity in the impact of alcohol between surgery and radiotherapy was significant (for interaction, P = 0.048). Furthermore, among patients with oral cavity cancer treated by surgery, a significant impact of drinking on survival was seen with tongue cancer, but not with non‐tongue oral cancer. We observed a significant inverse association between alcohol drinking and prognosis among HNSCC patients, and its impact was heterogeneous by treatment method and primary site.

Gastric cancer is the third leading cause of cancer mortality in Japan and worldwide. Although previous studies identify various genetic variations associated with gastric cancer, host genetic factors are largely unidentified. To identify novel gastric cancer loci in the Japanese population, herein, we carried out a large-scale genome-wide association study using 6171 cases and 27 178 controls followed by three replication analyses. Analysis using a total of 11 507 cases and 38 904 controls identified two novel loci on 12q24.11-12 (rs6490061, P = 3.20 × 10-8 with an odds ratio [OR] of 0.905) and 20q11.21 (rs2376549, P = 8.11 × 10-10 with an OR of 1.109). rs6490061 is located at intron 19 of the CUX2 gene, and its expression was suppressed by Helicobacter pylori infection. rs2376549 is included within the gene cluster of DEFB families that encode antibacterial peptides. We also found a significant association of rs7849280 in the ABO gene locus on 9q34.2 (P = 2.64 × 10-13 with an OR of 1.148). CUX2 and ABO expression in gastric mucosal tissues was significantly associated with rs6490061 and rs7849280 (P = 0.0153 and 8.00 × 10-11 ), respectively. Our findings show the crucial roles of genetic variations in the pathogenesis of gastric cancer.

Gastric cancer incidence and mortality have been decreasing in Japan. These decreases are likely due to a decrease in prevalence of Helicobacter pylori infection. Our aim was to characterize the trends in prevalence of H. pylori infection focused on birth‐year. We carried out a cross‐sectional study that included 4285 subjects who were born from 1926 to 1989. We defined H. pylori infection by the serum H. pylori antibody titer. Individuals having H. pylori infection and those with negative H. pylori antibody titer and positive pepsinogen test were defined as high‐risk individuals for gastric cancer. We estimated the birth‐year percent change (BPC) of the prevalence by Joinpoint regression analysis. The prevalence of H. pylori infection among the subjects born from 1927 to 1949 decreased from 54.0% to 42.0% with a BPC of −1.2%. It was followed by a rapid decline in those born between 1949 (42.0%) and 1961 (24.0%) with a BPC of −4.5%, which was followed by those born between 1961 (24.0%) and 1988 (14.0%) with a BPC of −2.1%. The proportion of high‐risk individuals for gastric cancer among the subjects born from 1927 to 1942 decreased from 62.0% to 55.0% with a BPC of −0.8%. A subsequent rapid declining trend was observed in those born between 1942 (55.0%) and 1972 (18.0%) with a BPC of −3.6%, and then it became stable. These remarkable declining trends in the prevalence of H. pylori infection by birth‐year would be useful to predict the future trend in gastric cancer incidence in Japan.

The preventive effect of coffee on cancer at different sites has been reported, but the effect on all-sites cancer incidence has not been extensively investigated. We evaluated the association between frequency of coffee consumption and risk of all-sites cancer incidence and mortality among 39 685 men and 43 124 women (age 40–79 years, at baseline), in the Three-Prefecture Cohort Study. The association between frequency of coffee consumption and risk of all-sites cancer incidence and mortality was assessed by a Cox proportional hazards regression model, adjusted for potential confounders. During 411 341 person-years among men and 472 433 person-years among women, a total of 4244 men and 2601 women developed cancer at different sites and a total of 3021 men and 1635 women died of cancer at different sites. We showed an inverse association between frequency of coffee consumption and all-sites cancer incidence in both men and women. Comparing participants who consumed coffee with those who never drank coffee, the adjusted hazard ratios (95% confidential interval) for all-sites cancer incidence was 0.74 (0.62–0.88) for coffee consumption of ≥5 cups/day in men (P for trend

Although we usually report 5-year cancer survival using population-based cancer registry data, nowadays many cancer patients survive longer and need to be followed-up for more than 5 years. Long-term cancer survival figures are scarce in Japan. Here we report 10-year cancer survival and conditional survival using an established statistical approach. We received data on 1,387,489 cancer cases from six prefectural population-based cancer registries in Japan, diagnosed between 1993 and 2009 and followed-up for at least 5 years. We estimated the 10-year relative survival of patients who were followed-up between 2002 and 2006 using period analysis. Using this 10-year survival, we also calculated the conditional 5-year survival for cancer survivors who lived for some years after diagnosis. We reported 10-year survival and conditional survival of 23 types of cancer for 15-99-year-old patients and four types of cancer for children (0-14 years old) and adolescent and young adults (15-29 years old) patients by sex. Variation in 10-year cancer survival by site was wide, from 5% for pancreatic cancer to 95% for female thyroid cancer. Approximately 70-80% of children and adolescent and young adult cancer patients survived for more than 10 years. Conditional 5-year survival for most cancer sites increased according to years, whereas those for liver cancer and multiple myeloma did not increase. We reported 10-year cancer survival and conditional survival using population-based cancer registries in Japan. It is important for patients and clinicians to report these relevant figures using population-based data.

Adult T‐cell leukemia/lymphoma (ATLL) is a peripheral T cell neoplasm that is associated with infection by the human T‐cell leukemia virus type I (HTLV‐1). Although the high incidence of ATLL in HTLV‐1‐endemic areas is well known, population‐based evidence concerning the incidence of ATLL in non‐endemic areas is scarce. To answer this, we estimated the age‐standardized incidence of ATLL from 1993 to 2006 for Japan and 1993 to 2008 for the US and assessed its trend using data from a population‐based cancer registry in Japan and Surveillance Epidemiology and End Results (SEER) in the US. The Japanese data were collected from 15 prefectures. A total of 2055 patients in the three prefectures in Kyushu and 1380 patients in the 12 prefectures in Honshu were diagnosed with ATLL in the study period. In the US, a total of 140 patients were diagnosed with ATLL. The results showed that the age‐standardized incidence in non‐endemic areas in Japan and in the US significantly increased during this period (annual percent change [95%CI]; Japan‐Honshu: +4.6% [1.1, 8.2]; US: +6.2% [1.5, 11.1]), while in the endemic areas of Japan there was no change (annual percent change [95%CI]; Japan‐Kyushu: 0.0% [−1.6, 1.7]). This result indicates that the disease has been spread by carriers to non‐endemic areas, and suggests the necessity of establishing a standard preventive strategy.

The insulin-like growth factor (IGF) signaling system plays a central role in cellular growth, differentiation and proliferation. Although the association between IGF1 gene polymorphisms and cancer risk has been evaluated for several carcinomas, this association has not yet been examined for stomach cancer. We investigated the association between IGF1 polymorphisms and the risk of stomach cancer in a Japanese population. A total of 703 patients with stomach cancer and 1462 non-cancer control subjects were enrolled in this case–control study. Associations between polymorphisms of 10 IGF1 loci and the risk of stomach cancer were evaluated using odds ratios (OR) and 95% confidence intervals (CI) in multiple logistic regression models. We observed that the C allele in rs1520220 and the G allele in rs4764887 were significantly associated with stomach cancer risk in the per-allele model after adjusting for other risk factors (OR: 1.14 [95% CI: 1.00–1.30] and OR: 1.18 [95% CI: 1.02-1.36], respectively). We also observed a positive and dose-dependent association between the number of risk alleles and stomach cancer risk (P-trend: 0.019) when examining the two loci in the same model. These associations were still seen after adjusting for potential confounders, including sex, age, smoking status, history of diabetes and family history of stomach cancer. We did not find any significant interaction between these factors and the number of risk alleles. In conclusion, we observed a significant association between IGF1 polymorphisms and stomach cancer risk among a Japanese population. Examination of the biological significance of IGF1 is warranted. (Cancer Sci 2011; 102: 2231–2235)

Some Japanese exhibit facial flushing after drinking alcohol. Facial flushing was considered to be caused by acetaldehydemia. The concentration of blood acetaldehyde was concerned with the catalytic activity of acetaldehyde dehydrogenase (ALDH). Acetaldehyde dehydrogenase (ALDH)-2 polymorphism (rs671, Glu504Lys) was known to be associated with upper aerodigestive tract (UAT) cancer due to modulation of ALDH2 enzyme activity. It remains controversial whether facial flushing is useful in predicting UAT cancer risk as a surrogate marker of ALDH2 polymorphism. We conducted a case-control study to assess the risk of UAT cancer and facial flushing and ALDH2 polymorphism. Cases and controls were 585 UAT cancer patients and matched 1170 noncancer outpatients of Aichi Cancer Center Hospital. Information on facial flushing and other lifestyle factors was collected via a self-administered questionnaire. Association between facial flushing, polymorphism, and UAT cancer was assessed by odds ratios and 95% confidence intervals by using conditional logistic regression models. The facial flushing had no significant association with UAT cancer, although ALDH2 Lys allele was significantly associated with UAT cancer. No significant interaction between facial flushing and alcohol consumption was observed in this study, whereas ALDH2 Lys allele had significant association with UAT cancer. The misclassification between facial flushing and ALDH2 genotype was observed in 18% of controls with ALDH2 Glu/Glu genotype and in 16% of controls with ALDH2 Glu/Lys genotype. Facial flushing was less useful to predict UAT cancer risk than genotyping ALDH2 polymorphism.

The present study aimed to assess the impact of smoking and sex for the risk of non-small-cell lung cancer (NSCLC) with or without epidermal growth factor receptor (EGFR) mutation. We conducted a case-control study using 152 patients with EGFR-mutated (EGFRmut) NSCLC, 283 with EGFR-wild-type (EGFRwt) NSCLC and 2175 age- and sex-frequency-matched controls. Smoking was a significant risk factor for EGFRwt NSCLC (odds ratio [OR] for ever-smokers, 4.05; 95% confidence interval [CI], 2.79-5.88) but not for EGFRmut NSCLC (OR, 0.73; CI, 0.46-1.14). Sex did not affect this association. The association was observed consistently with other smoking-related parameters including pack-years. Sex was the sole risk factor for EGFRmut NSCLC (OR for women relative to men, 2.19; CI, 1.41-3.39) and there was no significant interaction between women and smoking. In contrast, sex, smoking and their interaction were significant in EGFRwt NSCLC. The impact of sex on EGFR mutation status was assessed by several indicators of reproductive history among women. Total fertile years showed a significant positive association with EGFRmut NSCLC but not with EGFRwt NSCLC. Other indicators showed similar trends and this result may partly explain the sexual difference in the acquisition of EGFR mutation. In conclusion, our case-control study clearly demonstrated that the impacts of smoking and sex on the risk of EGFRmut NSCLC are different from those for EGFRwt NSCLC. Further epidemiological evaluation is warranted.

The peroxisome proliferator-activated receptor gamma (PPARgamma) gene plays important roles in energy homeostasis. To examine interactions between consumption of foods and fatty acids and the Pro12Ala and C161T (His447His) polymorphisms for colorectal cancer, we performed two case-control studies in Japanese. In study 1, there were 128 colorectal cancer cases and 238 non-cancer controls, and in study 2 there were 257 cases and 771 (age- and sex-matched) non-cancer controls. Assessment of food and nutrients consumption in study 1 was via a nine-item questionnaire, while in study 2 assessment of consumption was according to a more detailed semiquantitative food frequency questionnaire. Consumption of foods and fatty acids was divided into low, moderate and high groups. The overall frequency of the Ala allele was

Several intervention trials and prospective studies have reported that beta-carotene supplementation is not associated with a decreased risk of several cancers among smokers and drinkers, and that it may even have adverse effects in these groups. The relationship between dietary antioxidant intake and the risk of head and neck squamous cell carcinoma (HNSCC) has been examined intensively, but little is known about the effects of antioxidants on HNSCC with respect to smoking and drinking habits. Here, we conducted a case-control study of 385 histologically confirmed cases of HNSCC (193 oral, 132 pharyngeal and 60 laryngeal), excluding nasal and paranasal cancer, and 1925 age-matched and sex-matched cancer-free outpatient controls using data from the Hospital-based Epidemiologic Research Program at Aichi Cancer Center, Japan. The intake of nutrients and food groups was assessed with a food frequency questionnaire, and multivariate-adjusted odds ratios for cancer were estimated for smoking and drinking habits using logistic models. The results showed an overall inverse association between the intake of dietary antioxidants, including carotene, and vitamins C and E, and risk of HNSCC. The protective effect of these antioxidants was seen in both men and women. High consumption of antioxidants was associated with a decreased risk of HNSCC among smokers, drinkers and those with both smoking and drinking habits. These findings suggest that dietary antioxidant intake prevents HNSCC in smokers and drinkers.

Several studies have investigated a possible association between the ABO blood group and the risk of pancreatic cancer (PC), but this association has not been fully evaluated in Asian populations. The present study aimed to assess the impact of genotype-derived ABO blood types, particularly ABO alleles, on the risk of PC in a Japanese population. We conducted a case-control study using 185 PC and 1465 control patients who visited Aichi Cancer Center in Nagoya, Japan. Using rs8176719 as a marker for the O allele, and rs8176746 and rs8176747 for the B allele, all participants' two ABO alleles were inferred. The impact of ABO blood type on PC risk was examined by multivariate analysis, with adjustment for potential confounders to estimate odds ratios (OR) and 95% confidence intervals (CI). An increased risk of PC was observed with the addition of any non-O allele (trend P = 0.012). Compared with subjects with the OO genotype, those with AO and BB genotypes had significantly increased OR of 1.67 (CI, 1.08-2.57) and 3.28 (CI, 1.38-7.80), respectively. Consistent with earlier reports showing a higher risk of PC for individuals with the non-O blood type, the previously reported protective allele (T) for rs505922 was found to be strongly correlated (r(2) = 0.96) with the O allele. In conclusion, this case-control study showed a statistically significant association between ABO blood group and PC risk in a Japanese population. Further studies are necessary to define the mechanisms by which the ABO gene or closely linked genetic variants influence PC risk.

Epidermal growth factor receptor (EGFR) mutations play substantial roles in genesis and proliferation of non-small-cell lung cancers (NSCLCs). We recently found that reproductive factors have a substantial impact on risk of development of NSCLCs featuring such EGFR mutations. Therefore, we explored the influence of dietary habits on NSCLC risk with reference to the EGFR mutational status. We conducted a case-control study using 353 patients with NSCLCs (122 EGFR mutated and 231 EGFR wild-type) and 1765 age-sex matched non-cancer control subjects. Dietary exposure was based on a semiquantitative food frequency questionnaire and impact of major food items, like meats, seafoods, vegetables and soybean products was assessed by multivariate logistic regression. Soybean products demonstrated a protective association with EGFR mutated, but not EGFR wild-type NSCLCs, with multivariate-adjusted odds ratios and 95% confidence intervals for the 2nd and 3rd tertile of soybean product consumption of 0.79 (0.50-1.27) and 0.56 (0.34-0.93) relative to those in the lowest tertile (trend P = 0.023). In conclusion, soy consumption may exert a protective association against the development of NSCLCs with EGFR mutations, providing possible insights into mechanisms of their genesis.