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In 1988, Blot and colleagues reported results from a U.S. case–control study of oral cavity or pharyngeal (oropharyngeal and hypopharyngeal) cancers, with results showing independent associations of smoking and alcohol with increased risk, multiplicative interaction effects between smoking and alcohol, and that nearly three-quarters of these cancers are attributable to smoking and alcohol. The report by Blot and colleagues represents a landmark in oropharyngeal cancer epidemiology. This study, the largest at the time, introduced several novel concepts in oropharyngeal cancer epidemiology that remain relevant today—etiologic heterogeneity, statistical interaction effects, adjusted attributable fractions, and disparities by sex and race/ethnicity. Perhaps the most significant recognition in the field since 1988 is the etiologic association of human papillomavirus (HPV, primarily HPV16) with cancers arising in the oropharynx. Today, more than 80% of oropharyngeal cancers in the United States are caused by HPV while only approximately 3% of oral cavity cancers are caused by HPV. This etiologic heterogeneity across head and cancer subsites revealed by HPV is manifest at the genetic/genomic, epidemiologic, and clinical levels. Tobacco and alcohol remain the major etiologic factors for oral cavity cancers while HPV is the major cause of oropharyngeal cancers. Thus, tobacco and alcohol control and prophylactic HPV vaccination remain the most promising prevention tools for oral cavity and oropharyngeal cancers at this time. Importantly, the ever-emerging alternative tobacco products, such as smokeless tobacco/snus, hookah and water pipes, e-cigarettes, flavored cigars and cigarillos, and oral dissolvable products, represent a key public health concern and the carcinogenic effects of these products remains an active area of investigation. See related article by Blot and colleagues, Cancer Res 1988;48:3282–7

The average age at menarche declined in European and U.S. populations during the 19th and 20th centuries. The timing of pubertal events may have broad implications for chronic disease risks in aging women. Here we tested for associations of recalled menarcheal age with risks of 19 cancers in 536,450 women [median age, 60 years (range, 31–39 years)] in nine prospective U.S. and European cohorts that enrolled participants from 1981 to 1998. Cox regression estimated multivariable-adjusted HRs and 95% confidence intervals (CI) for associations of the age at menarche with risk of each cancer in each cohort and random-effects meta-analysis was used to generate summary estimates for each cancer. Over a median 10 years of follow-up, 60,968 women were diagnosed with a first primary incident cancer. Inverse linear associations were observed for seven of 19 cancers studied. Each additional year in the age at menarche was associated with reduced risks of endometrial cancer (HR = 0.91; 95% CI, 0.89–0.94), liver cancer (HR = 0.92; 95% CI, 0.85–0.99), melanoma (HR = 0.95; 95% CI, 0.93–0.98), bladder cancer (HR = 0.96; 95% CI, 0.93–0.99), and cancers of the colon (HR = 0.97; 95% CI, 0.96–0.99), lung (HR = 0.98; 95% CI, 0.96–0.99), and breast (HR = 0.98; 95% CI, 0.93–0.99). All but one of these associations remained statistically significant following adjustment for baseline body mass index. Similarities in the observed associations between menarche and seven cancers suggest shared underlying causes rooted early in life. We propose as a testable hypothesis that early exposure to sex hormones increases mid-life cancer risks by altering functional capacities of stem cells with roles in systemic energy balance and tissue homeostasis. Significance: Age at menarche is associated with risk for seven cancers in middle-aged women, and understanding the shared underlying causal pathways across these cancers may suggest new avenues for cancer prevention.

Introduction: Chronic stress affects immune function and hormonal signaling and has been hypothesized to be associated with breast cancer, although results from the few prior studies are mixed and have not examined potential differences by estrogen receptor (ER) status. We investigated the relationship between stressful life events and incident breast cancer by ER status among postmenopausal women. We further evaluated whether this association is modified by social support. Methods: Our analysis included 76,951 postmenopausal women enrolled in the Women’s Health Initiative. Participants were followed for events for up to 26 years (median, 16.7). We generated Cox proportional hazards models adjusting for demographic, clinical, lifestyle/behavioral, and social factors to estimate hazard ratios (HR) and 95% confidence intervals (95%CI) for associations between baseline self-reported stressful life events and incident breast cancer by ER status. Results: The mean age was 63 (SD 7.3), and majority of participants were White race (83.5%) and married or in a marriage-like relationship (63.0%). In analyses stratified by ER status, there was no relationship between stressful life events and ER-positive breast cancer. In contrast, compared to women in the lowest quartile, those in higher quartiles had an increased risk of ER-negative breast cancer, where those in quartile 4 had the highest risk (Quartile 4 vs Quartile 1; HR=1.30; 95%CI 1.01-1.68; Ptrend=0.050). Additionally, associations were stronger for the highest versus lowest quartile of stressful life events among widowed women (HR=2.39; 95%CI 1.29-4.44; Pinteraction Conclusion: In this cohort of postmenopausal women, higher experiences of pre-diagnostic stressful life events were associated with increased risk of ER-negative breast cancer. Citation Format: Wayne R. Lawrence, Jasmine A. McDonald, Faustine Williams, Meredith S. Shiels, Neal D. Freedman, Ziqiang Lin, Jared W. Magnani. Psychosocial stress, social support, and incident breast cancer by estrogen receptor status [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2023; Part 1 (Regular and Invited Abstracts); 2023 Apr 14-19; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2023;83(7_Suppl):Abstract nr 3011.

Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19–1.36), IHBDC (HR = 1.32; 95% CI, 1.21–1.45), and EHBDC (HR = 1.13; 95% CI, 1.03–1.23), but not AVC (HR = 0.99; 95% CI, 0.88–1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. Significance: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.

Abstract Background: Laboratory and emerging epidemiologic data suggest that bile acids (BAs), major regulators of the gut microbiota, play an important role in liver disease and cancer etiology. However, few epidemiologic studies have comprehensively examined associations between BAs and either liver endpoints or biliary cancer. Methods: In the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study, we designed 1:1 matched nested case-control studies of primary liver cancer (n=247 cases), fatal liver disease (n=261 cases), and primary biliary cancer (n=92 cases). Using baseline serum collected ≤30 years prior to diagnosis or death, we measured concentrations of 15 BAs with liquid chromatography tandem mass spectrometry. We used multivariable conditional logistic regression to estimate adjusted odds ratios (ORs) and 95% confidence intervals (CIs) between BAs and each endpoint, accounting for multiple comparisons. Results: Comparing the highest to the lowest quartile, ten BAs were positively associated with liver cancer risk, including taurocholic (OR =4.70, 95% CI=2.51-8.78; Q-trend1. Conclusion: Conjugated BAs were strongly associated with increased risk of liver cancer and fatal liver disease, suggesting mechanistic links between the gut microbiota, BA signaling pathways, and liver cancer or death from liver disease. Citation Format: Zeinab Farhat, Neal D. Freedman, Joshua N. Sampson, Roni T. Falk, Jill Koshiol, Stephanie J. Weinstein, Demetrius Albanes, Rashmi Sinha, Erikka Loftfield. A prospective investigation of serum bile acids with risk of liver cancer, fatal liver disease, and biliary cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 2385.

Prostate-specific antigen (PSA) screening for prostate cancer (PCa) remains controversial due to poor sensitivity and specificity that lead to overdiagnosis and overtreatment. The aim of our study is to characterize genetic determinants of PSA levels in cancer-free men in order to personalize PCa screening. We hypothesize that test accuracy may be improved by accounting for PSA variation that is due to genetic factors and does not reflect PCa. We conducted the largest ever genome-wide association study (GWAS) of PSA in men without PCa (N=95,768; 85,924 predominantly European ancestry) using data from the UK Biobank, BioVU, PLCO, and Kaiser Permanente cohorts. Our GWAS discovered 129 PSA-associated variants (P Potential clinical utility of PSA genetic adjustment was explored by examining reclassification at thresholds used for biopsy referrals in a real-world setting at Kaiser Permanente. We estimated that correction using PGSPSA would have avoided 21.2% of negative biopsies in non-cases. Reclassification below the biopsy referral threshold was also more common in cases, particularly with low-grade disease with Gleason score Next, we evaluated genetically adjusted PSA in the context of detection of aggressive PCa, defined as Gleason score ≥7, PSA ≥10 ng/mL, T3-T4 stage, and/or distant or nodal metastases. Genetically adjusted baseline PSA was more robustly associated with aggressive PCa than observed PSA and yielded a higher area under the curve (AUC) in PCPT (OR=3.03, p=3.5×10-7; AUC: 0.72 vs. 0.68) and SELECT (OR=3.37, p=3.5×10-11; AUC: 0.78 vs. 0.74) when added to a baseline model with age and trial arm. Furthermore, genetically adjusted PSA provides complementary information to PCa risk variants. In PCPT, a logistic regression model that included genetically corrected PSA and the 269-variant PGSPCa achieved a significantly higher AUC than PGSPCa-269 alone for aggressive PCa (AUC: 0.73 vs. 0.65, p=3.3×10-4) and overall PCa (AUC=0.69 vs. 0.66, p=3.3×10-6). Our work provides evidence that accounting for genetic determinants of PSA has the potential to reduce unnecessary testing and overdiagnosis of low-risk PCa, as well as increase detection of aggressive disease. Larger and more diverse study populations are required to fully characterize the genetic basis of PSA variation and optimize its clinical utility. Citation Format: Linda Kachuri, Rebecca E. Graff, Sonja I. Berndt, Mitchell Machiela, Neal D. Freedman, Stephen J. Chanock, John P. Shelley, Kerry Schaffer, Jonathan D. Mosley, Phyllis J. Goodman, Cathee Till, Ian Thompson, Robert J. Klein, Stephen K. Van Den Eeden, Thomas J. Hoffmann, John S. Witte. Genetic determinants of PSA levels improve prostate cancer screening [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2022; 2022 Apr 8-13. Philadelphia (PA): AACR; Cancer Res 2022;82(12_Suppl):Abstract nr 1441.

Background: Alcohol is an established risk factor for several cancers, but modest alcohol-cancer associations may be missed due to measurement error in self-reported assessments. The identification of biomarkers of habitual alcohol intake may enhance evidence on the role of alcohol in cancer onset. Methods: Untargeted metabolomics was used to identify metabolites correlated with habitual alcohol intake in a discovery dataset from the European Prospective Investigation into Cancer and Nutrition (EPIC; n=454). Significant correlations were replicated in independent datasets of controls from case-control studies nested within EPIC (n=281) and the Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC; n=438) study. Conditional logistic regression was used to estimate odds ratios (OR) and 95% confidence intervals (CI) for associations of alcohol-associated metabolites and self-reported alcohol intake with risk of pancreatic cancer, hepatocellular carcinoma (HCC), liver cancer, and liver disease mortality in the contributing studies. Results: Two metabolites displayed a dose-response association with alcohol intake: 2-hydroxy-3-methylbutyric acid and an unidentified compound (m/z(+):231.0839). A 1-SD increase in log2-transformed levels of 2-hydroxy-3-methylbutyric acid was associated with risk of HCC (OR=2.14; 95% CI=1.39-3.31) and pancreatic cancer (OR=1.65; 95% CI=1.17-2.32) in EPIC and liver cancer (OR=2.00; 95% CI=1.44-2.77) and liver disease mortality (OR=2.16; 95% CI=1.63-2.86) in ATBC. Conversely, a 1-SD increase in log2-transformed questionnaire-derived alcohol intake was not associated with risk of HCC or pancreatic cancer in EPIC or liver cancer in ATBC but was associated with risk of liver disease mortality (OR=2.19; 95% CI=1.60-2.98) in ATBC. Conclusions: 2-Hydroxy-3-methylbutyric acid is a candidate biomarker of habitual alcohol intake that may advance the study of alcohol and cancer risk in population-based studies. Citation Format: Erikka Loftfield, Magdalena Stepien, Vivian Viallon, Laura Trijsburg, Joseph Rothwell, Nivonirina Robinot, Carine Biessy, Ingvar A. Bergdahl, Stina Bodén, Matthias B. Schulze, Manuela Bergmann, Elisabete Weiderpass, Julie A. Schmidt, Rual Zamora-Ros, Therese H. Nøst, Torkjel M. Sandanger, Emily Sonestedt, Bodil Ohlsson, Verena Katzke, Rudolf Kaaks, Fulvio Ricceri, Anne Tjønneland, Christina C. Dahm, Maria-Jose Sánchez, Antonia Trichopoulou, Rosario Tumino, María-Dolores Chirlaque, Giovanna Masala, Eva Ardanaz, Roel Vermeulen, Paul Brennan, Demetrius Albanes, Stephanie J. Weinstein, Augustin Scalbert, Augustin Scalbert, Neal D. Freedman, Marc J. Gunter, Mazda Jenab, Rashmi Sinha, Pekka Keski-Rahkonen, Pietro Ferrari. Novel biomarkers of habitual alcohol intake and associations with risk of pancreatic and liver cancers and liver disease mortality [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 747.

Background: Genomic regions that confer susceptibility for bladder cancer have provided important insights into the mechanisms of this disease. Sixteen genomic regions harboring bladder cancer susceptibility loci have been reported to date. To identify additional loci associated with bladder cancer risk, we conducted a meta-analysis including data from previously published genome-wide association studies as well as unpublished data. Methods: Data from 32 studies including 13,790 bladder cancer cases and 343,502 controls of European ancestry were included. Stratified analyses by sex and smoking status, as well as heterogeneity in risk by muscle-invasiveness, were also conducted. We tested for multiplicative and additive interactions between cigarette smoking and susceptibility loci that achieved genome-wide significance. After genotyping, quality control, and imputation log-additive effects were calculated by study/array group using regression models adjusting for age and significant eigenvectors. Results were combined by meta-analysis using a fixed-effects model. Results: We report strengthened or independent signals in several previously published regions at 4p16.3 (TACC3, FGFR3), 5p15.33 (CLPTM1L, TERT) and 11p15.5 (TNNT3, LSP1), as well as nine novel loci. In addition, we observed the first evidence of effect modification by sex at the FGFR3 locus, with a stronger risk observed in women (pmultiplicative-interaction=0.002). Further, we confirmed an interaction between smoking and a susceptibility locus at 8p22 (NAT2), indicating an increased risk of bladder cancer among smokers with the NAT2 slow acetylation genotype/phenotype (pmultiplicative-interaction=0.001). We also identified additional multiplicative, as well as additive, interactions between several novel loci and cigarette smoking status. In addition, we are currently building a risk stratification model using the combined effects of smoking and genetic susceptibility to identify subgroups of individuals at higher and lower absolute risk of bladder cancer. Conclusions: This meta-analysis identified 3 novel loci in previously reported regions and 9 novel bladder cancer susceptibility loci in new regions. These results add to our knowledge of the genetic architecture of bladder cancer. In addition, observed gene-smoking interactions suggest that risk stratification models may have translational implications, informing future disease screening efforts. Citation Format: Stella Koutros, Lambertus A. Kiemeney, Roger L. Milne, Yuanqing Ye, Vijai Joseph, Jonine Figueroa, Nilanjan Chatterjee, Graham G. Giles, Michelle A. Hildebrandt, Lars Dyrskjot, Kenneth Offit, Manolis Kogevinas, Elisabete Weiderpass, Marjorie L. McCullough, Neal D. Freedman, Demetrius Albanes, Charles Kooperberg, Victoria Cortessis, Margaret R. Karagas, Dalsu Baris, Alison Johnson, Molly R. Schwenn, Helena Furberg, Dean F. Bajorin, Parichoy Pal Choudhury, Oscar Florez-Vargas, Olivier Cussenot, Geraldine Cancel-Tassin, Simone Benhamou, Peter Kraft, Stefano Porru, Mark P. Purdue, Katherine A. McGlynn, Cari M. Kitahara, Christopher A. Haiman, Mark H. Greene, Thorunn Rafnar, Stephen J. Chanock, Xifeng Wu, Francisco X. Real, Debra T. Silverman, Montserrat Garcia-Closas, Kari Stefansson, Ludmila Prokunina-Olsson, Nuria Malats, Nathaniel Rothman. Large-scale genome-wide association study identifies multiple novel germline susceptibility variants associated with bladder cancer risk [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2021; 2021 Apr 10-15 and May 17-21. Philadelphia (PA): AACR; Cancer Res 2021;81(13_Suppl):Abstract nr 826.

Incidence rates for liver cancer have increased 3-fold since the mid-1970s in the United States in parallel with increasing trends for obesity and type II diabetes mellitus. We conducted an analysis of baseline body mass index (BMI), waist circumference (WC), and type II diabetes mellitus with risk of liver cancer. The Liver Cancer Pooling Project maintains harmonized data from 1.57 million adults enrolled in 14 U.S.-based prospective studies. Cox regression estimated HRs and 95% confidence intervals (CI) adjusted for age, sex, study center, alcohol, smoking, race, and BMI (for WC and type II diabetes mellitus). Stratified analyses assessed whether the BMI–liver cancer associations differed by hepatitis sera-positivity in nested analyses for a subset of cases (n = 220) and controls (n = 547). After enrollment, 2,162 incident liver cancer diagnoses were identified. BMI, per 5 kg/m2, was associated with higher risks of liver cancer, more so for men (HR = 1.38; 95% CI, 1.30–1.46) than women (HR = 1.25; 95% CI, 1.17–1.35; Pinteraction = 0.02). WC, per 5 cm, was associated with higher risks of liver cancer, approximately equally by sex (overall, HR = 1.08; 95% CI, 1.04–1.13). Type II diabetes mellitus was associated with higher risk of liver cancer (HR = 2.61; 95% CI, 2.34–2.91). In stratified analyses, there was a null association between BMI and liver cancer risk for participants who were sera-positive for hepatitis. This study suggests that high BMI, high WC, and type II diabetes mellitus are associated with higher risks of liver cancer and that the association may differ by status of viral hepatitis infection. Cancer Res; 76(20); 6076–83. ©2016 AACR.

Background: Coffee consumption has been associated with lower all-cause mortality; however, its relationship to cancer risk is unclear. Evidence of inverse associations with cancers of the endometrium and liver were noted in a 2016 expert panel review convened by the International Agency for Research on Cancer, while findings for other malignancies were inconclusive. In the case of coffee and renal cell carcinoma (RCC), past studies have been limited by inadequate statistical power to detect modest effect sizes. To address this weakness in the existing literature, we investigated the relationship between coffee consumption and RCC risk in a large prospective cohort. Methods: Coffee intake was assessed at baseline with a food frequency questionnaire in the National Institutes of Health-AARP Diet and Health Study. Among 420,139 participants who were cancer-free at baseline, 2,674 incident cases of RCC were identified with a median of 16 years of follow-up. We fit multivariable-adjusted Cox proportional hazards models to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) for coffee intake, with non-coffee drinkers as the reference group. We also conducted stratified analysis by sex, diabetes, and smoking status and subgroup analyses by consumption of predominately caffeinated vs. decaffeinated coffee. Results: We observed HRs for RCC of 0.95 (95% CI 0.82, 1.10), 0.95 (0.81, 1.10), 0.80 (0.70, 0.92) and 0.76 (0.65, 0.89) for usual coffee intake of Conclusions: In this analysis of coffee consumption and RCC risk, to our knowledge the largest of its kind, we observed an approximately 20% reduced cancer risk for coffee consumption of 2 or more cups per day. Our findings provide the strongest epidemiologic evidence to date supporting an inverse association between coffee and RCC. Citation Format: Jongeun Rhee, Erikka Loftfield, Neal D. Freedman, Linda M. Liao, Rashmi Sinha, Mark P. Purdue. Coffee consumption and risk of renal cell carcinoma in the NIH-AARP Diet and Health 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 4650.

Background: The oral microbiota may be associated with lung cancer risk through direct mechanisms, including infection, immune responses, and periodontal disease, and through indirect mechanisms such as the modification of the oral microbiota by tobacco. We conducted a case-cohort study nested within three US prospective cohort studies to evaluate the association between oral microbiota ascertained years before a cancer diagnosis and risk of lung cancer. Methods: Incident lung cancer cases within the Agricultural Health Study (AHS; N=244), NIH-AARP Diet and Health Study (N=376), and the Prostate, Lung, Colorectum, and Ovarian Cancer Screening Trial (PLCO; N=700) who provided an oral wash sample were identified. The median time between oral sample collection and diagnosis was approximately 6.6 years, 3.4 years, and 4.5 years for AHS, NIH-AARP, and PLCO, respectively. A referent subcohort was randomly selected by strata of age, sex, and cigarette smoking history. We extracted DNA using the DSP DNA Virus Pathogen kit, and the V4 region of the 16S rRNA gene was PCR amplified and sequenced using the MiSeq. The sequencing data were processed using QIIME2 with the DADA2 plugin and we generated alpha and beta diversity metrics. Cox proportional hazards models were used to evaluate the hazard ratios (HR) and 95% confidence intervals (CI) for the association between the oral microbial measures and the risk of lung cancer with adjustment for known lung cancer risk factors, and estimates from the three cohorts were meta-analyzed. Results: Increased alpha diversity was associated with decreased lung cancer risk, although only the association with the Shannon Index reached statistical significance (HR for 5th quintile versus 1st quintile 0.74; 95% CI 0.60, 0.92) with no evidence of between-study heterogeneity (p = 0.5968). Specific principal coordinate vectors from the beta diversity matrices were also significantly associated with lung cancer risk, suggesting differing bacterial communities between future lung cancer cases. When stratified by histologic subtypes, the inverse association with alpha diversity was restricted to squamous cell carcinoma, with all alpha diversity metrics reaching statistical significance (e.g., Faith’s phylogenetic diversity HR for 5th quintile versus 1st quintile 0.57; 95% CI: 0.37, 0.87). Similarly, when stratified by smoking history, the inverse association with alpha diversity was restricted to former smokers (e.g., observed species HR for 5th quintile versus 1st quintile 0.63; 95% CI: 0.44, 0.89). Conclusions: In oral wash samples collected years before diagnosis, we found significant associations between both alpha and beta diversity metrics of the oral microbial communities and risk of lung cancer. Additional work is required to understand the associations by histologic subtype and smoking history. Citation Format: Emily Vogtmann, Xing Hua, Guoqin Yu, Autumn Hullings, Yunhu Wan, Casey L Dagnall, Kristine Jones, Belynda D. Hicks, Amy Hutchinson, Shalabh Suman, Bin Zhu, Barry Graubard, Mitchell H. Gail, J. Gregory Caporaso, William Wheeler, Dale Sandler, Laura E. Beane Freeman, Linda Liao, Neal D. Freedman, Neil Caporaso, Rashmi Sinha, Jianxin Shi, Christian C Abnet. The human oral microbiota and risk of lung cancer: An analysis of three prospective cohort studies [abstract]. In: Proceedings of the AACR Special Conference on the Microbiome, Viruses, and Cancer; 2020 Feb 21-24; Orlando, FL. Philadelphia (PA): AACR; Cancer Res 2020;80(8 Suppl):Abstract nr A39.

Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is a somatic event in which a fraction of leukocytes have lost the entire Y chromosome. The frequency of mLOY increases with age and may reflect poor genomic maintenance as well as clonal imbalances in normal immune function, making mLOY an attractive candidate marker for cancer risk. Here, we investigated the relationship between mLOY and incident cancer in a large sample of 207,603 cancer-free men from the UK Biobank, in which 13,895 men developed an incident solid tumor during follow-up. We identified mLOY by scanning for deviations in genotyping array log R intensity ratios across the male-specific chromosome Y region. Overall, we detected low proportions of cells with mLOY in 3,358 (1.6%) men and high proportions of mLOY in 524 (0.3%) men. We found an association of mLOY with overall solid tumor incidence using both low and high mLOY thresholds [HRlow = 1.18; 95% confidence interval (CI)low, 1.07–1.30; Plow = 0.001; HRhigh = 1.36; 95% CIhigh, 1.09–1.71; Phigh = 0.007] and more specifically we observed an association with lung cancer (HRhigh = 2.25; 95% CIhigh, 1.36–3.71; Phigh = 0.002). Stronger associations were observed without adjustment for smoking, suggesting that smoking is an important confounder of tumor incidence. It is unlikely that mLOY is a major mediator of the effect of cigarette smoking on cancer risk, as mLOY was observed in only a small fraction of smokers who developed cancer. In summary, mLOY was modestly associated with incidence of solid tumors in the UK Biobank, although for some cancer subtypes these findings may reflect residual confounding by smoking. Significance: Evidence from the UK Biobank indicates mosaic chromosome Y loss in leukocytes is moderately associated with increased incidence of select solid tumors.

Bacteria may play a role in esophageal adenocarcinoma (EAC) and esophageal squamous cell carcinoma (ESCC), although evidence is limited to cross-sectional studies. In this study, we examined the relationship of oral microbiota with EAC and ESCC risk in a prospective study nested in two cohorts. Oral bacteria were assessed using 16S rRNA gene sequencing in prediagnostic mouthwash samples from n = 81/160 EAC and n = 25/50 ESCC cases/matched controls. Findings were largely consistent across both cohorts. Metagenome content was predicted using PiCRUST. We examined associations between centered log-ratio transformed taxon or functional pathway abundances and risk using conditional logistic regression adjusting for BMI, smoking, and alcohol. We found the periodontal pathogen Tannerella forsythia to be associated with higher risk of EAC. Furthermore, we found that depletion of the commensal genus Neisseria and the species Streptococcus pneumoniae was associated with lower EAC risk. Bacterial biosynthesis of carotenoids was also associated with protection against EAC. Finally, the abundance of the periodontal pathogen Porphyromonas gingivalis trended with higher risk of ESCC. Overall, our findings have potential implications for the early detection and prevention of EAC and ESCC. Cancer Res; 77(23); 6777–87. ©2017 AACR.

Background: Known cutaneous malignant melanoma (CMM) genes account for melanoma risk in less than 40% of melanoma-prone families, suggesting the existence of additional risk genes or other modifiers. Whole exome sequencing (WES) of high-risk families usually results in the identification of a large number of potential disease-causing genes. However, prioritizing these genes and finding the true disease-causing ones have been challenging. We hypothesize that physically interacting proteins might have a similar effect on cell function and therefore, might produce a shared phenotype or increase the risk when mutated. To test this hypothesis, we applied a network approach integrating WES and protein-protein interaction (PPI) data to detect and prioritize rare variants in melanoma-prone families. Methods: We conducted WES analysis on germline DNA of 212 patients from 45 CMM families (2-5 affected people in a family) without known mutations. Variants that were rare ( Results: The WES analysis described above identified 546 genes that harbored rare variants, likely affect protein function and co-segregated in affected members in CMM families. After applying DADA across all networks, the rankings of these genes were fairly consistent. Top genes included both known CMM genes (such as MC1R, CDKN2B, KITLG, and TINF2) and genes that have not yet been associated with CMM susceptibility (such as FOXK1, AR, LEF1, RGL4, PABPC1, CHEK2, CTBP2, and BLM). These results highlight the importance of known CMM genes and their networks in CMM susceptibility, and demonstrate the potential value of network approaches in gene prioritization. Further evaluation of novel genes is in progress. Citation Format: Sally Yepes, Margaret Tucker, Hela Koka, Kristine Jones, Aurelie Vogt, Laurie Burdette, Wen Luo, Bin Zhu, Meredith Yeager, Belynda Hicks, Neal D. Freedman, Stephen J. Chanock, Alisa M. Goldstein, Xiaohong R. Yang. Whole-exome sequencing and protein interaction networks to prioritize candidate genes for cutaneous melanoma susceptibility [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 1638.

Clonal hematopoiesis (CH) is an age-related accumulation of detectable somatic mutations in circulating leukocytes that is associated with diverse outcomes including hematologic cancer, solid tumors, cardiovascular disease, neurodegenerative disorders and overall mortality. The biological mechanisms by which CH is associated with disease is poorly understood, with hypotheses suggesting CH is a potential marker of genomic maintenance capacity or a potential marker of immune system imbalance. The most common age-related chromosomal alteration observed in men with CH is mosaic loss of the Y chromosome (mLOY). The relative high frequency of mLOY makes mLOY an attractive marker for investigating disease-related mechanisms associated with CH. In particular, leukocyte counts are associated with hematologic cancer, cardiovascular disease and mortality in men and may, in part, mediate some of the observed associations between CH and disease. We investigated mLOY in a large collection of 223,182 men from the UK Biobank to study potential impacts of mLOY on blood cell count indices. We used existing UK Biobank array intensity data from the male-specific region of the Y chromosome to detect deviations in the median log2 R ratio (mLRR) that signifies the presence of mLOY. In total, 3,789 men had evidence for mLOY, and of these 596 men had evidence for mLOY affecting high cellular proportions (approximately 24% of cells). Age and smoking adjusted models indicated leukocyte count is, on average, elevated by 5.82% (95% CI=4.82-6.83, P-value=5.38×10−30) in men with mLOY and by 11.95% (95% CI=9.47-14.44, P-value=1.99×10−21) in men with high levels of mLOY. Analysis of leukocyte proportions indicated the association between mLOY and leukocyte count was restricted to myeloid progenitor cells, with significant elevations observed in neutrophil and monocyte counts (P-values=1.06×10−25 and 4.89×10−56, respectively). Neutrophil count was most highly altered with average changes in cell count of 8.69% (95% CI=7.60-9.77) in men with mLOY and 14.70% (95% CI=12.04-17.37, P-value=2.32×10−156) in men with high levels of mLOY. Sensitivity analyses in never smokers observed similar elevations in leukocyte, neutrophil and monocyte count in men with mLOY, suggesting our findings were not a result of residual confounding by smoking. Furthermore, elevations in platelet count and reductions in erythrocyte count in men with mLOY provide additional evidence myeloid progenitor cells are impacted by mLOY. We found no evidence suggesting lymphocytes are impacted by mLOY. Together, these observations indicate that men with mLOY have substantial deviations in blood cell counts, particularly in neutrophil count. In this way, alterations in leukocyte counts may be one mechanism by which CH contributes to disease. Citation Format: Mitchell J. Machiela, Weiyin Zhou, Erikka Loftfield, Meredith Yeager, Neal D. Freedman, Stephen J. Chanock. Clonal hematopoiesis alters blood cell counts in the UK Biobank [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 607.

Ewing sarcoma (EWS), a pediatric tumor predominantly occurring in children of European ancestry, is characterized by the EWSR1-FLI1 fusion oncogene. We performed a genome-wide association study (GWAS) of 749 EWS cases and 1,378 unaffected individuals of European ancestry. Our study replicated previously reported susceptibility loci at 1p36.22, 10q21.3, and 15q15.1 and identified new loci at 6p25.1, 8q24.23, 20p11.22, and 20p11.23 (P-values Citation Format: Mitchell J. Machiela, Thomas G.P. Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetete-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Nathalie Gaspar, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Neal D. Freedman, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdett, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G. Cox, Robert N. Hoover, Javed Khan, Gregory T. Armstrong, Wendy M. Leisenring, Smita Bhatia, Leslie L. Robison, Uta Dirksen, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Andreas E. Kulozik, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen Chanock, Olivier Delattre. Genome-wide association study identifies multiple new loci associated with Ewing sarcoma susceptibility [abstract]. In: Proceedings of the AACR Special Conference: Pediatric Cancer Research: From Basic Science to the Clinic; 2017 Dec 3-6; Atlanta, Georgia. Philadelphia (PA): AACR; Cancer Res 2018;78(19 Suppl):Abstract nr A13.

Objective: The 2016 WCRF Continuous Update Project reported that consumption of alcoholic drinks probably causes gastric cancer, but the magnitude of the association was small, there was moderate heterogeneity among the studies included in the meta-analysis, and most studies were from Asian populations, with only 401 cases from North American studies. Therefore, we re-evaluated the association between alcohol intake and gastric cancer in a large US cohort that has accrued more than 1300 gastric cancer cases. Methods: We prospectively investigated the associations of alcohol consumption with gastric cardia adenocarcinoma (GCA) and gastric non-cardia adenocarcinoma (GNCA) in 490,605 members aged 50-71 years at baseline in the NIH-AARP Diet and Health Study cohort. Alcohol consumption was assessed during the baseline questionnaire in 1995/1996 and evaluated as grams of ethanol intake and as a categorical variable: never, up to or including one drink/day, one to three drinks/day, and greater than three drinks/day. We used Cox proportional hazard regression to calculate the hazard ratios and 95% confidence intervals for associations between alcohol intake and risk of gastric adenocarcinomas with adjustment for several potential confounders. Results: Through 2011, 662 incident cases of GCA and 713 of GNCA occurred in the cohort. We found no association between higher alcohol consumption and GCA or GNCA, regardless of whether analyzed as total alcoholic beverage intake or the individual beverage types of beer, wine and liquor and no evidence for a dose-response. Furthermore, we observed no association by stratum of sex, ethnic group, educational level, or smoking status. Although there were no overall associations, we found some evidence for lower risk of GNCA among people who drank up to one drink per day (HR=0.81, 95%CIs:0.67-0.97) compared to nondrinkers. Conclusion: Alcohol consumption was not associated with increased risk of gastric cardia adenocarcinoma or gastric non-cardia adenocarcinoma in this large US prospective cohort. Citation Format: ShaoMing Wang, Neal D. Freedman, Erikka Loftfield, Xing Hua, Christian C. Abnet. Alcohol consumption and risk of gastric cardia adenocarcinoma and gastric non-cardia adenocarcinoma: A prospective analysis from the NIH-AARP Diet and Health cohort [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5260.

Background: Rhabdomyosarcoma (RMS) is the most common soft tissue sarcoma in children and has one of the poorest survival rates among all pediatric cancers. The two major histologic subtypes of RMS are embryonal (eRMS) and alveolar (aRMS), which display differences in terms of age-incidence patterns and somatic mutations. Approximately 10% of RMS cases are associated with germline mutations in known cancer predisposition genes (e.g., TP53, NF1), but very little is known about the genetic susceptibility to the ~90% of RMS cases that are sporadic. We conducted the first multi-institutional genome-wide association study (GWAS) of RMS in 727 cases and 3,384 controls. Methods: Phase 1 of the GWAS included 421 RMS cases from Children's Oncology Group clinical trials, Texas Children's Hospital, and the Universidad de Navarra. Controls (n=2,763) were cancer-free individuals included in previous studies at the National Cancer Institute (NCI). Phase 2 included 306 cases from the Childhood Cancer Survivor Study and 621 independent controls from NCI. Genotypes were generated using the Illumina OmniExpress or the HumanOmni5Exome array and imputed based on the 1000 Genomes Project. Analyses were restricted to those of European (EUR) ancestry, and controls were matched to the cases based on principal components and genotype platform. Assuming an additive genetic model in SNPTEST, we used multivariable logistic regression models to estimate the odds ratio (OR), 95% confidence interval (CI), and P value for each variant on RMS overall and by two RMS subtypes: eRMS and aRMS. Results: After quality control filtering and assessment of population substructure, there were 555 combined EUR RMS cases and 1,561 controls, which included: 1) 278 cases and 1,112 controls in phase 1; and 2) 277 cases and 449 controls in phase 2. In the combined set, we identified a new locus at chromosome 11p15.2 that was strongly associated with an increased risk of aRMS and significant at the genome-wide level (OR=2.3, P=2.2x10-8). Results were consistent across studies: phase 1 OR=2.3, 95% CI 1.7-3.2; and phase 2 OR=2.3, 95% CI 1.2-4.5. The top variant, rs12785926, mapped to an intron in the PSMA1 (proteasome subunit alpha 1) gene. Based on data from GTEx, rs12785926 is significantly associated with RRAS2 expression across multiple tissues. RRAS2 is involved in cell proliferation and is somatically mutated in several tumors. When evaluating eRMS and RMS overall in the combined set, there were no variants significant at the genome-wide level. Conclusion: In the first GWAS of pediatric RMS, we identified a susceptibility locus associated with the more aggressive aRMS subtype that has a poorer prognosis. Additional replication analyses are underway using DNA obtained from archived newborn blood spots linked to population-based cancer registries, as well as other institutional cohorts. Further investigation will advance understanding of RMS etiology and biology. Citation Format: Philip J. Lupo, Libby Morimoto, Eric Karlins, Xiaorong Shao, Lindsay M. Morton, Michael E. Scheurer, Smita Bhatia, Leslie L. Robison, Gregory T. Armstrong, Simone Hettmer, Javed Khan, Stephen J. Chanock, Neal D. Freedman, Kathleen Wyatt, Belynda D. Hicks, Meredith Yeager, Casey L. Dagnall, Shengchao A. Li, Stephen X. Skapek, Douglas S. Hawkins, Catherine Metayer, Lisa Mirabello. A genome-wide scan identifies a new locus associated with pediatric rhabdomyosarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2966.

Background: Despite declining prevalence, cigarette smoking causes about 30% of all cancer deaths in the United States. More than a quarter of daily cigarette smokers in the United States smoke 10 or less cigarettes per day (CPD), encompassing a heterogeneous group of lifelong low-intensity smokers and formerly heavier smokers who have cut down their CPD. The impact of prior smoking history on the disease risks of low-intensity cigarette smokers is poorly understood. Methods: In the National Institutes of Health-AARP Diet and Health Study, a prospective cohort study of older adults in the United States, a questionnaire administered in 2004-2005 assessed CPD during nine age-periods over the lifetime ( Results: We identified nine trajectory patterns in both men and women. Mortality risks varied substantially by trajectory: the HRs for overall cancer mortality ranged from 1.17 to 4.03 in men and 0.83 to 3.42 in women. Similarly, the HRs for lung cancer mortality ranged from 5.20 to 23.88 in men and 8.00 to 23.08 in women. Mortality risks were substantially higher among participants who had cut down their CPD than among participants who reported smoking at low-intensity for all age-periods that they smoked. For example, in men, the HR for lung cancer mortality was 23.88 (95% CI=12.10-47.13) among low-intensity smokers who previously smoked 31-40 CPD, whereas it was 9.36 (95% CI=5.92-14.79) among lifelong 1-10 CPD smokers. Similarly, in women, the HR for lung cancer mortality was 19.76 (95% CI=8.71-44.85) among women who previously smoked 21-30 CPD, whereas it was 9.26 (95% CI=2.98-14.34) among lifelong 1-10 CPD smokers. Conclusions: In a large prospective cohort study of older adults in the United States, risks among low-intensity smokers for overall and lung-cancer mortality varied substantially by prior smoking history. These results suggest that it is important for risk prediction models, such as for lung cancer-screening, to incorporate lifetime smoking history into their algorithms. Citation Format: Maki Inoue-Choi, Scott P. Kelly, Kelvin Choi, Neal D. Freedman. Lifetime trajectories of cigarette smoking and cancer mortality among older adults in a large cohort in the United States [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5246.

Ewing sarcoma (EWS) is a rare pediatric tumor predominantly occurring in children of European ancestry and is characterized by the pathognomonic EWSR1-FLI1 fusion oncogene. To identify germline susceptibility loci associated with EWS risk, we performed a genome-wide association study (GWAS) meta-analysis of 749 EWS cases and 1,378 unaffected individuals of European ancestry from sample collections within the Institut Curie, National Cancer Institute and the Childhood Cancer Survivor Study. Our study replicated previously reported susceptibility loci at 1p36.22, 10q21.3 and 15q15.1 as well as identified novel loci at 6p25.1, 8q24.23, 20p11.22 and 20p11.23 (P-values Citation Format: Mitchell J. Machiela, Thomas G. Grünewald, Didier Surdez, Stephanie Reynaud, Olivier Mirabeau, Eric Karlins, Rebeca Alba Rubio, Sakina Zaidi, Sandrine Grossetete-Lalami, Stelly Ballet, Eve Lapouble, Valérie Laurence, Jean Michon, Gaelle Pierron, Heinrich Kovar, Nathalie Gaspar, Udo Kontny, Anna González-Neira, Piero Picci, Javier Alonso, Ana Patino-Garcia, Nadège Corradini, Neal D. Freedman, Nathaniel Rothman, Casey L. Dagnall, Laurie Burdette, Kristine Jones, Michelle Manning, Kathleen Wyatt, Weiyin Zhou, Meredith Yeager, David G. Cox, Robert N. Hoover, Javed Khan, Gregory T. Armstrong, Wendy M. Leisenring, Smita Bhatia, Leslie L. Robison, Uta Dirksen, Markus Metzler, Wolfgang Hartmann, Konstantin Strauch, Thomas Kirchner, Andreas E. Kulozik, Lindsay M. Morton, Lisa Mirabello, Margaret A. Tucker, Franck Tirode, Stephen J. Chanock, Olivier Delattre. Multiple new susceptibility loci identified in genome-wide association study of Ewing sarcoma [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 2970.

Mosaic loss of the Y chromosome (mLOY) in peripheral leukocytes is an age-related event commonly observed in men older than 50 years of age in which a fraction of leukocytes loses the Y chromosome. In addition to age, previous studies have indicated an association between smoking and increased risk of mLOY. The relationship between mLOY and other health-related exposures (e.g., obesity and alcohol consumption) and with disease outcomes (e.g., cancer risk and overall mortality) remains unclear. We therefore investigated the causes and consequences of mLOY in a large collection of 223,338 men from the UK Biobank. We scanned Y chromosomes for deviations in genotyping array log R ratio intensities for evidence of mLOY. A total of 3,789 (1.7%) men showed evidence for mLOY with median chromosome Y LRR values less than -0.15 and 596 (0.3%) men had high proportions of cells affected with mLOY with median LRR values less than -0.40. Our analysis robustly confirms prior associations of increasing mLOY risk with increasing age (Padj Citation Format: Erikka Loftfield, Weiyin Zhou, Meredith Yeager, Stephen J. Chanock, Neal D. Freedman, Mitchell J. Machiela. Predictors of mosaic chromosome Y loss and associations with mortality in 223,338 men of the UK Biobank [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3379.

Low-income countries across the world are increasingly burdened with growing rates of cancer incidence and mortality. Opportunities for prevention in these populations may be realized most readily for cancer sites with known etiologies that are amenable to intervention. Liver cancer is the sixth-most commonly occurring cancer worldwide and is the second-most common contributor to global cancer mortality. Aflatoxin B1 (AFB1) is a known and potent human hepatocarcinogen, with exposure occurring via ingestion of grains - especially maize - contaminated with Aspergillus flavus. Previous work in regions with endemic levels of liver cancer has shown that reducing AFB1 exposure attenuated liver cancer mortality - even in the presence of other known etiological exposures, such as hepatitis B virus. Guatemala experiences high rates of liver cancer - which is uniquely distributed equally between men and women - and consumes maize as a dietary staple, making the assessment of AFB1 exposure a high priority for cancer prevention efforts in this country. Therefore, we measured circulating levels of the AFB1-albumin adduct, an established biomarker of AFB1 exposure, in adults residing in five geographically and ecologically dispersed departments of Guatemala (Guatemala, Suchitepéquez, Sololá, Escuintla, and Quiché). Healthy men and women aged 40 and older were recruited for the study. Pregnant women or individuals with implanted cardiac devices were excluded from participation. Subjects (n=436) gave informed consent and provided demographic information and a venipuncture blood sample during a clinic visit. Serum was separated from whole blood, digested with protease, subjected to solid-phase extraction, and analyzed with isotope dilution ultrahigh-performance liquid chromatography-triple quadrupole mass spectrometry. Serum albumin was measured by ELISA. AFB1-albumin adducts (pg AFB1-lysine adduct/mg albumin) were detectable in 100% of samples, with a mean ± SEM of 21.6 ± 2.5 and range of 0.2 - 814.8. These levels are similar to those observed in regions of China in the 1980s, prior to reductions in AFB1 exposure and liver cancer mortality. Stratification by demographic factors revealed significant differences in aflatoxin levels in urban (9.6 ± 1.3) versus rural (28.8 ± 3.9) subjects (p ≤ 0.001). Accordingly, AFB1-albumin adduct levels were lowest in the urban municipality of Escuintla (5.8 ± 1.1) and highest in rural Suchitepéquez (36.4 ± 4.8). Exposure was significantly different by sex, with men having higher levels compared to women (30.0 ± 5.4 vs. 15.3 ± 1.3, p = 0.01). These data show that AFB1 exposure in Guatemalan adults is similar to levels previously shown to increase liver cancer risk. Larger cohort and prospective studies are warranted to assess the relationship between liver cancer incidence and AFB1 exposure in this population. Citation Format: Joshua W. Smith, Patricia A. Egner, Mariana Lazo, Alvaro Rivera, Fernanda Kroker, Neal D. Freedman, Katherine A. McGlynn, Manuel Ramirez-Zea, Eliseo Guallar, John D. Groopman. Quantitative measurement of aflatoxin-serum albumin adducts reveals substantial exposure in Guatemala, a country with high rates of liver cancer mortality in men and women [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 4247. doi:10.1158/1538-7445.AM2017-4247

Background: Since 1980, liver cancer has been among the most rapidly increasing cancer types in the United States (US), with 5-year survival rates of approximately 17%. While tobacco and alcohol are known to be associated with primary liver cancer, it is unclear whether they only increase the risk of hepatocellular carcinoma (HCC), the most common type of liver cancer, or whether they also increase risk of intrahepatic cholangiocarcinoma (ICC), second most common histologic type. Additionally, it is unclear what amount of alcohol consumption is associated with an increased risk of liver cancer. As liver cancer is a rare cancer type, we conducted a study of pooled data from the National Cancer Institute Cohort Consortium to examine the associations between smoking and alcohol use and liver cancer, stratified by histologic subtype. Methods: In the Liver Cancer Pooling Project, a consortium of US-based cohort studies, we pooled data from 1,518,741 individuals (HCC n=1,423, ICC n=410) in 14 cohorts. Multivariable-adjusted hazard ratios (HRs) and 95% confidence intervals (CI) were estimated using proportional hazards regression. Cubic splines were used to model the association between alcohol and liver cancer risk. Results: Compared to never smokers, both former and current smokers at study baseline had an increased risk of ICC (HR=1.32, 95% CI: 1.03-1.68 and HR=1.47, 95% CI: 1.07-2.02, respectively) and HCC (HR=1.24, 95% CI: 1.08-1.43 and HR=1.86, 95% CI: 1.57-2.20, respectively). This finding was consistent for heavier smoking intensity, longer duration of smoking, and more pack-years of smoking. Heavy alcohol consumption was associated with an 87% increased risk of HCC (HR≥7 drinks/day v. non-drinker=1.87, 95% CI: 1.41-2.47) and a non-significant 68% increased risk of ICC (HR≥5 drinks/day v. non-drinker=1.68, 95% CI: 0.99-2.86). Risk of HCC significantly increased at 4.5 alcoholic drinks per day, while risk of ICC was non-significantly increased with any amount of consumption. Conclusions: These findings suggest that, in a US population, cigarette smoking is associated with an increased risk of both histologic subtypes of primary liver cancer - HCC and ICC. In contrast, alcohol consumption was primarily associated with an increased risk of HCC. These results suggest that smoking cessation and alcohol reduction programs could be important intervention opportunities for these lethal cancer types. Citation Format: Jessica Leigh Petrick, Peter T. Campbell, Jill Koshiol, Jake E. Thistle, Gabriella Andreotti, Laura E. Beane-Freeman, Julie E. Buring, Andrew T. Chan, Dawn Q. Chong, Michele M. Doody, Susan M. Gapstur, John Michael Gaziano, Edward Giovannucci, Barry I. Graubard, I-Min Lee, Linda M. Liao, Martha S. Linet, Julie R. Palmer, Jenny N. Poynter, Mark P. Purdue, Kim Robien, Lynn Rosenberg, Catherine Schairer, Howard D. Sesso, Rashmi Sinha, Meir J. Stampfer, Marcia Stefanick, Jean Wactawski-Wende, Xuehong Zhang, Anne Zeleniuch-Jacquotte, Neal D. Freedman, Katherine A. McGlynn. Tobacco smoking, alcohol use and risk of hepatocellular carcinoma and intrahepatic cholangiocarcinoma: The Liver Cancer Pooling Project [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr 3007. doi:10.1158/1538-7445.AM2017-3007

In the National Lung Screening Trial (NLST), the effectiveness of lung cancer screening by low-dose computed tomography (CT) depended on individual lung cancer risk. Time to fist cigarette (TTFC) is an easily assessed component of nicotine dependency that may be an independent predictor of lung cancer risk. We validated the independent association of TTFC with lung cancer and assessed whether including TTFC into risk prediction models might improve CT screening effectiveness. We examined associations between TTFC and lung cancer incidence and mortality in the 18,729 participants of the ACRIN component of the NLST, which included 773 lung cancer diagnoses and 299 lung cancer deaths. Multivariable cox-proportional hazard regression models, adjusted for other metrics of smoking use and lung cancer risk factors, were used. In terms of screening effectiveness, we predicted each participant's 5-year cumulative lung cancer death risk using multivariable models that excluded or included TTFC. We then investigated 3 possible screening strategies based on risk scores from each model (for a total of six strategies): in each model scenario, those with a 5-year risk score above one of three thresholds (0.5%, 0.75%, and 1%) would be screened, whereas others would not. For each risk threshold, we compared screening sensitivities (the percentage who would have been screened among smokers who died of lung cancer) and specificities (the percentages who would not have been screened among smokers without lung cancer) between models without and with TTFC. We also estimated the absolute reduction in lung cancer death risk, due to screening, within each TTFC group ( Compared to smokers with TTFC≥60 min, smokers with shorter TTFC had higher lung cancer incidence [hazard ratios (HR) and 95% confidence intervals (CI) for TTFC 30-59 min = 1.69(1.19-2.41), HR15-29min = 1.72(1.22-2.43), HR6-14min = 2.05(1.48-2.84), HR We confirmed the independent inverse association between TTFC and lung cancer in NLST. Smokers with a TTFC greater than 60 min had less benefit from CT screening than smokers with a shorter TTFC. By increasing specificity and maintaining sensitivity, including TTFC in risk prediction models may more precisely identify those who benefit less from CT lung screening. Citation Format: Fangyi Gu, Hormuzd Katki, Neal Freedman, Pam Marcus, Neil Caporaso. Time to first morning cigarette and lung cancer in National Lung Screening Trial. [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 2596.

Background: The pathogenesis of non-cardia gastric adenocarcinoma (NCGA) begins with Helicobacter pylori (Hp) infection, which induces atrophic gastritis, a pre-neoplastic state characterized by gland loss and achlorhydria. In parallel, vitamin B12 absorption requires intact gastric mucosa which can produce acid and intrinsic factor. Several previous studies have suggested that Hp infection, the primary risk factor for NCGA, impairs vitamin B12 absorption. Other studies have shown that previous diagnosis of pernicious anemia, the most common form of vitamin B12 deficiency and autoimmune atrophic gastritis, predicts later NCGA. We hypothesized that decreased serum vitamin B12 would predict subsequent incidence of NCGA in a dose-dependent fashion. Methods: To examine the relationship between serum vitamin B12 and risk of NCGA, we conducted a nested case-control study within the prospective Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study of male Finnish smokers aged 50-69 at baseline (1985-1988). Vitamin B12 concentrations were measured in serum samples that were collected at study enrollment. Subjects were followed for 17 years for cancer development (mean time to NCGA diagnosis = 7.5 years). 177 NCGA cases were matched 1:1 on age and date of serum collection with cancer-free controls. We calculated odds ratios (OR) and 95% confidence intervals (CI) by conditional logistic regression, controlling for Hp infection, smoking, fruit and vegetable intake, and other potential confounders. Results: Baseline mean pre-diagnostic serum vitamin B12 concentrations were 16% lower in subjects who subsequently developed NCGA (Cases: 435 pg/mL, SE = 129; Controls: 516 pg/mL, SE = 207; p = 0.0001; serum vitamin B12 levels >200 pg/mL are clinically normal.) Lower serum vitamin B12 at baseline was associated with subsequent incidence of NCGA during follow-up (OR = 7.24; 95% CI = 2.12 to 24.73 for lowest quartile compared to highest, p-trend = 0.002). This association remained after restricting the analysis to subjects who developed cancer more than 10 years after baseline serum vitamin B12 measurements. Conclusion: Lower serum vitamin B12 concentrations were associated with an increased risk of NCGA even among subjects who were diagnosed more than 10 years after their enrollment in the study. Our findings suggest a possible role for serum vitamin B12 as a biomarker for the atrophic gastritis that precedes NCGA. Citation Format: Eugenia Miranti, Rachael Stolzenberg-Solomon, Stephanie Weinstein, Jacob Selhub, Satu Männistö, Philip R. Taylor, Neal D. Freedman, Demetrius Albanes, Christian Abnet, Gwen Murphy. Serum vitamin B12 and development of non-cardia gastric cancer: a prospective study. [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 4301.

Background: Populations in north central China are at high risk for esophageal squamous cell carcinoma (ESCC) and gastric cancer (GC), and genetic variation in epigenetic machinery genes and pathways may contribute to this risk. Methods: We used the adaptive multilocus joint test (AdaJoint) to analyze 191 epigenetic genes involved in DNA methylation, chromatin remodeling, and microRNA biosynthesis in 1942 ESCC and 1758 GC cases [1126 cardia (GCA) and 632 non-cardia adenocarcinoma (GNCA)] and 2111 controls with Chinese ancestry. We examined the regulatory function of risk SNPs using in silico analyses and expression quantitative trait loci (eQTL) analysis in normal esophageal and gastric tissues. Results: Significant pathway-based associations were observed for the overall epigenetics (P = 3.4E-02) and chromatin remodeling (P = 3.9E-02) pathways with GCA risk, but not GC, GNCA or ESCC. SETD1B, CBX4, KAT5, ZGPAT, BTD, EED, SMARCD1, POLE3, AGO2, RING1 and MBD3L1 were associated with ESCC risk, and SUV42OH1, ASH1L, KAT5, JARID2, PRMT1, MBD3L1, SRRT, KDM5A, DROSHA and KAT6A were associated with GC risk overall (nominal P < 0.05). We identified EED rs10898459 (rho = -0.22, P = 2.9E-02) as a potential esophageal eQTL; DICER1 rs7157322 (rho = -0.42, P = 1.4E-02) and PPP1CA rs1790733 (rho = -0.41, P = 2.1E-03) as potential gastric eQTLs; and ASH1L rs12724079 and rs8179271 as potential gastric subtype eQTLs. Significance: As one of the first attempts to investigate epigenetic gene and pathway-level associations, our results suggest that chromatin remodeling and epigenetic pathways warrant further evaluation in relation to GC risk in other populations. Citation Format: Hyuna Sung, Howard H. Yang, Han Zhang, Qi Yang, Nan Hu, Ze-Zhong Tang, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Jin-Hu Fan, You-Lin Qiao, William Wheeler, Carol Giffen, Laurie Burdett, Zhaoming Wang, Maxwell P. Lee, Stephen J. Chanock, Sanford M. Dawsey, Neal D. Freedman, Christian C. Abnet, Alisa M. Goldstein, Kai Yu, Philip R. Taylor, Paula L. Hyland. Common genetic variants in epigenetic machinery genes and risk of upper gastrointestinal cancers. [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 4622. doi:10.1158/1538-7445.AM2015-4622

The absolute risk of carcinogenic progression given Barrett's esophagus (BE) is low and a majority of esophageal adenocarcinoma (EA) cases are diagnosed at first endoscopy without having had a prior diagnosis of BE. Therefore the research field has largely utilized case-control study designs with the implicit assumption that each case-group assessed (reflux, BE, EA) is representative of that stage in a linear progression towards cancer. To test the assumption that EA cases are a homogeneous group and therefore research findings may contribute to evidence-based prevention programs for diagnosed BE populations, we conducted a case-case study comparing the clinical presentation, medical history and survival of EA patients with and without a prior diagnosis of BE in the SEER-Medicare database. Eligible EA cases were diagnosed at ages > = 68 years during 1994-2009. Exposures were captured for a 2 year period starting 3 years prior to diagnosis. There were 5,271 EA patients in this study, 87% (n = 4,609) of which lacked a previous diagnosis of BE (“EA-no prior BE”). In univariate case-case comparisons, patient characteristics (age, sex, race, etc.) were mostly similar with the exceptions that EA-prior BE cases had lower comorbidity scores and a higher average number of physician visits. Conversely, tumor and treatment characteristics were starkly different; EA-prior BE cases were typically diagnosed with lower stage, lower grade, smaller tumors, and were less likely to have metastatic disease. EA-prior BE cases were also more likely to receive surgery and less likely to receive chemotherapy and radiotherapy. Multivariable case-case comparisons of exposures evidenced positive associations of GERD, ever-cigarette smoking, hypertension, dyslipidemia, weight-loss, peptic ulcer, pernicious anemia/celiac disease, and irritable bowel disease each in relation to EA-prior BE compared with EA-no prior BE. Obesity, metabolic syndrome, impaired fasting glucose, diabetes and depression did not differ between the case groups. EA-prior BE cases had better overall mean survival (2.5 vs. 1.4 years), particularly for localized disease (3.3 vs 2.3 years). Such a survival advantage persisted after adjustment for age at diagnosis, sex, race, education and registry (hazard ratio (HR) = 0.53, 95% confidence interval (CI): 0.48, 0.58). Further adjustment for stage, grade, tumor size, metastatic disease, surgery, chemotherapy, radiotherapy, & Charlson comorbidity score attenuated but did not diminish the association (HR = 0.70, 95%CI: 0.64, 0.78). In sum, our study provides evidence that EA cases occurring among patients previously diagnosed with BE are dramatically different from those that were not, differing in clinical presentation, medical history, and survival. These findings underscore the importance of a prudent approach when attempting to reconstruct the natural history of this malignancy with utility for cancer prevention. Citation Format: Michael B. Cook, Jennifer Drahos, Shannon Wood, Lindsey Enewold, Ruth Parsons, Neal D. Freedman, Philip R. Taylor, Winnie Ricker, Christian C. Abnet. Pathogenesis and progression of esophageal adenocarcinoma by prior diagnosis of Barrett's esophagus. [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 837. doi:10.1158/1538-7445.AM2015-837

Introduction: The oral microbiome is intimately involved in inflammatory processes in the oral cavity and may be involved in metabolism of carcinogens in tobacco smoke. Our hypothesis is that oral microbiota may promote head and neck carcinogenesis, possibly related to smoking. To test this hypothesis, we conducted a nested case-control study to prospectively examine the role of the oral microbiome in head and neck cancer, in the Prostate, Lung, Colorectal, and Ovarian (PLCO) Cancer Screening Trial cohort. Methods: Subjects in the PLCO Trial completed risk factor questionnaires and provided oral wash samples. Trial participants were followed for cancer incidence by annual follow-up, medical chart review and search of mortality databases. During follow-up, 87 histologically confirmed head and neck cancer cases occurred subsequent to oral wash sample collection. We matched these cases to 174 cohort-nested controls (matched by age, gender, and race). DNA was extracted from oral wash samples, 16S rRNA genes were amplified by universal primers, and product was bar-coded and sequenced by 454 FLX technology. 16S rRNA bacterial gene sequences were binned into operational taxonomic units (based on 97% identity) and further assigned to taxonomy in the QIIME pipeline. We performed nonparametric Wilcoxon signed-rank tests and conditional logistic regression to compare differences between head and neck cancer cases and controls, with respect to overall bacterial community structure and relative abundance of specific taxa. Results: From 261 oral samples, we obtained 2,548,067 high quality 16S rRNA gene sequence reads. Overall community structure, based on a weighted UniFrac phylogenetic distance index, did not differ significantly between cases and controls (p>0.05). The major phyla in controls were Firmicutes (59.5%), Actinobacteria (15.5%), Bacteroidetes (11.3%), Proteobacteria (10.3%), and Fusobacteria (2.8%). Decreased abundance of Proteobacteria was observed in cases (7.8%) compared to controls (Wilcoxon test, p = 0.008, FDR controlled p=0.041). After consideration of age, race and sex in conditional logistic regression analysis, an inverse association of Proteobacteria with head and neck cancer risk was observed in smokers (OR comparing extreme tertiles =0.34, 95% CI 0.15-0.79; ptrend = 0.009 [FDR controlled p=0.065]), but not in non-smokers (ptrend=0.62). We also noted a relative increase in abundance of Bifidobacteriales order (multivariate p=0.002, FDR controlled p=0.045) and Lactobacillaceae family (multivariate p=0.005, FDR controlled p>0.05) in cases compared with controls. Conclusion: This first prospective study of the oral microbiome and head and neck cancer suggests that Proteobacteria and Bifidobacteriales are related to risk of head and neck cancer. Replication of these first observations is needed. Citation Format: Jiyoung Ahn, Yingfei Ma, Mark P. Purdue, Neal D. Freedman, Susan M. Gapstur, Liying Yang, Richard B. Hayes, Zhiheng Pei. Oral microbiome and risk of head and neck cancer, a nested case-control study. [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 4143. doi:10.1158/1538-7445.AM2014-4143

We conducted a joint (pooled) analysis of three genome-wide association studies (GWAS) of esophageal squamous cell carcinoma (ESCC) in ethnic Chinese (5,337 ESCC cases and 5,787 controls) with 9,654 ESCC cases and 10,058 controls for follow-up. In a logistic regression model adjusted for age, sex, study, and two eigenvectors, two new loci achieved genome-wide significance, marked by rs7447927 at 5q31.2 (per-allele odds ratio (OR) = 0.85, 95% Confidence Interval (CI) = 0.82-0.88; P = 7.72x10-20) and rs1642764 at 17p13.1 (per-allele OR = 0.88, 95% CI = 0.85-0.91; P = 3.10x10-13). rs7447927 is a synonymous single nucleotide polymorphism (SNP) in TMEM173 and rs1642764 is an intronic SNP in ATP1B2, near TP53. Furthermore, a locus in the HLA class II region at 6p21.32 (rs35597309) achieved genome-wide significance in the two populations at highest risk for ESSC (per-allele OR = 1.33, 95% CI = 1.22-1.46; P = 1.99x10-10). Our joint analysis revealed new ESCC susceptibility loci overall as well as a new locus unique to the ESCC high risk Taihang Mountain region. Citation Format: Chen Wu, Zhaoming Wang, Xin Song, Xiao-Shan Feng, Christian C. Abnet, Jie He, Nan Hu, Xian-Bo Zuo, Wen Tan, Xue-Jun Zhang, Neal D. Freedman, Alisa M. Goldstein, Dongxin Lin, Philip R. Taylor, Li-Dong Wang, Stephen J. Chanock. Joint analysis of three genome-wide association studies of esophageal squamous cell carcinoma in Chinese populations reveals new susceptibility loci. [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 2204. doi:10.1158/1538-7445.AM2014-2204

With nearly 77,000 new cases and 9,500 deaths in 2013, cutaneous melanoma is the 5th most common cancer and the leading cause of skin cancer death in the US. Modifiable risk factors, with the exception of exposure to ultraviolet (UV) radiation, are poorly understood. Coffee contains numerous bioactive compounds and may be associated inversely with melanoma. However, epidemiological evidence is limited to a few case-control and prospective cohort studies with inconsistent results. To better understand this association, we analyzed data from the large, prospective NIH-AARP Study. Coffee intake was assessed at baseline with a food frequency questionnaire. Among 447,357 non-Hispanic whites who were cancer-free at baseline, 2,904 incident cases of melanoma were identified by linkage between NIH-AARP cohort membership and 11 state cancer registries during 4,329,044 person years of follow up. Respondents were followed from baseline until the date of first skin cancer diagnosis, the date of death, the end of study follow-up (December 31, 2006), or the date the subject moved out of the registry ascertainment area, whichever came first. We used Cox proportional hazards models adjusted for multiple potential confounders to estimate hazard ratios (HR) and 95% confidence intervals (CI) for melanoma risk in relation to level of coffee intake. Increasing coffee intake was inversely associated with risk of melanoma (p-trend = 0.013), and those who consumed ≥4 cups/d had a 20% reduction in the risk of melanoma compared to those who consumed no coffee. This association was significant for caffeinated coffee (≥4 vs. 0 cups/d: HR=0.75, 95% CI=0.64-0.89; p-trend = 0.008) but was not observed for decaffeinated coffee (≥4 vs. 0 cups/d: HR=0.95, 95% CI=0.76-1.18; p-trend = 0.55). Coffee intake was inversely associated with melanoma risk in this large US cohort study. Additional investigations of coffee intake and its constituents, particularly caffeine, in the prevention of melanoma are warranted. Table.Association of Daily Coffee Consumption with MelanomaTotal Coffee Intakep-trendNone (Ref.)≤1 cup/d2-3 cups/d≥4 cups/dNo. cases3109421253399–Age & sex-adjusted HR (95% CI)1.000.90 (0.80-1.03)0.88 (0.78-1.00)0.72 (0.62-0.83) Citation Format: Erikka Loftfield, Susan Mayne, Fatma Shebl, Neal Freedman, Barry Graubard, Rashmi Sinha. Prospective study of coffee drinking and risk of melanoma in the United States. [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 LB-280. doi:10.1158/1538-7445.AM2014-LB-280

Background: In China, esophageal cancer is the fourth leading cause of cancer death and essentially all cases are histologically esophageal squamous cell carcinoma (ESCC). Agnostic pathway-based analyses applied to GWAS data can identify biological pathways and/or groups of genes enriched with disease-associated variants whose individual effect sizes may be too small to be detected by standard single locus methods. Methods: We used the adaptive rank-truncated product (ARTP) method to analyze 1,827 pathways containing 69,420 genes in GWAS data from 1942 ESCC cases and 2111 controls with Chinese ancestry. Pathways were retrieved from five databases: KEGG, BioCarta, Reactome, HumanCys and NCI-Nature curated. Statistical significance was determined by permutation. Results: Associations with ESCC risk (P Citation Format: Paula L. Hyland, Han Zhang, Qi Yang, Shih-Wen Lin, Dennis Maeder, Nan Hu, Ze-Zhong Tang, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Jin-Hu Fan, You-Lin Qiao, William Wheeler, Carol Giffen, Laurie Burdett, Zhaoming Wang, Stephen J. Chanock, Sanford M. Dawsey, Neal D. Freedman, Christian C. Abnet, Alisa M. Goldstein, Kai Yu, Philip R. Taylor. Pathway analysis of genome-wide association study data highlights taste transduction and metabolic pathways and esophageal squamous cell carcinoma susceptibility. [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 2203. doi:10.1158/1538-7445.AM2014-2203

PURPOSE: Several observational studies and multinutrient interventional trials suggest that selenium compounds have potential chemopreventive effects on esophageal and gastric carcinogenesis, presumably via their influence on selenoproteins. We aimed to investigate associations between genetic variants in selenoprotein genes and risk of esophageal squamous cell carcinoma (ESCC), gastric carcinoma (GC) and GC subsets: cardia (GCA) and non-cardia (GNCA) using data from a genome-wide association study in a Han Chinese population in which ESCC and GC are predominant cancers. METHODS: 1944 ESCC cases, 1758 GC cases (1126 GCA and 632 GNCA) and 2111 controls from the Shanxi Upper GI Cancer Genetics project and the Linxian Nutritional Intervential Trials were genotyped for 243 SNPs in 24 selenoprotein genes. Logistic regression models were applied to evaluate SNP-level associations. Pathway- and gene-level associations were determined using the resampling-based adaptive rank-truncated product approach. RESULTS: Selenoproteins as a whole pathway were not significantly associated with ESCC (p=0.398) or GC (p=0.608), but five significant (p Citation Format: Sharon Li, Paula L. Hyland, Neal D. Freedman, Nan Hu, Hua Su, Lemin Wang, Chaoyu Wang, Ti Ding, Yuan Wang, Jin-Hu Fan, You-Lin Qiao, Xiaoqin Xiong, Kai Yu, Alisa M. Goldstein, Sanford M. Dawsey, Philip R. Taylor, Christian C. Abnet, Shih-Wen Lin. Genetic variants in selenoprotein genes and risk of esophageal squamous cell carcinoma and gastric cancer in a Chinese population. [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 2206. doi:10.1158/1538-7445.AM2014-2206

Objectives: Esophageal cancer is the fifth leading cause of cancer death worldwide. The five-year survival is approximately 16%. Patients can be successfully treated if diagnosed early, but current early detection screening tests are inadequate. Balloon cytology is a simple and inexpensive method of retrieving esophageal cells, but traditional cytologic examination of these cells has poor sensitivity and specificity. We examined whether telomere length, a marker for chromosomal instability, in DNA extracted from balloon cytology-collected esophageal cells is associated with precursor lesions of esophageal squamous cell carcinoma. Methods: The Cytology Sampling Study 2, a population-based esophageal cancer early detection screening study, recruited over 700 healthy subjects from a high-risk population in Linxian, China. The screening study used a mesh-covered balloon to collect esophageal cells. All subjects underwent endoscopy, and precursor lesions were diagnosed by biopsy. Using a nested case-control study design, we examined the association between telomere length and dysplasia in 37 low-grade dysplasia cases, 52 high-grade dysplasia cases, and 92 matched controls. DNA was extracted from cells collected by balloon cytology, and telomere length was measured in triplicate by a quantitative PCR assay. Logistic regression models adjusted for age, sex, smoking tobacco, alcohol intake, and hypertension were used to examine the association between telomere length and risk of low-grade dysplasia and high-grade dysplasia, compared with normal controls. Results: Telomere lengths were comparable among the low-grade dysplasia cases, high-grade dysplasia cases, and controls, with a median of 0.93 [interquartile range (IQR), 0.84-1.06], 0.94 (IQR, 0.82-1.09), and 0.93 (IQR, 0.78-1.05), respectively. Overall, telomere length was not associated with risk of low-grade dysplasia or high-grade dysplasia, with an odds ratio [OR, 95% confidence interval (CI)] of 1.16 (0.87-1.54) and 1.20 (0.92-1.56), respectively. Conclusions: Given that esophageal cancers have very poor prognoses, it is of utmost importance to improve early detection. In this study, esophageal cell telomere length was not associated with esophageal precursor lesions and cannot serve as an early detection marker. Citation Format: Shih-Wen Lin, Christian C. Abnet, Neal D. Freedman, Rosana Risques, Donna Prunkard, Peter Rabinovitch, Ning Lu, You-Lin Qiao, Sanford M. Dawsey. Measuring telomere length for the early detection of precursor lesions of esophageal squamous cell carcinoma. [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 1165. doi:10.1158/1538-7445.AM2013-1165

Digestive system cancers include cancers of the oral cavity, esophagus, stomach, pancreas, liver, gallbladder, small intestine, colon and rectum, making it the second organ system most commonly affected by cancers in the world. These cancers are among the deadliest cancers worldwide. Gallstones (GS) can lead to inflammation and trauma (which are positively associated with cancer development) in digestive system organs adjacent to the gallbladder. However, the association between gallstones and digestive system cancers outside of the biliary tract has not been well established, especially in the presence of cofounders, such as obesity, physical activity, and alcohol consumption. Cholecystectomy (CH), the most common treatment for GS, can ameliorate inflammation, but has been shown to increase the exposure of the stomach the small intestine to bile. We hypothesized that GS and CH are differentially associated with cancers of the digestive system outside of the biliary tract. Within the National Institutes of Health-AARP Diet and Health Study (n=487,207) we used Cox proportional hazards regression models adjusted for age, gender, race, smoking, alcohol consumption, body mass index, caloric intake, physical activity, and non-steroidal anti-inflammatory drugs intake to investigate GS (n=30,674) and CH (n=25,457) in relation to cancers of the oral cavity (n=1,004), esophagus (adenocarcinoma n=392 and squamous cell carcinoma n=138), stomach (cardia n=264 and non-cardia n=292), small intestine (n=192), colon (n=3,865), rectum (n=1,410), pancreas (n=1,268), and liver (n=414). GS were associated with liver cancer [Hazard Ratio = 1.80 (95% confidence interval = 1.37, 2.37)], while CH was not [1.43 (0.83, 2.48)]. In contrast, CH was associated with non-cardia gastric cancer [2.67 (1.45, 4.90)], colon cancer [1.45 (1.29, 1.63)], and esophageal adenocarcinoma [1.74 (1.02, 2.97)] while GS were not [1.31 (0.90, 1.90), 1.06 (0.95, 1.18), and [1.16 (0.81, 1.65)], respectively]. CH was also associated with pancreatic [1.99 (1.49, 2.66)] and small intestine cancer [2.61 (1.61, 4.23), as was GS [1.19 (1.00, 1.43) and 1.61 (1.07, 2.42), respectively]. Neither GS nor CH was associated with oral cavity cancers, esophageal squamous cell carcinoma, or rectal cancer. A major strength of this large study was the ability to adjust for important cancer risk factors, including tobacco smoking, alcohol intake, and obesity. Nonetheless, future studies are needed to replicate our findings and establish the underlying mechanisms responsible for the identified associations. Citation Format: Leticia Nogueira, Amanda Cross, Neal Freedman, Gabriel Lai, Felipe Castro, Jill Koshiol. Gallstones, cholecystectomy, and risk of digestive system cancers. [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 4804. doi:10.1158/1538-7445.AM2013-4804 Note: This abstract was not presented at the AACR Annual Meeting 2013 because the presenter was unable to attend.

Background: The association between body size and head and neck cancers has not been well understood, partly because of the biases in case-control studies (such as reverse causation due to pre-diagnosis weight loss and use of recalled weight), and partly because of the difficulties in adjusting for confounders such as tobacco smoking. The only published cohort study on this relationship showed reduced mortality, but not incidence, among overweight and obese people, which was only significant among smokers. Methods: In the prospective NIH-AARP cohort study, 218,854 participants (132,288 men and 86,566 women) aged 50-71, were cancer-free at baseline, and had valid data on weight, height, and waist and hip circumference. Cox proportional hazards regression was used to examine the associations between overall (BMI) and abdominal (waist and waist-to-hip ratio) body size and head and neck cancers (squamous cell carcinomas of the oral cavity, oro-and hypopharynx, larynx, and nasopharynx). The analyses were adjusted for confounders, among them current and past smoking habits, alcohol intake, education, race and fruit and vegetable consumption. Additional analyses were also done separately among never- and ever-smokers. Results: During follow-up from the study baseline (1995 and 1996) to 31 December 2006, a total of 779 incident head and neck cancers accrued to the cohort, including 342 in the oral cavity, 120 in the oro- and hypo-pharynx, 265 in the larynx, 12 in the nasopharynx, and 40 in more than one site. Overweight (BMI 25-30) was associated with a decreased risk of the overall head and neck cancer incidence (HR: 0.83; 95%CI 0.70-0.97). Among never-smokers, total head and neck cancer incidence was not associated with BMI, while in ever-smokers, having a BMI over 35 was associated with a lower risk (HR: 0.42; 95%CI: 0.21-0.83), adjusted for the number of past and current cigarettes smoked. Oro-and hypo-pharyngeal cancers showed an increased risk among lean people (BMI< 18.5 versus normal; HR: 4.32; 95CI: 1.53-12.18). For oro- and hypo-pharyngeal cancers, leanness increased the risk both in ever and never-smokers. Waist circumference and waist-to-hip ratio did not show significant associations with any of the cancer sites studied. Conclusion: This is the first prospective study to show that overall (but not abdominal) obesity was associated with a lower risk of incident head and neck cancers, especially among smokers. Risk of oro- and hypopharyngeal cancers showed an inverse association with BMI, irrespective of smoking habits, which may be due to their stronger link to HPV infection rather than smoking. Citation Format: Arash Etemadi, Mark G. O'Doherty, Neal D. Freedman, Albert R. Hollenbeck, Sanford M. Dawsey, Christian C. Abnet. A prospective cohort study of body size and risk of head and neck cancers in the NIH-AARP Diet and Health Study. [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 2529. doi:10.1158/1538-7445.AM2013-2529

Background Diet may affect esophageal and gastric cancer risk, but associations have been inconsistent. Due to the complexity of the diet, studies of dietary patterns may elucidate the associations between diet and cancer better than studies of individual foods. Yet, studies evaluating the association between index-based dietary patterns and incident esophageal and gastric cancers have been sparse. Objectives We aimed to prospectively evaluate the association between two diet quality indices, the Healthy Eating Index-2005 (HEI-2005) and the alternate Mediterranean Diet Score (aMED), and risk of esophageal and gastric cancers in the United States. Methods In sum, 494,968 participants from the National Institutes of Health-AARP Diet and Health study completed a self-administered baseline food frequency questionnaire which was used to estimate scores for each index. Results During the follow-up (1995-2006), we documented 215 esophageal squamous cell carcinomas (ESCC), 633 esophageal adenocarcinomas (EAC), 453 gastric cardia adenocarcinomas, and 501 gastric noncardia adenocarcinomas. Higher scores in the HEI-2005, reflecting healthy eating patterns, were associated with a reduced risk of ESCC (the highest quintile compared to lowest: hazard ratio (HR) =0.51, 95% confidence interval (CI): 0.31-0.86, Ptrend =0.001), and EAC (HR=0.75, 95% CI: 0.57-0.98, Ptrend=0.01). We observed an inverse association of ESCC with higher diet quality as assessed by aMED, but not for EAC. No significant associations for gastric cardia or noncardia adenocarcinomas were found with either HEI-2005 or aMED. Conclusions In this prospective study, the HEI-2005 was inversely associated with risk of both ESCC and EAC, while the aMED was associated with reduced risk of ESCC, suggesting that adherence to dietary recommendations may help prevent esophageal cancer. Citation Format: Wen-qing Li, Yikyung Park, Jennifer W. Wu, Jian-song Ren, Alisa M. Goldstein, Philip R. Taylor, Albert R. Hollenbeck, Neal D. Freedman, Christian C. Abnet. Index-based dietary patterns and risk of esophageal cancer and gastric cancer in the NIH-AARP diet and health study. [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 4805. doi:10.1158/1538-7445.AM2013-4805

Background: Glioma is a relatively uncommon and highly fatal malignancy with few known risk factors. Alcohol consumption and cigarette smoking are associated with an increased risk of several types of cancer, but whether these exposures are related to the risk of glioma remains unclear. Methods: We prospectively examined the relationship between cigarette smoking, alcohol intake, and risk of glioma in the National Institutes of Health-AARP Diet and Health Study, a large prospective cohort of 477,095 U.S. men and women between the ages of 50-71 years. Hazard ratios (HRs) and 95% confidence intervals (CIs) for glioma risk according to alcohol intake (total alcohol, beer, wine, and liquor) and smoking status, intensity, and, among former smokers, time since quitting were calculated using models adjusted for sex, education, marital status, and race/ethnicity. Results: During a median 10.5 person-years of follow-up, 492 men and 212 women were diagnosed with glioma. Among men, current, heavier (>20 cigarettes per day) smoking was associated with a reduced risk of glioma compared to never smoking (HR=0.40, 95% CI: 0.21-0.79). Men who quit smoking 2 drinks per day versus 2 drinks per day versus Conclusions: Among men, current, heavy cigarette smoking and greater alcohol, particularly beer, consumption were inversely associated with the risk of glioma. Pooled analyses of prospective studies are needed to investigate more precisely the potential influence of these exposures on glioma risk. Citation Format: Melissa Z. Braganza, Preetha Rajaraman, Yikyung Park, Peter D. Inskip, Neal D. Freedman, Amy Berrington de González, Cari M. Kitahara. Are alcohol drinking and cigarette smoking related to risk of glioma? A large prospective U.S. cohort study. [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 2516. doi:10.1158/1538-7445.AM2013-2516

Chromosome 9p21 has been implicated in the pathogenesis of cutaneous malignant melanoma (CMM), glioma, non-small cell lung cancer, and leukemia. This region includes cyclin-dependent kinase inhibitor 2A (CDKN2A), the major known high-risk susceptibility gene for CMM; CDKN2B; antisense noncoding RNA in the INK4 locus (ANRIL), a GWAS hotspot for multiple phenotypes including cancers; methylthioadenosine phosphorylase (MTAP), a gene with tumor suppressor function and a cluster of type I interferon (IFN) genes. The goal of this study was to examine the association between genetic variation in the 9p21 region and multiple cancer outcomes using genotyping data from studies participating in the National Cancer Institute's (NCI) iSelect project. We evaluated up to 202 tagSNPs in 22 genes in the 9p21 region (19.9-32.8 Mb), in case-control studies of thyroid cancer (THC), endometrial cancer (EC), testicular cancer (TC), renal cell carcinoma (RCC), colorectal cancer (CRC), colorectal adenoma (CA), esophageal squamous cell carcinoma (ESCC), gastric cardia cancer (GCC) and osteosarcoma (OS). The number of cases in each of the nine studies ranged from 96 to 1234. We first performed single SNP-based analyses for each study separately, using logistic regression adjusted for age and study-specific covariates. To combine SNP based analyses, we used a newly developed subset-based statistical approach (ASSET), which allow for heterogeneity of SNP effect on different outcomes. This approach exhaustively explores subsets of studies for the presence of association signals, and then evaluates the significance from subsets with the strongest association signal, meanwhile accounting for multiple tests required by the subset search. Gene based P-values were computed using an adaptive rank truncated product (ARTP) statistic and a permutation-based sampling procedure (10,000 permutations) that took into account the numbers of SNPs in each gene and their linkage disequilibrium structure. When analyzing each study separately, we found that a SNP (rs3731257) in CDKN2A was significantly associated with the risk of ESCC after Bonferroni correction for number of SNPs and studies (P=7 x 10-6). Meta-analyses by ASSET found that this SNP was significantly associated with both ESCC and EC (PASSET 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 LB-330. doi:1538-7445.AM2012-LB-330

Objectives: Both iron overload and iron deficiency cause oxidative stress and DNA damage, which increase carcinogenesis risk, especially in the gastrointestinal (GI) tract. In animal models, iron overload causes forestomach tumors, and in epidemiologic studies, high heme iron intake is associated with some upper GI cancers. Hemochromatosis, which results in excessive iron absorption in the GI tract, is also associated with GI cancer. The mechanism of increased cancer risk may involve the impairment of iron-dependent metabolic functions related to genome protection and maintenance. Genetic variants of genes with iron-dependent metabolic functions may confer differential GI cancer risk. Therefore, we comprehensively examined the genetic variants of these genes and risk of esophageal squamous cell carcinoma (ESCC) and gastric cardia adenocarcinoma (GCA) in a high-risk population in China. Methods: We genotyped 249 tag single nucleotide polymorphisms (SNPs) in 23 genes with known iron-dependent metabolic function in 1027 ESCC cases and 752 GCA cases plus 1452 controls from two epidemiologic studies in a high-risk region in China. For all genes as a single pathway and each gene individually, we calculated summary p-values using the adaptive rank truncated product (ARTP) method. For SNPs, logistic regression models were used to estimate odds ratios (OR) and 95% confidence intervals (CI). Results: In pathway-based tests, the iron pathway was not associated with either ESCC (p=0.320) or GCA (p=0.550). However, in gene-based tests, HMOX2 (heme oxygenase 2, p=0.018) and BMP2 (bone morphogenetic protein 2, p=0.032) were associated with ESCC risk, and IREB2 (iron-responsive element binding protein 2, p=0.033) was associated with GCA risk. In SNP-based tests, RS235756 (OR=0.78, CI=0.66-0.91) and RS910141 (OR=0.76, CI=0.63-0.93) tagged to BMP2 (linkage disequilibrium of pairwise r2=0.55) were associated with ESCC risk. RS6500609 (OR=1.30, CI=1.08-1.57) tagged to HMOX2 was also associated with ESCC risk. RS12910090 (OR=0.83, CI=0.72-0.94) and RS2568500 (OR=0.83, CI=0.73-0.95) tagged to IREB2 (r2=0.90) were associated with GCA risk. RS11630228 (OR=1.21, CI=1.06-1.38) also tagged to IREB2 (r2 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 2632. doi:1538-7445.AM2012-2632

Objective: Incidence rates for diabetes and cancer are increasing globally. Epidemiologic studies have observed increased risk between diabetes and several cancers, including breast, colorectal, liver, and pancreatic. Yet, the association between diabetes and other cancers remains unclear. Thus, we evaluated the association between diabetes and cancer incidence and mortality in the prospective NIH-AARP Diet and Health Study. Methods: Our analysis included 295,287 men and 199,665 women who resided in one of eight states (CA, FL, GA, LA, MI, NC, NJ, and PA) at baseline (1995-1996). Diabetes was assessed by self-report. Hazard ratios and 95% confidence intervals were estimated from Cox proportional hazards models adjusted for age, education, BMI, smoking status, self-reported health status, physical activity, vitamin supplement use, intake of alcohol, fruits, vegetables and meat, family history of cancer, and among women, menopausal hormonal therapy. Results: After 11 years of follow-up, 55,888 men and 26,364 women were diagnosed with incident cancer; 13,037 men and 6,474 women died of cancer. We observed a modest inverse association between diabetes and total incident cancer in men (HR=0.96, 95% CI: 0.93-0.99) and a modest positive association in women (1.06, 1.02-1.12). Inverse associations in men stemmed from prostate cancer (n=23,483 cases, 42% of incident cancers; 0.75, 0.71-0.79). After excluding prostate cancer, diabetes became positively associated with cancer in men (1.08, 1.05-1.12). For total cancer mortality, we observed a positive association in men (1.20, 1.14-1.27) and women (1.15, 1.05-1.26). Associations were similar for cancers occurring during the first year, years 1 to 5, and years 5 to 11 of follow-up. When evaluated by site, diabetes was positively associated with cancers of the colon (1.15, 1.04-1.28; 1.33, 1.13-1.55), rectum (1.28, 1.08-1.51; 1.45, 1.10-1.91), and liver (2.40, 1.90-3.02; 1.90, 1.16-3.10) in both men and women. In men, diabetes was positively associated with cancers of the pancreas (1.47, 1.24-1.75) and urinary bladder (1.10, 1.01-1.20); risk estimates for these cancers were similar in women but not statistically significant. In women, diabetes was positively associated with cancers of the stomach (1.74, 1.14-2.67), anus (2.44, 1.18-5.02), and corpus and uterus (1.20, 1.01-1.41); the risk estimate for stomach cancer was similar in men but not statistically significant. We observed no association between diabetes and lung (1.02, 0.94-1.10; 0.97, 0.85-1.10), skin (0.99, 0.88-1.11; 0.97, 0.76-1.24), or other cancers. Discussion: Diabetes was associated with lower rates of incident prostate cancer in men, but with higher incidence rates for a number of other cancers in both sexes. Diabetes was also associated with higher cancer mortality rates. Our results suggest that preventing or controlling diabetes may contribute to decreased cancer incidence and mortality. 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 947. doi:10.1158/1538-7445.AM2011-947

INTRODUCTION: Previous research has noted that cancer mortality rates are higher for males than females, but no extensive analysis of this has been conducted. We wanted to study the extent of sex disparities in cancer mortality and if these disparities persist after adjustment for characteristics of the person and cancer. METHODS: We extracted U.S. vital statistics mortality data and cancer incidence and survival data from the SEER*Stat system for 36 cancers and undertook age-adjusted mortality rates and survival analyses. For the age-adjusted mortality rate analyses we extracted mortality count, person-years, and mortality rate per 100,000 for each cancer, stratified by sex and age for the period 1977-2006. Male-to-female mortality rate ratios (MRRs) were calculated. For each cancer, we plotted sex-specific mortality rates and male-to-female MRRs. For the survival analyses, we extracted patient id, age and date of diagnosis, sex, primary site, stage, grade, survival time, vital status and cause of death. Relative hazards for the 5-year period following diagnosis were estimated from Cox proportional hazard models adjusted for age, stage, grade, and year of diagnosis. RESULTS: For the vast majority of cancers, age-adjusted mortality rates were higher among males than females; the 5 cancers with the highest male-to-female MRR were lip (5.51, 95% confidence interval (CI):5.05-6.03), larynx (5.37, 95%CI:5.29-5.45), hypopharynx (4.47, 95%CI:4.30-4.65), esophagus (4.08, 95%CI:4.05-4.11) and urinary bladder (3.36, 95%CI:3.34-3.39). Only 3 cancers had a higher mortality rate among females than males: peritoneum, omentum and mesentery (MRR=0.39, 95%CI:0.38-0.41); gallbladder (0.56, 95%CI:0.55-0.57); and anus, anal canal and anorectum (0.78, 95%CI:0.75-0.81). The survival analyses indicated that males had a significantly increased risk of death, relative to females, for the cancers: anus, anal canal and anorectum (hazard ratio: 1.21, 95%CI:1.03-1.44); colon and rectum (1.08, 95%CI:1.07-1.09); floor of mouth (1.29, 95%CI:1.04-1.59); larynx (1.09, 95%CI:1.01-1.18); liver and intrahepatic bile duct (1.20, 95%CI:1.14-1.26); lung and bronchus (1.19, 95%CI:1.17-1.20); pancreas (1.06, 95%CI:1.03-1.08); small intestine (1.16, 95%CI:1.04-1.29); and soft tissue including heart (1.12, 95%CI:1.03-1.21). Females had higher mortality risks for the cancers tongue (0.87, 95%CI:0.81-0.94) and urinary bladder (0.83, 95%CI:0.81-0.86). DISCUSSION: Male cancer mortality rates were higher than equivalent female rates for the majority of cancers studied. Moreover, males also had higher risk of cancer mortality following diagnosis, relative to females, for many cancers even after adjustment for age of diagnosis, stage, grade and year of diagnosis. These observations indicate that there are sex differences in exposure and/or endogenous metabolic processes which modify risk of both cancer incidence and cancer mortality following diagnosis. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 1834.

Previous studies have shown moderate drinking of alcohol to be inversely related to heart disease but heavy drinking directly associated with some cancers and other chronic diseases. Moreover, there has been some question about whether the relation between alcohol and health differs by sex. We therefore investigated alcohol consumption in relation to both total and cause-specific mortality in the National Institutes of Health (NIH)-AARP Diet and Health study, a large prospective cohort of men and women. The NIH-AARP study recruited over 500,000 men and women, 50-71 years old and living in one of eight states in 1995-96. At baseline, we assessed diet including alcohol with a food frequency questionnaire and collected information on demographics, lifestyle, and medical history. Vital status and specific causes of death were ascertained through a periodic linkage of the cohort to the Social Security Administration Death Master File and the National Death Index Plus. We estimated relative risks (RR) and 95% confidence intervals using Cox proportional hazards models adjusting for age, race, body mass index, marital status, self-rated health status, physical activity, smoking status, time since quitting smoking, smoking dose, aspirin use, menopausal hormone therapy use in women, and intakes of red meat and total energy. After excluding participants with prevalent cancer and chronic diseases, the analytic cohort consisted of 218,953 men and 168,660 women. During an average of 9 years of follow-up, we identified a total of 20,081 deaths in men and 11,246 deaths in women. 18% of the men and 26% of the women did not drink alcohol, whereas 12% of the men drank 3+ drinks/day and 5% of women drank 2+ drinks/day. In men, compared to 2-0- In conclusion, the effect of alcohol on mortality may differ by sex, disease and the amount consumed. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 2808.

Introduction: Epidemiologic studies have consistently shown an association between alcohol use and invasive postmenopausal breast cancer. Experimental data suggest that alcohol intake increases risk of breast cancer through its effect on estrogen, but observational studies of the association between alcohol use and breast cancer according to hormone receptor status have been sparse and inconsistent. In this context, we investigated if the relation between alcohol and breast cancer differed by hormone receptor status in postmenopausal women. Methods: We analyzed 184,418 postmenopausal women (mean baseline age of 62 years) in the prospective NIH-AARP Diet and Health Study. At baseline, we assessed alcohol and other nutrient intakes with a food frequency questionnaire, and collected data on demographics, lifestyle, and medical history. We used Cox proportional hazards models to calculate relative risks (RR) and 95% confidence intervals (CI), adjusting for age, race, height, body mass index (BMI), physical activity, smoking history, parity, age at first birth, age at menopause, family history of breast cancer, frequency of breast biopsy, hormone replacement therapy (HRT) use, and intakes of fat, folate and energy. Results: During an average of 7 years of follow-up, we identified 5,461 invasive breast cancer cases. 2,391 cases had hormone receptor status information: 1,641 ER+/PR+ cases, 366 ER-/PR-, 336 ER+/PR-, and 48 ER-/PR+ cases. 30.0% of women did not drink alcohol; the mean alcohol intake among drinkers was 8.2g/day (10th-90th percentile = 0.4-20.1 g/day). Alcohol was associated with increased risk of breast cancer: compared to no alcohol, the multivariate RR(95% CI) for 45g/day of intake, were 1.04 (0.98-1.11), 1.05 (0.93-1.17), 1.14 (1.03-1.26), 1.25 (1.09-1.42), 1.32 (1.00-1.74), 1.38 (1.17-1.62) ( p for trend Conclusion: Alcohol consumption, even at moderate levels, increased the risk of breast cancer. This positive association was largely confined to ER+/PR+ tumors.