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Background: Cigarette smoking is the major cause for upper aerodigestive tract (UADT) cancers. The time to first cigarette (TTFC) of the day is a distinct indicator of nicotine dependence, but scanty information is available on its possible relation with UADT cancers (oral, oropharyngeal, hypopharyngeal, laryngeal, nasopharyngeal, and esophageal cancers). Methods: This case–control study includes a total of 1,009 incident UADT cancer cases and 3,027 age- and sex-matched noncancer controls admitted to the Aichi Cancer Center (Nagoya, Japan) between 2001 and 2005. We estimated OR and 95% confidence intervals (CI) for TTFC using logistic regression models after adjustment for several potential confounders. Results: TTFC was inversely related to the risk of UADT cancer, and this association was consistent across subtypes of head and neck cancer and esophageal cancer. For all UADT cancers considered among ever smokers and after accurate allowance for smoking quantity and duration, besides other relevant covariates, compared with TTFC more than 60 minutes, the adjusted ORs were 1.40 (95% CI: 0.93–2.11) for 31 to 60 minutes, 1.76 (95% CI: 1.20–2.58) for 6 to 30 minutes, and 2.43 (95% CI: 1.64–3.61) for within 5 minutes. No significant heterogeneity was found in strata of sex, age, alcohol consumption, fruit and vegetable intake, and occupation for overall and site-specific analysis. Conclusion: Nicotine dependence, as indicated by the TTFC, is associated with increased risk of UADT cancers and is therefore an independent marker of exposure to smoking. Impact: Our result indicates more detailed risk evaluation of UADT cancers that is enabled by the TTFC. Cancer Epidemiol Biomarkers Prev; 21(11); 1986–92. ©2012 AACR.

Background: The TGF-β signaling pathway plays a significant role in the carcinogenic process of breast cancer. Methods: We systematically evaluated associations of common variants in TGF-β signaling pathway genes with breast cancer risk using a multistage, case–control study among Asian women. Results: In the first stage, 341 single-nucleotide polymorphisms with minor allele frequencies ≥ 0.05 across 11 genes were evaluated among 2,926 cases and 2,380 controls recruited as a part of the Shanghai Breast Cancer Genetics Study (SBCGS). In the second stage, 20 SNPs with promising associations were evaluated among an additional 1,890 cases and 2,000 controls from the SBCGS. One variant, TGFBR2 rs1078985, had highly consistent and significant associations with breast cancer risk among participants in both study stages, as well as promising results from in silico analysis. Additional genotyping was carried out among 2,475 cases and 2,343 controls from the SBCGS, as well as among 5,077 cases and 5,384 controls from six studies in the Asian Breast Cancer Consortium (stage III). Pooled analysis of all data indicated that minor allele homozygotes (GG) of TGFBR2 rs1078985 had a 24% reduced risk of breast cancer compared with major allele carriers (AG or AA; OR, 0.76; 95% CI, 0.65–0.89; P = 8.42 × 10−4). Conclusion: These findings support a role for common genetic variation in TGF-β signaling pathway genes, specifically in TGFBR2, in breast cancer susceptibility. Impact: These findings may provide new insights into the etiology of breast cancer as well as future potential therapeutic targets. Cancer Epidemiol Biomarkers Prev; 21(7); 1176–84. ©2012 AACR.

Background: Although several studies have investigated the association between ABO blood type and risk of gastric cancer (GC), atrophic gastritis (AG), and Helicobacter pylori (HP) infection, no study has investigated these associations by using ABO genotype. Methods: We conducted a case–control study in 703 patients with GC and 1,465 noncancer patients. We also conducted a cross-sectional study by using 1,406 of these 1,465 controls, who were examined for pepsinogens and anti-HP IgG antibody levels in serum. ABO genotype was determined from single nucleotide polymorphisms in ABO gene. We used rs8176719 to mark the O allele, and rs8176746 and rs8176747 to mark the B allele. ORs and 95% CIs were calculated by a multivariate logistic model. Results: We observed significant associations between ABO genotype and GC, AG, and HP infection. ORs (95% CIs) of GC were 0.70 (0.50–0.99) for OO and 0.53 (0.36–0.77) for BO relative to AA genotype. An increased risk of GC was observed with addition of the A allele (Ptrend < 0.001), and a decreased risk with that of the B allele (Ptrend = 0.023). An OR of AG was 0.73 (95% CI, 0.53–0.99) for blood type B relative to blood type A, and an OR of HP infection was 0.39 (95% CI, 0.17–0.87) for BB relative to AA genotype. Conclusion: This study identified a statistically significant association between ABO genotype and GC risk. In addition, ABO gene locus may influence AG prevalence and HP infection. Impact: Further studies are necessary to confirm these findings. Cancer Epidemiol Biomarkers Prev; 20(8); 1665–72. ©2011 AACR.

Alcohol intake is positively associated with the risk of upper aerodigestive tract (UAT) cancer. The genes that encode alcohol-metabolizing enzymes, primarily alcohol dehydrogenases (ADH) and aldehyde dehydrogenases (ALDH), are polymorphic. In Caucasians, significant associations between polymorphisms in ADH1B (rs1229984) and ADH1C (rs698 and rs1693482), and UAT cancer have been observed, despite strong linkage disequilibrium among them. Moreover, UAT cancer was significantly associated with rs1573496 in ADH7, and not with rs1984362 in ADH4. However, little evidence is available concerning ADH4 or ADH7 polymorphisms in Asian populations. We conducted a matched case-control study to clarify the role of ADH polymorphisms in a Japanese population. Cases and controls were 585 patients with UAT cancer and 1,170 noncancer outpatients. Genotyping for ADHs and ALDH2 was done using TaqMan assays. Associations between polymorphisms and UAT cancer were assessed by odds ratios and 95% confidence intervals using conditional logistic regression models that adjusted for age, sex, smoking, drinking, and ALDH2. Adjusted odds ratios were significant for rs4148887 and rs3805322 in ADH4, rs1229984 in ADH1B, rs698 and rs1693482 in ADH1C, and rs284787, rs1154460, and rs3737482 in ADH7. We also observed that ADH7 rs3737482 and ADH4 rs4148887 had independently and statistically significant effects on UAT cancer. The magnitude of effect of these ADH polymorphisms was greater in subjects who were heavy drinkers, heavy smokers, and had esophageal cancer. These findings show that multiple ADH gene polymorphisms were associated with UAT cancer in this Japanese population. Further studies in various ethnicities are required. (Cancer Epidemiol Biomarkers Prev 2009;18(11):3097–102)

Consumption of fish rich in n-3 polyunsaturated fatty acids (PUFAs), such as docosahexaenoic acid, is suggested to reduce colorectal cancer risk through inhibition of the arachidonic acid (AA) cascade related to tumorigenesis and cell proliferation. High intake of saturated fatty acids (SFAs) may increase the risk. To examine associations between colorectal cancer risk and fatty acid compositions in erythrocyte membranes, as biomarkers for dietary intakes of fish, fat, and fatty acids, we conducted a case-control study with 74 incident cases and 221 noncancer controls (matched by age, sex, and season of sample collection). Erythrocyte fatty acids were measured using an accelerated solvent extraction and a gas-liquid chromatography. Colorectal cancer had no association with dietary intakes of meat, fish, fat, and fatty acids. However, the risk was inversely associated with erythrocyte compositions of docosahexaenoic acid, AA, and PUFAs [the highest to the lowest tertile, odds ratios, 0.36, 0.42, and 0.15; 95% confidence intervals, 0.14-0.93, 0.18-0.95, and 0.05-0.46; Ptrend < 0.05, respectively] and positively with those of palmitic acid, SFAs, and the ratio of SFAs/PUFAs (odds ratios, 6.46, 8.20, and 9.45; 95% confidence intervals, 2.41-17.26, 2.86-23.52, and 2.84-31.43; Ptrend < 0.005, respectively). In conclusion, we could clearly show decreased and increased risks for colorectal cancer related to PUFAs and SFAs compositions in erythrocyte membranes, respectively, but further research is needed to investigate the discrepancy between our findings and the generally accepted role of the AA cascade. (Cancer Epidemiol Biomarkers Prev 2006;15(10):1791–8)

Although the functional effect of alcohol dehydrogenase 2 (ADH2) His47Arg polymorphism has been elucidated, its effect on habitual drinking remains unknown. Here, we conducted a cross-sectional study in 2,299 nonalcoholic Japanese subjects (989 men and 1,310 women). Drinking status, ethanol consumption, and physical reaction to one glass of beer were examined with regard to ADH2 and aldehyde dehydrogenase 2 (ALDH2) polymorphism. Strength of associations were assessed by age-, sex-, smoking status-, and genotype-adjusted odds ratios and their 95% confidence intervals. ADH2 His/Arg and Arg/Arg genotypes showed higher risk for habitual drinking. Among men, ALDH2 genotype- and confounder-adjusted odds ratios (95% confidence intervals) were 1.30 (0.89-1.89) and 3.16 (1.03-9.70), and this trend was significant (P = 0.024). A similar trend was observed among women. The combination genotypes of two polymorphisms revealed the clear effect of the ADH2 Arg allele among those with ALDH2 Glu/Lys in both sexes (Ptrend = 0.007 for men and 0.024 for women). Physical reactions, such as flushing and palpitation, were significantly less common in those with Arg/Arg compared with other ADH2 genotypes, and this was marked when combined with ALDH2 Glu/Lys. Heavy drinker status was also strongly associated with ADH2 Arg alleles. In conclusion, this study showed the strong effect of ADH2 His47Arg polymorphism on habitual drinking regardless of ALDH2 genotype. (Cancer Epidemiol Biomarkers Prev 2006;15(5):1009–13)

Advances in molecular genetics have the potential to impact cancer prevention. However, the contribution of this information to determining the risk of cancer of the stomach at the population level in combination with biological and lifestyle-related factors has not been evaluated. Here, we established a risk prediction model of gastric cancer using genetic, biological, and lifestyle-related risk factors as a potential practical application in interventions for cancer prevention. We conducted two independent age- and sex-matched case-control studies, the first for model derivation (697 cases and 1,372 controls) and the second (678 and 678) for external validation. Using the derivation study data, we developed a prediction model by fitting a conditional logistic regression model using the following predictors: age, ABCD classification defined by H.pylori infection and atrophic gastritis, smoking, fruit and vegetable intake, and selected GWAS-identified genotypes. Performance was assessed regarding discrimination (area under the curve, AUC), calibration (calibration plots and Hosmer-Lemeshow test) and reclassification (integrated discrimination improvement (IDI)). We preliminarily found that a combination of rs229400, one of the GWAS-identified SNPs, H.Pylori infection, atrophic gastritis, smoking and fruit and vegetable intake provided high discriminatory accuracy and good calibration in both the derivation and validation studies, with AUCs of 0.78 (95% confidence intervals, 0.76-0.80) and 0.80 (0.77-0.82), respectively. The calibration plots of both studies stayed close to the ideal calibration line. IDI indices were 0.12 (p Citation Format: Hidemi Ito, Isao Oze, Keitaro Matsuo. Risk prediction for gastric cancer using the GWAS-identified SNPs, Helicobacter pylori infection and lifestyle-related risk factors in a Japanese population. [abstract]. In: Proceedings of the AACR Special Conference: Improving Cancer Risk Prediction for Prevention and Early Detection; Nov 16-19, 2016; Orlando, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2017;26(5 Suppl):Abstract nr A03.

Genome-wide association studies (GWASs) have identified genetic variants associated with breast cancer. Most GWASs to date have been conducted in women of European descent, however, and the contribution of these variants as predictors in Japanese women is unknown. Here, we analyzed 79 genetic variants identified in previous GWASs and conducted a case–control study with 697 case subjects and 1,394 age- and menopausal status-matched controls. We fit conditional regression models with genetic variants and conventional risk factors. In addition, we created a polygenetic risk score, using those variants with a statistically significant association with breast cancer risk, and also evaluated the contribution of these genetic predictors using the c statistic. Twenty-three single nucleotide polymorphisms (SNPs) revealed significant associations with breast cancer risk. A dose-dependent association was observed between the risk of breast cancer and the genetic risk score, which was an aggregate measure of alleles in seven selected variants. Compared to women with scores of 33 to 35, odds ratios (ORs) for women with scores of 23–25, 26–29, 30–32, and 10 or more were 1.28 (95% confidence interval, 0.93-1.76), 2.16 (1.61-2.95), 3.17 (2.07-4.87), and 7.7 (2.69-22.0), respectively (Ptrend = 1.28 × 10−13). The c statistic for a model including the genetic risk score in addition to the conventional risk factors was 0.726, versus 0.675 with the conventional risk factors only (P Citation Format: Hidemi Ito, Aiko Sueta, Hiroji Iwata, Satoyo Hosono, Isao Oze, Miki Watanabe, Hirotaka Iwase, Hideo Tanaka, Keitaro Matsuo. A genetic risk predictor for breast cancer using a combination of low-penetrance polymorphisms in a Japanese population. [abstract]. In: Proceedings of the AACR Special Conference on Post-GWAS Horizons in Molecular Epidemiology: Digging Deeper into the Environment; 2012 Nov 11-14; Hollywood, FL. Philadelphia (PA): AACR; Cancer Epidemiol Biomarkers Prev 2012;21(11 Suppl):Abstract nr 06.