Biliary Tract Cancer: Risk Factors Bile ductAmpulla of Vater Gallbladder Female excess Obesity Parity Gallstones Inflammation Cholecystitis Genetics Typhoid? Helicobacter? Obesity Gallstones Cholangitis Infection Inflammation ?
Hsing et al. Int J Cancer 1998 Incidence Trends in Shanghai 1972-74 to 1993-94 2/100,000
8 What are the risk factors? Why are rates increasing? Research Questions
GeneticsInfectionsLifestyle Factors Main Hypotheses Shanghai Biliary Study
Shanghai Biliary Tract Cancer Study Interviews Body size Blood DNA Gallstones Bile Tissue Urine Abdominal ultrasound Shanghai 539 cancer cases 280 gallbladder 191 bile duct 68 ampulla of Vater 1,000 gallstone cases 1,000 population controls Biological Samples Case ascertainment >95% Response rate Cases >95% Controls 82% Population-Based
Shanghai Biliary Study GeneticsInfectionLifestyle factors Increased Risk Gallstones (Hsing et al. BJC 2007) Cholecystitis (Andreotti et al. 2010, Submitted) Liver cirrhosis (Hsing et al. IJC 2007) Obesity (Hsing et al. BJC 2008) Diabetes (Shebl et al. BJC 2010) Metabolic syndrome (Shebl et al. 2010, Submitted ) Parity (Andreotti et al. BJC 2010) Decreased Risk Aspirin use Tea drinking
GeneticsInfectionLifestyle Factors Increased Risk HBV (bile duct only, OR=2.4) Hsing et al. IJC 2008 No Association HCV Chronic typhoid Safaeian et al. CEBP (Submitted) Investigation Ongoing H. pylori Helicobacter sp. Shanghai Biliary Study (1.2-4.5) Bile duct HBV
Shanghai Biliary Study GeneticsInfectionLifestyle factors Family history of gallstones (Hsing et al. IJC 2007) Lipid metabolism (LPLR, APOE, ABCG8, etc.) (Andreotti et al. IJC 2008) Insulin signaling (PPAR, INS) (Chang et al. Carcinogenesis 2008) Hormone metabolism (ER, AR, CYP17, COMT, etc.) (Park et al. Carcinogenesis 2009) (Meyer et al. CEBP 2010) (Xu et al., Carcinogenesis 2010) Inflammation (PTGS2, IL8, TNF, VEGF, etc.) (Sakoda et al. Carcinogenesis 2006) (Hsing et al. Cancer Res 2008) Candidate SNP Candidate gene Candidate pathway iSelect GWAS
Inflammation OR 95% CI Gallstones 20.9 (14.2-31.8) Cholecystitis 1.7 (1.1-2.9) Gallstones/cholecystitis 34.3 (19.9-59.2) Liver cirrhosis 4.7 (1.9-11.7) Obesity 1.6 (1.2-2.1) Diabetes 2.5 (1.4-4.5) Metabolic syndrome 2.8 (1.8-4.1) Aspirin use 0.4 (0.2-0.9) HBsAg 2.4 (1.2-4.5) Serology Interview Data Genetic PTGS2, IL8, IL10, TNF, VEGF Shanghai Biliary Study
OR Gallstones Attributable Risk (%) 1% of gallstone patients develop gallbladder cancer Gallstones - necessary but not sufficient What’s Next? 90% 20% Cases Controls Prevalence of Gallstones
Biliary Tract Cancer: Opportunities International Consortium 19 studies from 12 countries (~2,000 cases and 5,000 controls) Pooled analysis to evaluate the role of cofactors GWAS Chile Gallbladder Study (proposed) 4,000 cases and 6,000 controls 90% 20% Larger N Cases Controls
Blood Interview Tissue 24-hour Urine 1,000-2,000 Gallstone cases 4,000-6,000 Population controls 4,000 Cases Anthropometry Chile Biliary Tract Cancer Study Study Design Clinical Trial
SS Antofagasta= 1 hospital 38 GBC deaths 0,79 % mapuches SS Valparaiso-San Antonio: 1 hospital 34 GBC deaths 1,12 % mapuches Santiago 3 hospitals SS del Lib.Bdo O´Higgins: 1 hospital 54 GBC deaths 1,17% mapuches SS del Maule: 1 hospital 102 GBC deaths 0,82 % mapuches Concepción SS Araucanía Sur: 1 hospital 96 GBC deaths 24,28 % mapuches Valdivia 80 cases 80 controls Chile Pilot Study Test Case recruitment Control selection Response rate Blood collection Blood processing Tissue collectio n
Acknowledgments E pidemiology Robert Hoover, M.D., NCI Lisa Chu, Ph.D., NCI Sabah Quraishi, M.P.H., NCI Tamra Meyer, Ph.D., DoD Christine Berg, M.D., NCI Alan Kristal, Ph.D., Fred Hutchinson Cancer Center Chris Haiman, Ph.D., USC Brian Henderson, M.D., USC Anand Chokkalingam, Ph.D., UC Berkeley Yu-Tang Gao, M.D., Shanghai Cancer Institute, China Richard Biritwum, M.D., University of Ghana Andrew Adjei, Ph.D., University of Ghana Pathology Isabel Sesterhenn, M.D., AFIP Angelo DeMarzo, M.D., Ph.D., JHU George Netto, M.D., JHU Yao Tetty, M.D., University of Ghana Urology Alan Partin, M.D., JHU Ian Thompson, M.D., University of Texas Edward Yeboah, M.D., University of Ghana Endocrinology Frank Stanczyk, Ph.D, USC Alain Belanger, Ph.D, Laval University Epidemiology Joseph F. Fraumeni, Jr., M.D., NCI Gabriella Andreotti, Ph.D., NCI Fatma Shebl, M.D., NCI Mahboobeh Safaeian, Ph.D., NCI Yu-Tang Gao, M.D., Shanghai Cancer Institute, China Pathology Asif Rashid, M.D., MD Anderson Cancer Center Ming-Chang Shen, M.D., Shanghai Tumor Hospital, China Gastroenterology Tian-Quinn Han, M.D., Raijin Hospital, Shanghai, China Bai-He Zhang, M.D., First Military Hospital, Shanghai, China Bin-Sheng Wang, M.D., Fudan University, Shanghai, China Virology/Microbiology Betty Conde, NCI-SAIC James Fox, DVM, MIT Torkel Wadstrom, Ph,D., Lund University, Sweden Genetics Stephen Chanock, M.D., NCI Juergen Reichardt, Ph.D., University of Sydney Jianfeng Xu, M.D., Ph.D., Wake Forest University Streamson Chu, M.D., Ph.D., Columbia University Statistics Phil Rosenberg, Ph.D., NCI Kai Yu, Ph.D., NCI Hong Zhang, Ph.D., NCI Jinbo Chen, Ph.D., University of Pennsylvania Cathy Tangen, Ph.D., Fred Hutchinson Cancer Center
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