Gallstones may result in inflammation, altered bile flow, and changes in metabolic hormone levels, thereby increasing cancer risk. However, previous studies for gallstones and cancers of the

liver, biliary tract and pancreas in the U.S. were relatively limited.

We followed 115,036 women from the Nurses’ Health Study (1982–2012) and 49,729 men from the Health Professionals Follow-up Study (1986–2012). History of gallstones, including with or without

performed cholecystectomy, was reported at baseline and updated through biennial questionnaires. The Cox proportional hazard regression model was used to calculate multivariable hazard

multivariable HRs for individuals with gallstones (untreated or with cholecystectomy) were 1.60 for liver cancer (95% CI: 1.14–2.26), 4.79 for biliary tract cancer (95% CI: 3.02–7.58), and

1.13 for pancreatic cancer (95% CI: 0.96–1.32). The multivariable HRs for individuals with cholecystectomy were 1.33 for liver cancer (95% CI: 0.90–1.95) and 1.15 for pancreatic cancer (95%

CI: 0.98–1.36).

Gallstones were associated with a higher risk of cancers of the liver, biliary tract and possibly pancreas.

Restrictions apply to the availability of these data, which were used under license for this study. Data are available [https://sites.google.com/channing.harvard.edu/cohortdocs/] with the

permission of BWH and Harvard T.H. Chan School of Public Health.

We would like to thank the participants and staff of the NHS and the HPFS for their valuable contributions as well as the following state cancer registries for their help: AL, AZ, AR, CA,

CO, CT, DE, FL, GA, ID, IL, IN, IA, KY, LA, ME, MD, MA, MI, NE, NH, NJ, NY, NC, ND, OH, OK, OR, PA, RI, SC, TN, TX, VA, WA and WY. The authors assume full responsibility for the analyses and

interpretation of these data.

The HPFS and NHS were supported by the NCI at the NIH (grant numbers UM1 CA186107, P50 CA127003, P01 CA87969 and U01 CA167552). This work was supported by NIH grants (K07 CA188126 to XZ, and

R21 CA238651 to XZ). XZ is also supported by the American Cancer Society Research Scholar Grant (RSG NEC-130476), NIH/NCI The Method to Extend Research in Time MERIT Award (R37 CA262299),

Dana-Farber Harvard Cancer Center (DF/HCC), as well as Zhu Family Center at Harvard T.H. Chan School of Public Health. The content is solely the responsibility of the authors and does not

necessarily represent the official views of NIH. The funders had no role in study design, data collection and analysis, decision to publish or preparation of the manuscript.

Department of Nutrition, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Xiao Luo, Kana Wu, Xing Liu, Edward L. Giovannucci & Xuehong Zhang

Department of Health Statistics, School of Public Health, China Medical University, Shenyang, Liaoning, P. R. China

Channing Division of Network Medicine, Department of Medicine, Brigham and Women’s Hospital and Harvard Medical School, Boston, MA, USA

Wanshui Yang, Amit D. Joshi, Lina Jin, Lu Long, Andrew T. Chan, Edward L. Giovannucci & Xuehong Zhang

School of Public Health, Anhui Medical University, Hefei, Anhui, P. R. China

Liver Center, Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Boston, MA, USA

Division of Gastroenterology, Department of Medicine, Massachusetts General Hospital, Harvard Medical School, Boston, MA, USA

Clinical and Translational Epidemiology Unit (CTEU), Massachusetts General Hospital, Boston, MA, USA

Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School, Boston, MA, USA

Department of Epidemiology and Biostatistics, Jilin University School of Public Health, Changchun, Jilin, P. R. China

Department of Epidemiology and Biostatistics, West China School of Public Health and West China Fourth Hospital, Sichuan University, Sichuan, P. R. China

Division of Gastroenterology, Department of Internal Medicine, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea

Laboratory of Clinical Epidemiology in Hepatology, CHA Bundang Medical Center, CHA University School of Medicine, Seongnam, Korea

Department of Epidemiology, School of Public Health, Fudan University, Shanghai, P. R. China

Department of Epidemiology, Harvard T.H. Chan School of Public Health, Boston, MA, USA

Drs. Luo and Zhang had full access to all the data in the study and took. responsibility for the integrity of the data and the accuracy of the data analysis. Acquisition of the data: KW,

BMW, ATC, ELG and XZ. Analysis and interpretation of the data: XL. Drafting of the manuscript: XL. Critical revision of the manuscript for important intellectual content: all authors.

Statistical analysis: XL. Obtained funding: ELG and XZ. Administrative, technical or material support: KW, BMW, ATC, ELG and XZ. Study supervision: ELG and XZ.

This study was approved by the Institutional Review Boards of the Brigham and Women’s Hospital and the Harvard T.H. Chan School of Public Health and of participating registries as required.

Completion of the questionnaire was considered to imply informed consent.

Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.

Anyone you share the following link with will be able to read this content: