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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 Higher intake of whole grain and dietary fiber has been associated with lower risk of insulin resistance, hyperinsulinemia, and inflammation, which are known predisposing factors for hepatocellular carcinoma (HCC). To our knowledge, no epidemiological study has yet examined the association between whole grain intake and HCC risk. Therefore, we hypothesized that long-term intake of whole grain and dietary fiber may be associated with lower risk of developing HCC. Methods We tested this hypothesis by utilizing data from two large U.S. prospective cohorts, the Nurses’ Health Study and Health Professionals Follow-up Study. Intake of whole grain and its subcomponents (bran and germ), and dietary fiber (cereal, fruit, and vegetable) were collected and updated almost every 4 years using validated food frequency questionnaires. Time-varying Cox proportional hazards regression model was utilized to estimate hazard ratios (HRs) and 95% confidence intervals (CIs) of of HCC by tertiles of energy-adjusted whole grain and fiber, after adjusting for sex, race, age, body mass index, alcohol drinking, smoking, physical activity, regular aspirin use, and type 2 diabetes. Results During up to 32 years of follow-up, we identified a total of 141 incident HCC cases. Higher whole grain intake was significantly associated with lower risk of HCC (the highest versus lowest tertile intake, HR=0.63, 95% CI: 0.41-0.96, Ptrend=0.04). A suggestive inverse HCC association was found for total bran (HR=0.70, 95% CI: 0.46-1.07, Ptrend=0.11), but not for germ. After mutual adjustment for bran and germ, the inverse association between total bran and HCC persisted (HR=0.66, 95% CI: 0.41-1.07, Ptrend=0.13). Increasing intake of cereal fiber (HR=0.68, 95% CI: 0.45-1.03, Ptrend=0.07), but not fruit or vegetable fiber, was also suggestively associated with reduced risk of HCC. In sensitivity analyses, the results did not materially change after excluding HCC cases with hepatitis B or C virus infections. In addition, we observed similar inverse associations for whole grain, bran and germ, or dietary fiber with risk of HCC subtypes by history of cirrhosis (i.e., cirrhotic versus non-cirrhotic HCC). Conclusions Intake of whole grains, cereal fiber, and bran could be associated with reduced risk of HCC among U.S. adults. Future studies that carefully consider hepatitis B and C virus infections are needed to replicate our findings, to examine these associations in other racial or high-risk populations, and to elucidate the underlying mechanisms. Citation Format: Wanshui Yang, Yanan Ma, Yue Liu, Smith-Warner Stephanie, Tracey G. Simon, Dawn Chong, Jeffrey A. Meyerhardt, Edward L. Giovannucci, Andrew T. Chan, Xuehong Zhang. Intake of whole grain and dietary fiber and risk of hepatocellular carcinoma among U.S. adults [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 2680.

Worldwide, hepatocellular carcinoma (HCC) is the fifth most common cancer and the second-leading cause of cancer-related death worldwide. In the U.S., the incidence rate of HCC has tripled since 1975. Although preliminary evidence suggesting a biological impact of diet on multiple inflammatory pathways implicated in hepatocarcinogenesis, the most comprehensive review by the WCRF/AICR concluded that the relationship between diet and HCC remains largely unknown. HCC is an inflammation-related cancer but few studies have investigated diet quality based on its inflammatory potential in relation to HCC risk. The empirical dietary inflammatory pattern scores (EDIP) score were calculated from validated food frequency questionnaires. It characterized dietary inflammatory potential based on circulating levels of inflammatory bio-markers. We prospectively followed 49,674 men in the Health Professionals Follow-up Study (1986-2012), and 74,139 women in the Nurses' Health Study (1984-2012). Cox regression analyses were used to calculate hazards ratios (HR) for HCC risk adjusting for body mass index, smoking, history of diabetes, race, physical activity, and regular aspirin use. We documented a total of 89 incident HCC cases (44 in women and 45 in men) over 28 years, encompassing 1,522,972 person-years of follow-up. Compared to the lowest tertile, the highest tertile of the EDIP score was associated with a multivariable HR for HCC of 2.86 (95%CI, 1.20-6.81) among women (P-trend=0.01) and of 0.68 (95%CI, 0.31-1.50) among men (P-trend=0.35). Future study is warranted to confirm this finding and elucidate the potential biological basis. Key words: inflammation, dietary patterns, HCC A. T. C. and X. Z contributed equally to this work. Citation Format: Yanan Ma, Tracey G. Simon, Fred K Tabung, Lindsay Y. King, Dawn Q. Chong, Long Nguyen, Trang VoPham, Charles S. Fuchs, Jeffrey A. Meyerhardt, Kathleen E. Corey, Hamed Khalili, Stephanie Smith-Warner, Raymond T. Chung, Edward L. Giovannucci, Andrew T. Chan, Xuehong Zhang. A prospective study of inflammatory diet potential and risk of hepatocellular carcinoma (HCC) [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 5256.

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