Ann Hsing, Ph.D.
Biliary Tract Cancers
Hsing et al, Oxford University Press 2006
Biliary Tract Cancer Biliary Tract Cancer
•Rare cancer •Highly fatal •Etiology •Obscure•Three sub-sites – distinct
Age-adjusted Incidence, Worldwide
Shanghai
South and Central American
North American
Asia
Europe
Oceania
Hsing et al, Oxford University Press 2006
Chile
5
Gallbladder Cancer Incidence
Biliary Tract Cancer: Risk Factors Biliary Tract Cancer: Risk Factors
Bile duct Ampulla 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 Research Questions
Genetics Infections Lifestyle 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
Genetics Infection Lifestyle 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
Genetics Infection Lifestyle 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
1.32.4
1.2
1.2 1.2 1.4
1 1 1
Gallbladder ampulla ofVater
Negative
Anti-HBc
HBsAg
(1.2-4.5)
Bile duct
HBV
Shanghai Biliary Study
Genetics Infection Lifestyle 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
•HBsAg 2.4 (1.2-4.5)
Serology
Interview Data
Genetic •PTGS2, IL8, IL10, TNF, VEGF
Shanghai Biliary Study
OR Gallstones
4.28.1
23.8
1
10
100
Ampulla ofVater
Bile Duct Gallbladder
41
59
81
0
50
100
Ampulla ofVater
Bile Duct Gallbladder
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 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
17
Chile
Gallbladder Cancer
Pilot Study
18
US-Chile Gallbladder Study
•Highest gallbladder cancer incidence in the world
•Leading cause of cancer deaths in women
• Chile and NCI MOU
Rationale
19
6.0
8.0
10.0
12.0
14.0
16.0
18.0
20.0
ADJU
STED
DEA
TH R
ATES
/100
000 W
OM
EN
TOP CANCER KILLERS AMONG CHILEAN WOMEN
biliar &GBCervixBreast
Biliary Tract Cancer
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 hospital34 GBC deaths 1,12 % mapuches
Santiago 3 hospitals
SS del Lib.Bdo O´Higgins: 1 hospital54 GBC deaths 1,17% mapuches
SS del Maule: 1 hospital102 GBC deaths 0,82 % mapuches
Concepción
SS Araucanía Sur: 1 hospital96 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 collection
Acknowledgments Epidemiology 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., JHUYao Tetty, M.D., University of Ghana
Urology Alan Partin, M.D., JHUIan 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 CenterMing-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-SAICJames Fox, DVM, MITTorkel 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., NCIHong Zhang, Ph.D., NCI Jinbo Chen, Ph.D., University of PennsylvaniaCathy Tangen, Ph.D., Fred Hutchinson Cancer Center