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Background: ATP binding cassette (ABC) transporters are members of membrane protein of transporters, genetic variations of which may influence their activity. ABCC11, a member of ABC transporters, has been known to export steroid sulfates such as E2-17bG and E3S that are precursor of active estradiol. Therefore, rs17822931, a functional single nucleotide polymorphisms (SNP) in the ABCC11, may play a role in carcinogenesis of breast cancer (BC) via estrogen exposure. Three previous studies about the association of this polymorphism with BC risk reported inconsistent results. In this study, we aimed to evaluate the association between ABCC11 rs17822931 and BC risk in a Japanese population. Subjects and Methods: We conducted a case-control study in 697 BC patients and 1394 age- and menopausal status- matched controls within the framework of the Hospital-based Epidemiological Research Program at Aichi Cancer Center II (HERPACC II). The odds ratio (OR) and 95 % confidence interval (CI) were calculated using the conditional logistic model adjusted for potential confounders to evaluate the association. We evaluated heterogeneity by BC subtype using Cochran's Q test, and that by estrogen exposure by multiplicative assumption in the conditional logistic regression model, which included an interaction term for genotype and estrogen exposure variable. Results: Compared with A-allele, G allele was inversely associated with BC risk (a per allele OR=0.76, 95% CI, 0.61–0.94, P = 0.012). In the stratified analysis, we found that this association was observed only in estrogen receptor (ER) positive BC. A per-allele OR for ER positive BC was 0.65 (95% CI 0.49–0.86) while that for ER negative BC was 1.10 (95% CI 0.77-1.72). We found a statistically significant heterogeneity by ER status (p for interaction = 0.047). We did not observe any heterogeneity in the stratified analysis by other tumor characteristics. When stratifying by factors related with estrogen exposure, we found that this polymorphism had a different impact on BC risk by levels of exposure. Compared to women with low exposure to estrogen, those with high exposure had a stronger impact of this polymorphism. Per allele ORs for women who had ever and never breastfeeding were 0.82 (95% CI, 0.65-1.04) and 0.45 (0.26-0.79), respectively. We found suggestive heterogeneity between rs17822931 and history of breastfeeding on BC risk (p for interaction = 0.093). Interestingly, we found heterogeneous impact of rs17822931 by the levels of soy food consumption which is well known that may exert their effects as estrogen antagonists (p=0.005). We observed that ORs for >50, 30-49 and Conclusion: Current case-control study showed the significant association between rs17822931 and the risk of BC, especially ER-positive BC, in Japanese women. Compared to women with low estrogen efflux activity with A allele, those with high efflux activity with G allele may have a lower risk of BC, especially in women with high estrogen exposure. To the best of our knowledge, this is the first study reporting the association between rs17822931 on ABCC11 and risk of BC considering levels of estrogen exposure. Citation Format: Ishiguro J, Ito H, Tsukamo M, Iwata H, Nakagawa H, Matsuo K. A functional single nucleotide polymorphisms in ABCC11, rs17822931, is associated with the risk of breast cancer in Japanese [abstract]. In: Proceedings of the 2017 San Antonio Breast Cancer Symposium; 2017 Dec 5-9; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2018;78(4 Suppl):Abstract nr P6-09-12.

Background: Germinal center-associated nuclear protein (GANP) is a phosphoprotein which is involved in mRNA export and the regulation of DNA recombination. We have previously demonstrated that deficiency of GANP led to spontaneous development of mammary gland tumors in a mouse model. In addition, we found that decreased GANP expression in human breast cancer tissue was an independent prognostic factor. Here, we conducted a case-control study and a retrospective cohort study to investigate whether single nucleotide polymorphisms (SNPs) of GANP are associated with sporadic breast cancer risk and prognosis in a Japanese population. Subjects and Methods: Six hundred-ninety-four breast cancer cases and 1,376 age- and menopausal status-matched controls were selected within the framework of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center. Cases and controls were genotyped using an Infinium iSelect custom array (iCOGS, Illumina Inc., San Diego, CA, USA). We assessed 13 SNPs at the GANP locus, 2 SNPs (rs2839178 and rs11702450) were selected for further analysis by considering linkage disequilibrium. Conditional logistic regression methods were used to estimate odds ratios (ORs) and 95% confidence intervals. In addition, the survival impact of the two SNPs was retrospectively analyzed using the 694 breast cancer cases. To evaluate the effect of SNPs on overall survival (OS) and disease-free survival (DFS), multivariate Cox proportional hazards modeling was applied. Results: Compared to the AA genotype of rs2839178, the GG genotype showed statistically significant associations with breast cancer risk (OR: 0.48, 95%CI:0.30–0.76, P = 0.002). In prognostic analysis, compared to those with the genotype AA at rs2839178, patients with AG or GG showed longer DFS (HR: 0.71, 95%CI: 0.49–1.04 and 0.42, 0.13–1.42, respectively, P for trend = 0.04). The GG genotype of rs2839178 also showed a positive tendency for longer OS although it was not statistically significant (HR: 0.69, 95%CI: 0.44–1.08, P = 0.11). We did not find that rs11702450 was associated with either breast cancer risk or prognosis. Conclusion: This is the first study to investigate the association between GANP SNPs and breast cancer risk and prognosis. The direction of association with DFS was consistent with that of susceptibility. These results demonstrate that GANP SNPs presumably prevent the occurrence and malignant advancement of sporadic breast cancers. Citation Format: Kotani H, Ito H, Kuwahara K, Kuzushima K, Iwata H, Tsunoda N, Nagino M, Tanaka H, Matsuo K. Impact of germinalcenter-associated nuclear protein polymorphisms on breast cancer risk and prognosis in a Japanese population [abstract]. In: Proceedings of the 2016 San Antonio Breast Cancer Symposium; 2016 Dec 6-10; San Antonio, TX. Philadelphia (PA): AACR; Cancer Res 2017;77(4 Suppl):Abstract nr P5-09-07.

Breast cancer risks conferred by many germline missense variants in the BRCA1 and BRCA2 genes, often referred to as variants of uncertain significance (VUS), have not been established. In this study, associations between 19 BRCA1 and 33 BRCA2 missense substitution variants and breast cancer risk were investigated through a breast cancer case–control study using genotyping data from 38 studies of predominantly European ancestry (41,890 cases and 41,607 controls) and nine studies of Asian ancestry (6,269 cases and 6,624 controls). The BRCA2 c.9104A>C, p.Tyr3035Ser (OR = 2.52; P = 0.04), and BRCA1 c.5096G>A, p.Arg1699Gln (OR = 4.29; P = 0.009) variant were associated with moderately increased risks of breast cancer among Europeans, whereas BRCA2 c.7522G>A, p.Gly2508Ser (OR = 2.68; P = 0.004), and c.8187G>T, p.Lys2729Asn (OR = 1.4; P = 0.004) were associated with moderate and low risks of breast cancer among Asians. Functional characterization of the BRCA2 variants using four quantitative assays showed reduced BRCA2 activity for p.Tyr3035Ser compared with wild-type. Overall, our results show how BRCA2 missense variants that influence protein function can confer clinically relevant, moderately increased risks of breast cancer, with potential implications for risk management guidelines in women with these specific variants. Cancer Res; 77(11); 2789–99. ©2017 AACR.

A genetic variant on aldehyde dehydrogenase 2 (ALDH2 rs671, Glu504Lys) contributes to carcinogenesis after alcohol consumption. Somewhat conversely, the ALDH2 Lys allele also confers a protective effect against alcohol-induced carcinogenesis by decreasing alcohol consumption due to acetaldehyde-related adverse effects. Here, we applied a mediation analysis to five case–control studies for head and neck, esophageal, stomach, small intestine, and colorectal cancers, with 4,099 cases and 6,065 controls, and explored the potentially heterogeneous impact of alcohol drinking on digestive tract carcinogenesis by decomposing the total effect of the ALDH2 Lys allele on digestive tract cancer risk into the two opposing effects of the carcinogenic effect (direct effect) and the protective effect (indirect effect mediated by drinking behavior). Alcohol was associated with an increased risk of most digestive tract cancers, but significant direct effects were observed only for upper gastrointestinal tract cancer risk, and varied substantially by site, with ORs (95% confidence interval) of 1.83 (1.43–2.36) for head and neck cancer, 21.15 (9.11–49.12) for esophageal cancer, and 1.65 (1.38–1.96) for stomach cancer. In contrast, a significant protective indirect effect was observed on risk for all cancers, except small intestine cancer. These findings suggest that alcohol is a major risk factor for digestive tract cancers, but its impact as a surrogate for acetaldehyde exposure appears heterogeneous by site. Meanwhile, the behavior-related effect of the ALDH2 Lys allele results in a decreased risk of most digestive tract cancers. Significance: These findings support that genetic alcohol avoidance is a factor against alcohol-induced cancers.

Background: Prospective cohort studies have shown a positive association between body mass index (BMI) and the risk of colorectal cancer (CRC). However, limitations inherent in traditional observational studies, such as reverse causality and residual confounding, might explain the association. To overcome these limitations, Mendelian randomization (MR) studies of the BMI-CRC association have been conducted in European and U.S. groups, but the association remains to be clarified in East Asians. Purpose: We performed MR analyses to investigate the causal association between BMI and CRC in Japanese populations. Methods: Our study design consisted of 4 steps. (1) Based on a previous Genome-Wide Association Study in Japanese populations, we selected 68 BMI-associated single nucleotide polymorphisms (SNPs), which explained about 2.0% of the BMI variance, as instruments. (2) We examined the associations between 68 SNPs and BMI among general Japanese populations in the Japanese Consortium of Genetic Epidemiology studies (N=36,253). (3) We performed a fixed-effect meta-analysis to investigate associations between 68 SNPs and CRC using individual-level data and publicly available summary-statistic data of Japanese populations (cases=7,473, controls=33,322). (4) Finally, we used the inverse-variance weighted (IVW) method to calculate MR estimates. Several sensitivity analyses were applied to assess robustness or horizontal pleiotropy using weighted median, weighted mode, MR-Egger regression, and MR-Pleiotropy Residual Sum and Outlier (PRESSO) methods. Results: In the main analysis using the IVW method, a one-unit increase in BMI was associated with an odds ratio of 1.12 (95% confidence interval [CI]: 1.06-1.20) for CRC. Sensitivity analyses consistently showed increased odds ratios for CRC per one-unit increase in BMI. The odds ratios for weighted median, weighted mode, and MR-Egger regression were 1.16 (95% CI: 1.06-1.27), 1.14 (95% CI: 1.05-1.24), and 1.10(95% CI: 0.98-1.23), respectively. The MR-Egger intercept P-value was 0.63. No outlier was detected using the MR-PRESSO method. Conclusions: Our MR analyses provide evidence that BMI is positively associated with CRC in Japanese populations. Our findings seem to suggest that MR estimates for the BMI-CRC association may be consistent across different ethnicities. Citation Format: Shiori Suzuki, Atsushi Goto, Masahiro Nakatochi, Akira Narita, Taiki Yamaji, Norie Sawada, Ryoko Katagiri, Tsuyoshi Hachiya, Yoichi Sutoh, Isao Oze, Yuriko Koyanagi, Yumiko Kasugai, Hidemi Ito, Hiroaki Ikezaki, Keitaro Tanaka, Takashi Tamura, Haruo Mikami, Toshiro Takezaki, Sadao Suzuki, Nagato Kuriyama, Kiyonori Kuriki, Yoshikuni Kita, Kokichi Arisawa, Kenji Takeuchi, Kozo Tanno, Atsushi Shimizu, Gen Tamiya, Atsushi Hozawa, Kengo Kinoshita, Kenji Wakai, Makoto Sasaki, Masayuki Yamamoto, Keitaro Matsuo, Shoichiro Tsugane, Motoki Iwasaki. Body mass index and colorectal cancer risk in Japanese populations: a Mendelian randomization study [abstract]. In: Proceedings of the Annual Meeting of the American Association for Cancer Research 2020; 2020 Apr 27-28 and Jun 22-24. Philadelphia (PA): AACR; Cancer Res 2020;80(16 Suppl):Abstract nr 3486.

Pancreatic cancer is one of the most challenging malignancies because of its dismal prognosis, largely unknown etiology, and absence of early detection method. Here we report the results of a meta-analysis of three genome-wide association studies (GWAS) involving 2039 pancreatic cancer cases and 32592 control subjects, which represent the largest sample size in the Japanese population. To complement the SNP-based GWAS, we performed a gene-based GWAS using MAGMA. Given the pleiotropic effects observed for the top variants, we performed a Mendelian randomization (MR) analysis to address the possible causal relationship between type-2 diabetes (T2D) and pancreatic cancer risk, using 82 T2D-related SNPs and 25 hemoglobin A1c (HbA1c)-related SNPs as instrumental variables. We identified 3 (13q12.2, 13q22.1, and 16p12.3) genome-wide significant loci (P Citation Format: Yingsong Lin, Masahiro Nakatochi, Hidemi Ito, Yoichiro Kamatani, Hiromi Sakamoto, Hiroshi Ishii, Naoki Sasahira, Makoto Ueno, Naoto Egawa, Mitsuru Mori, Haruhisa Nakao, Yasushi Adachi, Kenji Wakai, Shoichiro Tsugane, Masayuki Yamamoto, Atsushi Shimizu, Takashi Kadowaki, Teruhiko Yoshida, Fumihiko Matsuda, Michiaki Kubo, Shogo Kikuchi, Keitaro Matsuo. Genome-wide association meta-analysis identifies novel GP2 gene risk variants for pancreatic cancer in the Japanese population [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2019; 2019 Mar 29-Apr 3; Atlanta, GA. Philadelphia (PA): AACR; Cancer Res 2019;79(13 Suppl):Abstract nr LB-174.

Objective Genome-wide association studies (GWASs) have identified genetic variants associated with breast cancer. Most GWASs to data were conducted in women with European background and the extent to which these variants contribute as predictors of breast cancer among Japanese population is unknown. Methods We analyzed 24 genetic variants that have been identified in previous GWASs and conducted a case-control study with 697 cases and age- and menopausal status- matched 1394 controls in the framework of the Hospital-based Epidemiologic Study at Aichi Cancer Center (HERPACC). All subjects were asked to provide information on lifestyle factors and blood samples for genetic studies. We fit conditional regression models with genetic variants and conventional risk factors including age, age at menarche, menopausal status, current body-mass-index, age at first live birth, regular exercise, family history of breast cancer, and referral pattern to our hospital. In addition, we created a polygenetic risk score, using the single nucleotide polymorphisms (SNPs) with statistically significant association with the breast cancer risk to measure the cumulative effect of multiple genetic risk variants. Furthermore, we evaluated the prediction model that included conventional risk factors by comparing with and without the genetic risk score, using c statistic. Results Eleven SNPs (FGFR2-rs2981579, rs2981578, rs1219648, rs2420946, rs2981582, TOX3/TNRC9-rs8051542, rs3803662, LOC643714-rs4784227, C6orf97-rs2046210, 8q24-rs13281615, SLC4A7-rs4973768) revealed significant associations with breast cancer risk (each P < 0.05 in either per allele, dominant, or recessive model). A dose-dependent association was observed between the risk of breast cancer and the genetic risk score, which is an aggregate measure of the alleles in 7 selected variants; rs2981579, rs3803662, rs2046210, rs13281615, rs4973768, rs3817198 and rs10931936. Compared to women with scores of 3 or less, odds ratios (ORs) for women with scores of 4–5, 6–7, 8–9 and 10 or more were 1.33 (95% confidence interval, 1.00 - 1.80), 1.71 (1.26 - 2.30), 3.01 (1.97 - 4.58) and 8.69 (2.74 - 27.5), respectively (Ptrend < 0.001). The ORs for premenopausal women with the corresponding risk scores were 1.71 (1.12 - 2.63), 1.79 (1.15 - 2.78), 3.70 (1.98 - 6.93), and 14.0 (3.30–59.5), respectively, and those for postmenopausal women with the corresponding risk scores were 1.09 (0.72 - 1.66), 1.71 (1.12 - 2.61), 2.60 (1.44 - 4.71), 3.75 (0.57 - 24.4), respectively, compared to those with scores of 3 or less (each Ptrend < 0.001). The c statistic for a model including the genetic risk score in addition to the conventional risk factors was 0.633, whereas 0.602 without it (P < 0.001). Population-attributable fraction of the risk score was 33.8%. Conclusion we identified a genetic predictor of breast cancer in a Japanese population. A risk model including genetic risk score may be useful to distinguish women at high-risk of breast cancer from those at low-risk, particularly in the context of targeted prevention. Citation Information: Cancer Res 2011;71(24 Suppl):Abstract nr P1-09-04.

[Background] Helicobacter pylori (H. pylori) infection and atrophic gastritis (AG) following H. pylori infection are well-established risk factors worldwide. Smoking is a convincing risk factor and fruits and vegetables intake is a possible protective factor in Japanese populations. PSCA-rs2294008 is one of single nucleotide polymorphisms (SNPs) with the susceptibility of a stomach cancer risk identified by Genome-wide association studies in Japanese populations. The advances in molecular evidence may have a potential to impact cancer prevention. However, it has never been clear how much it may contribute to cancer risk of the stomach on a population level in combination with environmental factors. In this study, we established a risk prediction model of stomach cancer using these environmental, clinical and genetic risk factors as a potential practical application in cancer preventive intervention. [Methods] We conducted two age- and sex- matched case-control studies, one for model derivation (697 cases and 1,372 controls) and the second (678 cases and 678 controls) for external validation. Based on data from the derivation study, a prediction model was developed by fitting a conditional logistic regression model using the following predictors: age, ABCD category defined by H.pylori infection and AG, smoking, fruits and vegetable intakes and PSCA genotype. Performance of the model was assessed in terms of discrimination (C statistic), calibration (calibration plots and Hosmer-Lemeshow test) and Integrated discrimination improvement (IDI) index. Cumulative risks were obtained by combining odds ratios estimated from the risk model with the age-specific incidence rate and population size. [Results] The risk model, including a combination of PSCA genotype, smoking, fruit & vegetable intake and alcohol consumption, provided high discriminatory accuracy and good calibration in both the derivation and validation studies: C statistics were 0.78 (95% confidence intervals 0.76-0.80) and 0.80 (0.77-0.82), respectively, and the calibration plots of both studies stayed close to the ideal calibration line. IDI indices are 0.11 and 0.12 (p [Conclusion] The risk prediction model that includes these environmental, clinical and genetic factors could be useful to classify Japanese into relevant risk groups of stomach cancer for personalized prevention programs. Citation Format: Hidemi Ito, Isao Oze, Satoyo Hosono, Miki Watanabe, Hideo Tanaka, Keitaro Matsuo. Risk prediction for stomach cancer using helicobacter pylori infection and atrophic gastritis, fruits and vegetables, smoking and GWAS-identified genetic polymorphism (PSCA-rs2294008) in a Japanese population. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 2591.

Although colorectal cancer (CRC), a major cancer worldwide, has shown a proximal or right-sided shift in subsite distribution in western countries, trends in subsite incidence in Asian countries remain unclear. Here, we evaluated subsite-specific trends in CRC incidence rate between 1978 and 2004 in Japan using large data from 10 population-based cancer registries. The colorectal sites (C18-20) were categorized into three groups, proximal colon (C18.0-18.5), distal colon (C18.6-C18.7) and rectum (C19.9 and C20.9). Trends in age-standardized incidence rates (ASRs) were characterized by Joinpoint regression analysis. A total of 474,651 colorectal cancer cases were analyzed. Overall, ASRs increased remarkably until 1993, with an annual percent change (APC) of 4.9%, and then stabilized thereafter. By subsite, however, ASRs of proximal colon significantly increased, with APCs of 7.1% (1978∼1991), 3.8% (1991∼96) and 0.9% (1996∼2004); distal colon showed an initial significant increase, with an APC of 7.6%, but stabilized from 1991 until the end of observation; and rectal cancer showed an initial significant increase, with APCs of 1.9% (1978∼88) and 5.6% (1988∼92), but then decreased abruptly in 1992, the year colorectal cancer screening was introduced nationwide, with an APC of -1.0%. Thus, we revealed that changes in incidence trends for the three anatomic sites apparently began to differ in the 1990s, and this is a first report to our knowledge. We also discuss factors that could explain these changes in Japanese. Careful monitoring is necessary to confirm whether these trends are changing in the Japanese population. Citation Format: Hiroko Nakagawa, Hidemi Ito, Satoyo Hosono, Isao Oze, Haruo Mikami, Masakazu Hattori, Yoshikazu Nishino, Hiromi Sugiyama, Kayo Nakata, Hideo Tanaka. Changes in trends in colorectal cancer incidence rate by anatomic site between 1978 and 2004 in Japan. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5205.

The incidence of cancer of the corpus uteri (CC) in Japan is continuously increasing. To explore the trend in a survival of Japanese CC, we analyzed the population-based cancer registry data. We obtained data on 8,562 CC cases from six prefectural cancer registries. We defined two periods as 1993-2001 (1st period) and 2002-2006 (2nd period). Relative survival (RS) of each period was calculated using cohort analysis, and we compared them using excess mortality model adjusted for age categories and extent of disease. We also estimated RS by age group, extent of disease and histological subtype. For age groups, patients were classified into those aged 15-54, 55-69 and 70-99. For extent of disease, patients were classified into those staged localized, regional and distant group. For histological subgroups, patients were divided into eight histological categories according to ‘Cancer Incidence in Five Continents Vol.10’ partially modified. The 5-year RS was 78.1% in the 1st period and 80.1% in the 2nd period. Compared with the RS in the 1st period, RS in the 2nd period was significantly high [Excess Hazard Ratio (EHR): 0.805, 95%Confidence Interval (95%CI): 0.723-0.896, P In conclusion, we could reveal the improved prognosis of Japanese CC from the period of 1993-2001 to the period of 2002-2006, using population-based cancer registry data. The improvement of short-term RS was observed among elderly, distant or non-endometriod cases, whereas their long-term prognosis did not change during the study period. Improved prognosis might be attributed to the progress of treatment, especially due to chemotherapy or formulation of treatment guidelines in early 2000’s. Citation Format: Shusaku Inoue, Satoyo Hosono, Hidemi Ito, Isao Oze, Yoshikazu Nishino, Masakazu Hattori, Akiko Ioka, Tomio Nakayama, Keitato Matsuo, Mika Mizuno, Kiyoko Kato, Hideo Tanaka, Yuri Ito. Trends in a survival of cancer of the coupus uteri in Japan 1993-2006 (J-CANSIS). [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 5209.

Background. Numerous epidemiological studies consistently indicate that consumption of alcoholic beverages is an independent risk factor for female breast cancer. Although the mechanism underlying this effect remains unknown, it has been hypothesized that ethanol is mutagenic via its first metabolite, acetaldehyde. An impact of acetaldehyde on the carcinogenesis of several types of cancer has been shown in experimental models and in epidemiological studies in East Asian countries where a functional aldehyde dehydrogenase 2 (ALDH2) polymorphism Glu504Lys (rs671) is prevalent. However, its association with breast cancer risk has not been fully elucidated. We conducted an association analysis of original data from Asian studies participating in the Breast Cancer Association Consortium (BCAC). Patients and Methods. Nine studies were used for this analysis, including 6,624 cases and 5,750 controls. The pooled odds ratio (OR) with 95% confidence interval (CI) for breast cancer risk associated with the ALDH2 polymorphism was estimated using logistic regression models. We estimated unadjusted ORs and adjusted ORs for potential confounders. Results. In the unadjusted (crude) analysis, no significant association between ALDH2 polymorphism and breast cancer was observed, with ORs relative to Glu/Glu, of 1.02 (95% CI = 0.95-1.11; P = 0.51) for Glu/Lys, 1.13 (0.96-1.32; 0.14) for Lys/Lys and 1.04 (0.97-1.12; 0.29) for carriers of any Lys allele. In addition, after adjustment for all potential confounding factors, this lack of significant association was consistently observed, with ORs relative to Glu/Glu, of 0.95 (95% CI = 0.86-1.04; P = 0.25) for Glu/Lys, 0.99 (0.82-1.20; 0.93) for Lys/Lys and 0.95 (0.87-1.04; 0.29) for carriers of any Lys allele. These findings were consistent across ER, PR and HER2 status. Conclusions. No significant association between ALDH2 polymorphism and breast cancer was observed in this study. Considering the established impact of ALDH2 504Lys on the carcinogenesis of several types of alcohol-induced cancer, our findings suggest that acetaldehyde is less influential to the breast carcinogenesis induced by alcohol, as is the case for upper-aerodigestive tract cancers. Citation Format: Tomotaka Ugai, Roger L. Milne, Hidemi Ito, Keitaro Matsuo. A genetic polymorphism of ALDH2 and breast cancer risk: an analysis of 6,624 cases and 5,750 controls from the Breast Cancer Association Consortium. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 794.

[Introduction] The altered expression of germinal center-associated nuclear protein (GANP), a member of mammalian TREX2 complex, has been observed in various tumors. Previously, we demonstrated that deficiency of GANP developed mammary gland tumors resembling human breast cancers in two mouse models. In addition, we showed that decreased expression of GANP was an independent prognostic factor of human breast cancer in a retrospective cohort study. These results suggested that GANP might be associated with breast cancer development. Although a little is know about functional significance of ganp polymorphisms, we explored possible association. [Methods] We conducted a case-control study to examine association between ganp polymorphisms and risk of breast cancer among Japanese population within the framework of the Hospital-based Epidemiologic Research Program at Aichi Cancer Center (HERPACC). Cases are 694 incident cases who had been diagnosed as breast cancer at Aichi Cancer Center Hospital (ACCH) during 2001-2005. A total of 1,376 non-cancer controls were patients who visited ACCH at same period as cases and were confirmed to have no evidence of cancer. Controls were individually matched for age and menopausal status with cases. ganp polymorphisms were assessed by iCOGS chip (Reference: Michailidou K et al. Nat. Genet. 2013;45:353-361). Multivariable conditional logistic regression models were applied to estimate odds ratios (ORs) and 95% confidence intervals (CIs) for each locus. [Results] Ten out of 13 polymorphisms, in high linkage disequilibrium, showed statistically significant associations with breast cancer risk. For instance, in rs2839186, the OR for those with AA alleles compared with those with GG alleles is 0.41 (95% CI, 0.23-0.72, p = 0.002) in genotype model. As compared with those with G allele, the OR for those without was 0.40 (95% CI, 0.23-0.71, p = 0.002) in recessive model. On the other hand, in dominant model, the OR for those with A allele was 0.95 (95% CI, 0.78-1.16, p = 0.635) in comparison to those without that. [Conclusion] In this study, we clearly show that mutant SNPs in rs2839186 decrease breast cancer risk. We are currently analyzing if the ganp SNPs affect the prognosis of breast cancer patients. Citation Format: Kazuhiko Kuwahara, Hidemi Ito, Kiyotaka Kuzushima, Hiroji Iwata, Hideo Tanaka, Keitaro Matsuo. Molecular epidemiological studies of germinal center-associated nuclear protein (ganp) in the development of human sporadic breast cancers. [abstract]. In: Proceedings of the 107th Annual Meeting of the American Association for Cancer Research; 2016 Apr 16-20; New Orleans, LA. Philadelphia (PA): AACR; Cancer Res 2016;76(14 Suppl):Abstract nr 820.

Background: The impact of drinking and smoking on the risk of esophageal cancer has been established worldwide (IACR, 2012 updated). In our previous study, we found that the polymorphisms ofalcohol dehydrogenases 1B (ADH1B - rs1229984) and aldehyde dehydrogenases 2 (ALDH2 - rs671) were associated with esophageal cancer risk in a Japanese population (Matsuo K, 2001 & Oze I, 2009). However, the extent to which these environmental and genetic risk factors contribute as predictors of esophageal cancer among Japanese is unknown. The objective of our study was to evaluate the performance of a risk assessment model that incorporates both environmental and genetic risk factors in a Japanese population. Methods: We conducted a case-control study with 265 cases and age- and sex- matched 530 controls within the framework of the Hospital-based Epidemiological Research Program at Aichi Cancer Center (HERPACC). We fit regression models with the risk factors. For discrimination assessment, we compared the area under the curves (AUC) in the receiver - operating curve (ROC) analysis of Environmental model (E-model), Genetic model (G-model), and Inclusive model. In addition, we evaluated contribution to risk prediction for each risk factor by calculating the integrated discrimination improvement (IDI) index. Results: We created a risk prediction model for esophageal cancer by polymorphisms of ADH1B and ALDH2, drinking and smoking. The AUCs were 0.873 (0.847-0.898) for E-model and 0.747 (0.711-0.782) for G-model. The Inclusive model including all risk factors, with an AUC of 0.931 (0.912-0.949), showed promise for stratifying people into different risk groups. We found that each risk factor statistically significantly contributed to risk prediction for esophageal cancer (p< 0.001, the IDI indexes of 0.064 for rs1229984, 0.066 for rs671, 0.220 for drinking and 0.101 for smoking). Conclusion: The risk prediction model that includes these environmental and genetic factors could be useful to classify Japanese into relevant risk groups of esophageal cancer for personalized prevention programs. Citation Format: Hidemi Ito, Isao Oze, Satoyo Hosono, Miki Watanabe, Hideo Tanaka, Keitaro Matsuo. The risk prediction for esophageal cancer by drinking, smoking, and the polymorphisms of ALDH2 and ADH1B. [abstract]. In: Proceedings of the 106th Annual Meeting of the American Association for Cancer Research; 2015 Apr 18-22; Philadelphia, PA. Philadelphia (PA): AACR; Cancer Res 2015;75(15 Suppl):Abstract nr 4618. doi:10.1158/1538-7445.AM2015-4618

Appreciating lifetime risk of gastric cancer through established risk factors is one simple way to promote preventive behavior. We have estimated cumulative risks (CRs) of gastric cancer by genetic and environmental risk factors, PSCA-rs2294008 polymorphism, Helicobacter Pylori (HP) infection and smoking, based on a case-control study involving 697 cases and 1372 controls at Aichi Cancer Center. We estimated odds ratio (OR) and 95% confidence interval (CI) for groups by these factors using logistic regression model after adjustment for age, sex, family history of gastric cancer and intake of fruit and vegetable. The ORs were combined with gastric cancer incidence rates in Japan to calculate CRs using the Peto's method. The CRs by age of 75 varied according to the risk groups, from 0.9% (95% CI, 0.3%-3.3%) for never smokers without both HP infection and risk allele of rs2294008 to 13.4% (95% CI, 13.3%-13.4%) for ever smokers with HP infection and 1-2 risk alleles. Among those with 1-2 risk alleles, the CRs were reduced to 2.0% (95% CI, 1.9%-2.0%) in those without both smoking history and HP infection, 3.9% (95% CI, 3.8%-3.9%) for ever smokers without HP infection, 9.4% (95% CI, 9.4%-9.5%) for never smokers with HP infection, although it was 13.4% in those with both smoking history and HP infection. In conclusion, the findings based on genetic and environmental risk factors in this study would be important information for promoting primary and secondary prevention of gastric cancer. Citation Format: Hidemi Ito, Isao Oze, Satoyo Hosono, Miki Watanabe, Hideo Tanaka, Keitaro Matsuo. Cumulative risks of gastric cancer by PSCA polymorphism, Helicobacter Pylori infection and smoking history in Japan. [abstract]. In: Proceedings of the 105th Annual Meeting of the American Association for Cancer Research; 2014 Apr 5-9; San Diego, CA. Philadelphia (PA): AACR; Cancer Res 2014;74(19 Suppl):Abstract nr 2210. doi:10.1158/1538-7445.AM2014-2210

Background: The hematologic malignancies are a collection of heterogeneous diseases with diverse epidemiologic features for which a detailed classification of disease subtypes has evolved dramatically. The incidence of a malignant disease reflects the genetics and cumulative exposure to the environment of a population. Therefore, evaluation of the incidence and trend of a disease in different populations may provide insights into the etiology and pathogenesis of that disease. However, no detailed data based on population-based cancer registry in Asia to see each disease entities are available. Aims: The aim of this study is to assess the incidence and the trend of each hematologic malignancy and to evaluate the difference between Japan and US. The diseases evaluated in this study were acute myeloid leukemia (AML), acute lymphoblastic leukemia (ALL), chronic myelogenous leukemia (CML), multiple myeloma (MM), Hodgkin lymphoma (HL), and non-Hodgkin lymphoma (NHL). Methods: To evaluate the incidence of hematologic malignancies, we used population-based registry data in Japan and the United States (US). The population-based cancer registry of Japan included 100,637 cases and the data in the US, SEER included 172,925 cases. The period covered in this analysis is 1993-2006 in Japan and 1993-2008 in the US. Rates of sex-specific, age-standardized incidence with 95% confidence intervals were estimated and standardized by age-adjustment according to the world standard population. We also estimated the annual percent change using joinpoint regression analysis and evaluated the significance of the trend. Results: The overall age-standardized incidence rate of all hematologic malignancies per 100,000 in 2006 was 14.9 for males and 10.0 for females in Japan, 33.4 for males and 24.3 for females in the US. The difference in the incidence between Japan and US is impressive for HL, NHL and MM (approximately 3-10 fold), whereas AML, ALL, and CML have a similar incidence. The total number of hematologic malignancies was found to be increasing significantly in Japan whereas no obvious change was seen in the US {annual percent change (95%CI) Japan; +1.5% (0.9 to 2.1), US; +0.1% (-0.1 to 0.2)}. As for details, AML and the lymphoid malignancies (HL and NHL) are increasing significantly in Japan whereas there has been a marginal change in the US. Interestingly, the incidence of CML has been decreasing during this period in both Japan and the US, whereas no obvious change was seen in MM in their country. Conclusion: In conclusion, we showed the difference in the incidence of hematologic malignancies between Japan and the US. The incidence of hematologic malignancies is lower in Japan than the US, but is increasing significantly. The improvement in the quality of cancer registry systems and the organization of these registries between countries enables us to unite the data worldwide that will bring us new insights. Citation Format: Dai Chihara, Lidsay Morton, Hidemi Ito, Tomohiro Matsuda, Akiko Shibata, Tomotaka Sobue, Denis D. Weisenburger, Keitaro Matsuo. The difference in the incidence and the trend of hematologic malignancies in Japan and the United States. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 2535. doi:10.1158/1538-7445.AM2013-2535

Although cigarette smoking is the primary cause of lung cancer, it alone cannot explain large difference in risk of this malignancy worldwide. During the last three decades, age-adjusted male lung cancer mortality rates have been remarkably higher in Hungary than in Japan, but per capita cigarette consumption has remained lower in Hungary than in Japan. A similar pattern of difference has been observed between other Asian and western countries, (e.g., China, South Korea, Poland, and the US). It remains unclear why this lung cancer paradox occurs. Lung cancer incidence is generally high in countries with high intake of saturated fat. In addition, animal studies revealed a synergistic effect of fat and tobacco carcinogens on the development of lung tumors. Therefore, it is possible that different types of fat interact with cigarette smoking to modulate lung cancer risk. We sought to investigate this hypothesis in a hospital-based case-control study conducted from 2000 to 2005 in Nagoya, Japan. Cases (n=500), ages 20-79, were patients pathologically diagnosed with lung cancer at the Aichi Cancer Center. Controls (n=500) were recruited from visitors to the outpatient department of the same institution, and matched to cases by age (within 5 years) and sex. Fat intake was assessed with a validated food frequency questionnaire, and cigarette smoking was evaluated with a pre-tested risk factor questionnaire. Odds ratios (OR) and 95% confidence intervals (95% CI) were calculated using unconditional logistic regression. After adjustment for age, sex, BMI, energy intake, and alcohol drinking, lung cancer risk among heavy smokers (≥40 pack-years) decreased with increasing intake of monounsaturated fat (MUFA). Compared with never or light smokers (≤20 pack-years), ORs (95% CI) were 8.44 (4.53, 15.7), 4.34 (2.32, 8.13), and 3.63 (1.84, 7.04) for heavy smokers who were in the 1st(lowest), 2nd, and 3rd tertiles of MUFA intake, respectively. A similar pattern of interaction was present for intake of polyunsaturated fat (PUFA) and for moderate smokers (20-39 pack-years). To our knowledge, the present study is among the first to show that intake of unsaturated fat modifies the association between cigarette smoking and lung cancer risk, and thereby sheds new light on the etiology and prevention of this malignancy. Citation Format: Jianjun Zhang, Hideo Tanaka, Hidemi Ito, Keitaro Matsuo. Fat intake interacts with cigarette smoking to alter lung cancer risk. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3630. doi:10.1158/1538-7445.AM2013-3630

Introduction. Recently, the clinical relevance of molecular subtypes of breast cancer has been demonstrated, but the evidence on etiologic differences among them is limited. Some epidemiological studies in Western populations have shown that body-mass-index (BMI) is a risk factor for luminal-type breast cancer. However, it is unclear whether the impact of BMI on the risk differs among tumor subtypes in Japanese population. Methods. We conducted a case-control study with 715 case subjects and 1430 age- and menopausal status-matched controls to evaluate the associations of BMI at current age, age at 20 years, and its change (from age 20 years to the current age) with the breast cancer risk. We applied conditional logistic regression models to estimate odds ratios (ORs) and 95% confidence intervals (CIs). Tumor subtypes were determined by estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor 2(HER2) and divided into four subtypes: luminal, luminal / HER2, HER2-rich, and triple-negative subtype. Results. Current BMI and BMI change were positively associated with the risk of postmenopausal breast cancer. On stratified analyses by tumor subtype, we observed the associations between current BMI, BMI change and thepostmenopausal breast cancer risk for luminal subtype; OR for each 1 kg/m2increase of current BMI was 1.14 (95%CI: 1.07 - 1.20) and the corresponding OR of BMI change was 1.16 (1.09 - 1.23) (each Ptrend < 0.001). Additionally, we found the same tendency for triple-negative subtype; the OR for 1 kg/m2 increase of current BMI was 1.21 (1.05 - 1.39), and that for BMI change was 1.18 (1.02 - 1.36) (Ptrend was 0.008 and 0.024, respectively). No significant associations among them were seen for the other subtypes. In premenopausal women, the suggestive inverse association was observed between BMI change and breast cancer risk only for luminal subtype; OR of BMI change was 0.93 (0.87 - 1.00, Ptrend= 0.054). There were no associations between BMI at age 20 years and the risk for any tumor subtypes. Conclusions. BMI and its change are associated with the risk of both luminal and triple-negative breast cancer among postmenopausal women, despite the molecular and clinical differences between these two subtypes. Our results provide additional evidence for an etiological heterogeneity of breast cancer among tumor subtypes. Citation Format: Aiko Sueta, Hidemi Ito, Tania Islam, Satoyo Hosono, Miki Watanabe, Hiroji Iwata, Kazuo Tajima, Hideo Tanaka, Keitaro Matsuo, Hirotaka Iwase. Associations of body mass index and its change with breast cancer risk by molecular subtypes: a case-control study in Japanese women. [abstract]. In: Proceedings of the 104th Annual Meeting of the American Association for Cancer Research; 2013 Apr 6-10; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2013;73(8 Suppl):Abstract nr 3654. doi:10.1158/1538-7445.AM2013-3654

Background: Lung cancer is the leading cause of human cancer death worldwide. DNA methylation affects the aggressiveness of human malignancies. Cancers with CpG island methylator phenotype (CIMP), a distinct group with extensive DNA methylation, show characteristic features in several types of tumors. However, the existence and characteristics of CIMP in lung adenocarcinomas (AdCas) from the global point of view has remained elusive. The aim of this study is to clarify the significance of DNA methylation, especially the clinical impact of CIMP, in AdCas. Methods: Using genome-wide microarray analysis, DNA methylation profiling of 41 AdCas were initially examined. DNA methylation status of six CIMP markers newly identified by microarray analysis was further estimated in a validation set of 87 AdCas by bisulfate pyrosequencing. A total of 128 AdCas were examined for the significance of CIMP. In addition, responsiveness to DNA methylation inhibitor was examined in AdCa cell lines with different CIMP status. Results: Consensus clustering analysis based on DNA methylation showed that AdCas were classified into three subgroups, clusters 1, 2, and 3 (average of 767, 486, and 319 methylated genes in each subgroup, respectively; P Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 5003. doi:1538-7445.AM2012-5003

Malignant mesothelioma (MM) arises from the serosal cells of the pleural, peritoneal and pericardial cavities with poor prognosis because of its frequent diagnosis in advanced stages. The primary cause of this disease has often been linked to asbestos exposure, and the number of patients worldwide is expected to peak in the next two decades. There is no known curative therapy for MM and further understanding in molecular mechanism is needed to identify new candidates for targeted treatment. We found that the TGF-β pathway is associated with oncogenic mutations and loss of the tumor suppressor NF2, and induces pro-oncogenic biological activities. Loss of NF2 is one of the genetic lesions which have been related to the growth of human MM. The NF2 gene is responsible for neurofibromatosis type II syndrome and encodes Merlin which negatively regulates YAP function. Nearly 75% MM cases have inactivating mutations in the NF2 gene or in downstream signaling molecules of Hippo signaling cascade. We examined a functional interaction between the Hippo and TGF-β pathways and found that endothelin-1 and connective tissue growth factor (CTGF) are the only proteins affected by these two pathways in MM cells. The CTGF promoter contains both a YAP/TEAD-binding site and a consensus Smad-binding site adjacent to each other. The expression of CTGF induced by TGF-β in MM cell lines was greatly affected by the existence of YAP, by its binding with Smad3, forming a complex on CTGF promoter lesion. Knocking down CTGF expression in MM cells prolonged the survival of mice, and a significant association was seen between CTGF expression and extracellular matrix deposition in MM xenografts and in patient tissue specimens. This study elucidates a novel molecular mechanism induced by the TGF-β pathway, which may be applicable to malignancies with defective NF2 and of mesenchymal origin. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 103rd Annual Meeting of the American Association for Cancer Research; 2012 Mar 31-Apr 4; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2012;72(8 Suppl):Abstract nr 3082. doi:1538-7445.AM2012-3082

Common polymorphisms in DNA repair genes may affect an individual's capacity to repair damaged DNA. Although many former studies have reported an association between several types of cancers and DNA repair polymorphism, the association with endometrial cancer (EC) risk has not been investigated fully, especially in Asian population. To examine the association between DNA repair polymorphisms and postmenopausal EC risk, we conducted a case-control study with 91 EC cases (59 endometrioid adenocarcinoma and 32 other types of carcinoma) and 261 non-cancer female controls from database of Hospital based Epidemiologic Research Program at Aichi Cancer Center. We examined 16 coding SNPs (single nucleotide polymorphism) of 12 DNA repair genes (OGG1, MUTYH, XRCC1, APE1, ADPRT, XPA, XPC, XPD, ERCC1, RAD23B, XPG, ERCC6) by TaqMan Methods. We surveyed lifestyle/environmental information by self-administered questionnaire. Impact of each SNPs on EC risk was evaluated by multivariate unconditional logistic regression models. Further, we examined the gene-gene interaction. We observed significant association between EC risk and rs1799782 (C>T, Arg194Trp) of XRCC1 [CT: Odds ratio (OR) = 1.74, 95% confidence interval (95% CI) = 0.99-3.04, TT: OR = 2.76, 95% CI = 1.23-6.16; trend p = 0.007]; rs25487 (G>A, Arg399Gln) of XRCC1 [GA: OR = 0.66, 95% CI = 0.39-1.12, AA: OR = 0.15, 95% CI = 0.02-1.16; trend p = 0.019]; rs1136410 (T>C, Val762Ala) of ADPRT [TC: OR = 1.49, 95% CI = 0.84-2.64, CC: OR = 1.92, 95% CI = 0.88-4.18; trend p = 0.076]; and rs17655 (G>C, Asp1104His) of XPG [GC: OR = 0.68, 95% CI = 0.39-1.21, CC: OR = 0.54, 95% CI = 0.26-1.12; trend p = 0.082]. Although both XRCC1 and ADPRT involve in base excision repair, gene-gene interaction of these polymorphisms were not significant; the interaction p between rs1799782 and rs25487 was 0.687; that between rs25487 and rs1136410 was 0.328. In conclusion, we found significant association between EC risk among postmenopausal Japanese women and DNA repair polymorphisms. Gene-gene interactions between XRCC1 and ADPRT were not significant. These results suggests that DNA repair polymorphisms might be associated with etiology of EC. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 5618. doi:10.1158/1538-7445.AM2011-5618

[Background] Coffee and tea are the most common beverages worldwide. Specifically, green tea is the most common tea in Japan. Coffee and green tea are potentially thought to have anticancer effect because of the antioxidative components such as chlorogenic acids in coffee and catechins in tea. On the other hand, coffee and green tea are often consumed with high temperature. Hot foods and beverages are considered as risk factor for esophageal cancer (e.g. yarba mate in Latin America). Thus, coffee and green tea might be carcinogenic. Then, we conducted a case-control study to elucidate the association between UAT cancer and coffee and green tea consumption. [Method] Cases were 961 patients with histologically diagnosed as UAT cancer (head and neck cancer in 527 and esophageal cancer in 434) between January 2001 and December 2005 at Aichi Cancer Center Hospital. Controls were 2883 first-visit outpatients who were confirmed to have no cancer during the same period. Cases and Controls were matched by age and sex. Information on coffee and green tea consumption and other lifestyle factors were obtained via self-administered questionnaire. Associations between coffee and green tea consumption and UAT cancer were assessed by odds ratios (ORs) and 95% confidence intervals (CIs) by using conditional logistic regression models. [Result] Both coffee and green tea consumption had significant association with UAT cancer overall (trend p=0.011 and 0.007, respectively). Those who had three or more cups of coffee a day showed significantly lower OR for UAT cancer (OR 0.71, 95% CI 0.55-0.93) than those with non-daily consumers. In contrast, three or more cups of green tea consumption had significant positive association with UAT cancer (OR 1.28, 95% CI 1.06-1.56). These trends were not clear for esophageal cancer. The inverse association between coffee consumption and UAT cancer was evident among current drinkers, while the positive association between green tea and UAT cancer was evident among never drinkers. Similar trends were observed in other categories. [Conclusion] UAT cancer was inversely associated with coffee consumption, and positively associated with green tea consumption. Further epidemiologic studies are warranted. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 1905. doi:10.1158/1538-7445.AM2011-1905

Proceedings: AACR 102nd Annual Meeting 2011‐‐ Apr 2‐6, 2011; Orlando, FL Lung cancer is the leading cause of cancer death in many countries across the world. A growing body of evidence indicates that fat (especially saturated fat) is involved in lung carcinogenesis. Lung cancer incidence is higher among countries with high intake of fat. Some, although not all, epidemiologic studies have shown that fat intake was associated with an increased risk of lung cancer. Animal studies demonstrated that fat interacted with tobacco carcinogens to influence occurrence of lung tumors. Collectively, it is possible that genetic variability in lipid metabolism may modulate the risk of lung cancer. We sought to investigate this hypothesis in a hospital-based case-control study conducted from 2000 to 2005 in Nagoya, Japan. Cases (n=230), ages 20-79, were patients pathologically diagnosed with lung cancer at the Aichi Cancer Center, and controls (n=230) were recruited from visitors to the outpatient department of the Aichi Cancer Center and matched to cases by age (within 5 years) and sex. We genotyped polymorphisms in five genes: pancreatic lipase (PNLIP, rs2915748), apolipoprotein E (APOE, [rs440446][1]), hepatic lipase (LIPC, rs1800588), fatty acid desaturase 1 (FADS1, [rs174546][2]), and FADS ([rs174570][3]). Odds ratios (OR) and 95% confidence intervals (95% CI) were evaluated with unconditional logistic regression. After adjustment for age, sex, BMI, cigarette smoking (pack-years), a promoting effect was observed for the variant allele of PNLIP rs2915748 [OR (95%CI): 1.64 (1.09-2.47) for GA/AA vs. GG]. A similar effect was found for APOE [rs440446][1] [OR (95%CI): 1.71 (1.14-2.58) for CG/GG vs. CC)]. No significant associations were detected for other three sequence variants examined. To our knowledge, our study is among the first to suggest that genetic variations in the digestion and transport of lipids alter lung cancer risk. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 102nd Annual Meeting of the American Association for Cancer Research; 2011 Apr 2-6; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2011;71(8 Suppl):Abstract nr 888. doi:10.1158/1538-7445.AM2011-888 [1]: /lookup/external-ref?link_type=GEN&access_num=rs440446&atom=%2Fcanres%2F71%2F8_Supplement%2F888.atom [2]: /lookup/external-ref?link_type=GEN&access_num=rs174546&atom=%2Fcanres%2F71%2F8_Supplement%2F888.atom [3]: /lookup/external-ref?link_type=GEN&access_num=rs174570&atom=%2Fcanres%2F71%2F8_Supplement%2F888.atom