SEARCH

SEARCH BY CITATION

Keywords:

  • biliary tract cancer;
  • cholelithiasis;
  • familial aggregation;
  • genetic susceptibility;
  • China

Abstract

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Cancers of the biliary tract arise from the gallbladder, extrahepatic bile ducts and ampulla of Vater. Although relatively uncommon, the incidence of biliary tract cancer rose more than 100% in Shanghai, China between 1972 and 1994. Gallstones are the predominant risk factor for biliary tract cancers, with over 60% of the cancer cases having gallstones. A familial tendency to gallstones has been reported and may elevate the risk of gallbladder cancer further. As part of a large population-based case–control study of biliary tract cancers in Shanghai, China, we examined the association between a family history of gallstones and biliary tract cancers as well as biliary stones. A total of 627 biliary tract cancers (368 gallbladder, 191 bile duct, 68 ampulla of Vater), 1,037 biliary stone cases (774 gallbladder, 263 bile duct) and 959 healthy subjects randomly selected from the population were included in this study. Information on family history of gallstones among first-degree relatives (i.e., parents, siblings, offspring) was obtained through a self-reported history during in-person interviews. A family history of gallstones was associated with increased risks of biliary stones [odds ratio (OR) = 2.8, 95% confidence interval (CI) = 2.1–3.8], gallbladder cancer (OR = 2.1, 95% CI = 1.4–3.3) and bile duct cancer (OR = 1.5, 95% CI = 0.9–2.5), after adjustment for age, gender, marital status, education, smoking, alcohol drinking and body mass index. For gallbladder cancer, subjects with gallstones but without a family history of gallstones had a 21-fold risk (95% CI 14.8–30.1), while those with both gallstones and a positive family history had a 57-fold risk (95% CI 32.0–110.5). Significant risks for gallbladder cancer persisted after additional adjustment for gallstones, and when the analysis was restricted to subjects with first-degree relatives whose gallstones were treated with cholecystectomy. The significant associations with a family history of gallstones were seen for all first-degree relatives, including parents, siblings and offspring, but not spouses. This large population-based study not only supports the role of gallstones in biliary carcinogenesis but also suggests that the underlying genetic or lifestyle determinants of stones within families contribute to the risk of biliary tract cancer. © 2007 Wiley-Liss, Inc.

Biliary tract cancers, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, are relatively uncommon malignancies in most parts of the world.1 The highest incidence rates have been observed among Native Americans and Hispanics living in the Southwestern United States and among some populations in Central and South America, Eastern Europe and certain parts of Asia.1, 2 Between 1972 and 1994, the incidence rates for biliary tract cancer rose more rapidly than those for any other malignancy in Shanghai, China, with increases of 119% among men and 124% among women.3 The increases in incidence were seen for all 3 biliary tract subsites in all age groups.

Gallstones are the most important risk factor for biliary tract cancers,1, 4 especially for gallbladder cancer patients of whom 60–80% have a history of gallstones1, 5 (Hsing AW, Rashid A, Sakoda L, Deng J, Han T, Wang BS, Shen MC, Fraumeni JF Jr, Gao YT. Gallstones and the risk of biliary tract cancer: a population-based study. Br J Cancer, Submitted for publication). Both gallstones and gallbladder cancer occur more frequently among women and older persons. Ethnic and familial predisposition suggests the role of genetic predisposition or shared metabolic and lifestyle factors, including obesity, insulin resistance, or high-fat, high-caloric diet.1, 6, 7, 8

Familial aggregation of gallstones has been reported in several studies,9, 10, 11 but only one assessed the role of family history of gallstones in biliary tract cancer etiology. A case–control study of gallbladder cancer in Bolivia and Mexico reported that a family history of gallstones was associated with a 3.6-fold risk of gallbladder cancer.12 The mechanisms are unclear, but it is possible that some yet unidentified susceptibility mechanism may further elevate the risk of biliary tract cancer associated with stones.

To investigate the rapid rise in incidence rates of biliary tract cancers in Shanghai, we conducted a large population-based study in Shanghai between 1997 and 2001. In this report, we examined whether a family history of gallstones is an independent risk factor for biliary tract cancer and whether it augments the risk associated with the presence of gallstones.

Materials and methods

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Study subjects

Details of the study have been reported elsewhere.13, 14, 15, 16, 17, 18, 19, 20 Briefly, cancer cases newly diagnosed with primary biliary tract cancer (ICD-9 156) between 1997 and 2000 were identified through a rapid-reporting system established by the Shanghai Cancer Institute with 42 collaborating hospitals in urban Shanghai. This system captured more than 95% of all biliary tract cancers diagnosed in Shanghai. Case patients were permanent residents of urban Shanghai between 40 and 75 years of age. A total of 627 patients with biliary tract cancer (368 gallbladder, 191 bile duct and 68 ampulla of Vater) were included. In addition, we selected a total of 1,037 biliary stone cases (774 gallbladder and 263 bile duct) from the same hospitals from which the cancer cases were selected. Biliary stone cases had no history of cancer and were matched to index cancer cases on gender, age (within 5 years) and hospital. For comparison, we selected population controls from the Shanghai Resident Registry (6.5 million permanent residents). Initially, we selected 1,500 random records from the household registry and then verified the eligibility of the subjects through a household visit and invited them to participate in the study. Through this approach, we included 959 healthy subjects for the study. Controls were free of nonskin cancer, and were frequency-matched to cancer cases in a roughly 1:1.5 ratio by age (within 5 years) and gender distributions. All study subjects provided written informed consent. The Institutional Review Boards of the National Cancer Institute and the Shanghai Cancer Institute approved the study protocol.

Clinical and pathology review

Confirmation of biliary tract cancer and biliary stone diagnoses involved the review of pathology slides, imaging data, medical records and surgical reports. As part of the diagnostic procedures, all cancer cases underwent magnetic resonance imaging, endoscopic retrograde cholangiopancreatography (ERCP) or computed tomography. Pathology slides were available for 70% of cancer cases who underwent surgery and were reviewed by a panel of pathologists. Imaging studies, pathology and surgical reports and medical records of cancer cases were reviewed by a panel of clinicians, ultrasonographers and pathologists for the presence of cancer and for the classification of the anatomic subsite of tumors. Biliary stone cases were confirmed by abdominal ultrasound and ERCP films and by pathology review for those who underwent a cholecystectomy.

Interview

Study subjects who gave consent were interviewed by trained interviewers, using a structured questionnaire to obtain information on demographic, lifestyle and dietary factors. Interviewing of cancer and gallstone cases took place within 3 weeks of diagnosis. Subjects were asked whether any of their first-degree blood relative(s), including parents, siblings and offspring, or their spouse had ever been diagnosed with gallstones by a doctor. Study subjects were defined as having a family history of gallstones if at least one first-degree relative had a history of gallstones. If a positive family history of gallstones was reported, information on the relative's age at diagnosis and type of treatment, including cholecystectomy, was elicited. The response rate for interviews was over 95% among cases and 85% among controls. For quality-control purposes, all interviews were recorded and reviewed to ensure adherence to the study protocol. In addition, 5% of the subjects were randomly reinterviewed within 3 months of the first interview to assess reproducibility the concordance between the 2 interviews on responses to key questions was greater than 90%.

Gallstone assessment

All study subjects were evaluated for the presence of gallstones. Among cancer cases, gallstone disease was identified by self-reported information from interview data and clinically from medical, surgical, and radiology records, including magnetic resonance imaging, ERCP, computed tomography and ultrasound results. Among population controls, gallstone status was assessed by both self-reported history and by abdominal ultrasound among those who gave consent for the procedure (85% of all population controls). 100% of the gallstone cases had gallstones confirmed by imaging data or surgical reports.

Statistical analysis

Fisher's exact test was used to detect differences between cases and controls for selected characteristics. To make the appropriate case–control comparisons, gallbladder cancer cases were compared with controls without a history of cholecystectomy; bile duct and ampulla of Vater cancer cases were compared with all controls; and biliary stone cases were compared with population controls without biliary stones. Those characteristics with statistically significant differences (p < 0.05) were considered potential confounders for biliary tract cancers or stones.

To determine the risk of biliary tract cancers and stones associated with a family history of gallstones, we performed unconditional logistic regression to calculate odds ratios (ORs) and 95% confidence intervals (CIs). In the full regression model, we adjusted for age, sex, education, smoking, alcohol consumption, body mass index [BMI; weight (Kg)/ height (m2)] and gallstones (for cancer cases), and in the parsimonious model, we adjusted for age and sex. Whenever appropriate, we also adjusted for additional risk factors for gallstones and biliary tract cancer, including aspirin use, tea drinking, diabetes, hypertension and cholecystitis. To minimize misclassification of family history of gallstones, we also performed analysis restricted to relatives who had had gallstones treated with cholecystectomy. Risk estimates were assessed by gender and gallstone status to determine whether either factor modified the risk of biliary tract cancers or stones associated with a family history of gallstones.

Results

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

Selected characteristics of the study subjects are shown in Table I. As expected, most cases of gallbladder cancer (73.1%) and biliary stones (62.4%) were women, and only slightly more than half of bile duct (51.8%) and ampulla of Vater (54.4%) cancers were men. Compared with population controls, biliary stone cases were younger. Gallbladder cancer cases included fewer smokers, while bile duct and ampulla of Vater cancer cases included more smokers than controls. Gallbladder cancer and biliary stone cases were less likely to drink alcohol but had higher BMI and more diabetes than controls. For all 3 cancer types, cases were significantly more likely to have had gallstones than controls. Median family size, including the number of siblings and children, was similar in cases and controls, although gallstone patients had a slightly smaller family size because of their slightly younger age. Among controls, 23.4% had gallstones, with 6% of these having silent (asymptomatic) gallstones diagnosed through abdominal ultrasound provided by the study.

Table I. Selected Characteristics of Study Subjects by Case–Control Status
Selected characteristicsControl subjectsBiliary stonesBiliary tract cancer
All1Without cholecys tectomy2Without stones3All stones4GallbladderBile ductAmpulla of Vater
n (%)n (%)n (%)n (%)n (%)n (%)n (%)
  • 1

    All population controls compared with bile duct and ampulla vater cancer cases.

  • 2

    Population controls who did not have a cholesectomy compared to gallbadder cancer cases.

  • 3

    Population controls without biliary stones compared to biliary stone cases.

  • 4

    Includes gallstones and bile duct stones.

  • 5

    Ever smoked cigarettes for at least 6 consecutive months.

  • 6

    At least one affected first-degrees relative, i.e. parent, sibling offspring.

  • *p < 0.05, **p < 0.01, ***p < 0.001, for Fisher's exact test for difference between cases and controls.

All subjects959 (100.0)902 (100.0)735 (100.0)1037 (100.0)368 (100.0)191 (100.0)68 (100.0)
Gender
 Male373 (38.9)357 (39.6)313 (42.6)390 (37.6)*99 (26.9)***99 (51.8)***37 (54.4)**
 Female586 (61.1)545 (60.4)422 (57.4)647 (62.4)269 (73.1)92 (48.2)31 (45.6)
Age at interview
 34–54128 (13.3)126 (14.0)115 (15.6)307 (29.6)***49 (13.3)30 (15.7)6 (8.8)
 55–64269 (28.1)259 (28.7)207 (28.2)298 (28.7)96 (26.1)47 (24.6)20 (29.4)
 65–75562 (58.6)517 (57.3)413 (56.2)432 (41.7)233 (60.6)114 (59.7)42 (61.8)
Education
 Elementary396 (41.3)365 (40.5)285 (38.8)317 (30.6)**198 (53.8)***86 (45.0)29 (42.6)
 High school423 (44.1)405 (44.9)336 (45.7)537 (51.8)129 (35.1)74 (38.8)31 (45.6)
 Above high school140 (14.6)132 (14.6)114 (15.5)183 (17.6)41 (11.1)31 (16.2)8 (11.8)
Marital status
 Married751 (78.3)703 (78.0)584 (79.5)884 (85.2)**284 (77.2)161 (84.3)55 (80.9)
 Divorced, widowed196 (20.4)187 (20.7)143 (19.4)143 (13.8)81 (22.0)28 (14.7)13 (19.1)
 Single12 (1.3)12 (1.3)8 (1.1)10 (1.0)3 (0.8)2 (1.0)0 (0.0)
Ever smoked cigarettes5
 No674 (70.3)633 (70.2)508 (69.1)754 (72.7)278 (75.8)115 (60.2)38 (55.9)
 Yes285 (29.7)269 (29.8)227 (30.9)283 (27.3)89 (24.2)*76 (39.8)*30 (44.1)*
Ever drank alcohol
 No760 (79.3)715 (79.4)568 (77.4)869 (83.9)***316 (85.9)**141 (73.8)53 (77.9)
 Yes198 (20.7)186 (20.6)166 (22.6)167 (16.1)52 (14.1)50 (26.2)15 (22.1)
Body mass index (kg/m2)
 <18.584 (8.8)83 (9.2)70 (9.5)51 (4.9)***20 (5.4)***11 (5.8)1 (1.5)
 18.5–22.9400 (41.7)386 (42.8)336 (45.7)345 (33.3)130 (35.3)85 (44.5)29 (42.6)
 23.0–24.9198 (20.6)185 (20.5)147 (20.0)263 (25.4)73 (19.9)49 (25.6)15 (22.1)
 ≥25277 (28.9)248 (27.5)182 (24.8)378 (36.4)145 (39.4)46 (24.1)23 (33.8)
Diabetes
 No881 (91.9)834 (92.5)688 (93.6)925 (89.3)***316 (86.1)***171 (89.5)63 (92.6)
 Yes78 (8.1)68 (7.5)47 (6.4)111 (10.7)51 (13.9)20 (10.5)5 (7.4)
Hypertension
 No553 (57.7)526 (58.3)441 (60.0)695 (67.0)230 (62.5)130 (68.1)**48 (70.6)*
 Yes406 (42.3)376 (41.7)294 (40.0)342 (33.0)138 (37.5)61 (31.9)20 (29.4)
Gallstones
 No735 (76.6)735 (81.5)735 (100.0)0 (0.0)60 (16.3)***64 (33.5)***32 (47.1)***
 Yes224 (23.4)167 (18.5)0 (0.0)1037 (100.0)308 (83.7)127 (66.5)36 (52.9)
Family history of gallstones6
 No868 (90.5)820 (90.9)667 (90.7)792 (76.4)***297 (80.7)***162 (84.8)*58 (85.3)
 Yes91 (9.5)82 (9.1)68 (9.3)245 (23.6)71 (19.3)29 (15.2)10 (14.7)
 Treated with cholecystectomy49 (5.1)43 (4.8)33 (4.8)0 (0.0)36 (9.8)11 (5.8)6 (8.8)
Family history of any cancer6
 No620 (65.9)583 (65.7)486 (66.9)696 (68.2)266 (74.7)**120 (63.8)42 (61.8)
 Yes321 (34.1)304 (34.3)240 (33.1)325 (31.8)90 (25.3)68 (36.2)26 (38.2)
Family history of biliary tract cancer6
 No959 (100.0)902 (100.0)735 (100.0)1030 (99.3)**368 (100.0)189 (99.0)68 (100.0)
 Yes0 (0.0)0 (0.0)0 (0.0)7 (0.7)0 (0.0)2 (1.0)0 (0.0)
Have at least one sibling
 No48 (5.0)46 (5.1)34 (4.7)56 (5.4)26 (7.1)12 (6.3)5 (7.5)
 Yes905 (95.0)851 (94.9)697 (95.3)973 (94.6)340 (92.9)177 (93.7)62 (92.5)
Have at least one offspring
 No39 (4.1)37 (4.1)29 (4.0)47 (4.5)10 (2.7)10 (5.3)2 (2.9)
 Yes918 (95.9)863 (95.9)704 (96.0)988 (95.5)358 (97.3)180 (94.7)66 (97.1)
Number siblings and offspring
 <5212 (22.1)208 (23.0)179 (24.4)301 (29.0)*78 (21.2)43 (22.5)10 (14.7)
 5–7398 (41.5)374 (41.5)297 (40.4)427 (41.2)146 (39.7)83 (43.5)30 (44.1)
 8–9193 (20.1)182 (20.2)148 (20.1)186 (17.9)83 (22.5)38 (19.9)18 (26.5)
 ≥10156 (16.3)138 (15.3)111 (15.1)123 (11.9)61 (16.6)27 (14.1)10 (14.7)

A family history of gallstones was reported in 9.5% of population controls, 23.6% of biliary stone cases, 19.3% of gallbladder cancer cases, 15.2% of bile duct cancer cases, and 14.7% of ampulla of Vater cancer cases. Of subjects reporting a family history of gallstones, approximately 50% noted that their relatives had a history of cholecystectomy. Only 9 (0.3%) subjects (7 biliary stone cases and 2 bile duct cancer cases) reported a family history of biliary tract cancer; these numbers were too small to evaluate further.

A family history of gallstones was associated with excess risks of biliary stones (Table II). After adjustment for age, gender, education, smoking status, alcohol drinking status and BMI, subjects with a family history of gallstones had a 2.8-fold risk of biliary stones (95% CI = 2.1–3.8), compared with subjects without a family history. This estimate remained statistically significant when the analysis was restricted to subjects who had relatives with a history of biliary stones treated with cholecystectomy (OR = 3.3, 95% CI 2.0–5.6). Those with more than one relative reporting a history of gallstones had a 2.3-fold risk of biliary stones (95% CI 1.7–3.1). Although gallstones were more common in women, the risk of stones associated with a positive family history did not differ substantially by gender of subjects or family members. A family history of gallstones was associated with excess biliary stone risk in all types of first-degree relatives, with the highest risk seen for subjects having an affected sibling (OR = 4.0, 95% CI 2.5–6.4), especially brothers (OR = 5.0, 95% CI 2.3–10.8). No excess risk was associated with having a spouse with gallstones. The excess risk of gallstones associated with a family history of gallstones was more pronounced among diabetics (OR = 5.5, 95% CI 1.6–19.2), although there was no significant interaction between diabetes and a family history of gallstones.

Table II. Odds Ratios (ORs) and 95% Confidence Intervals (95% CI) for Biliary Tract Stones and Cancers in Relation to Family History of Gallstones
Characterisitcs of a family history of gallstonesControl subjectsBiliary stonesBiliary tract cancer
All1Without Cholecystectomy2Without stones3All stones4GallbladderBile ductAmpulla of Vater
n (%)n (%)n (%)n (%)OR5 (95% CI5)n (%)OR6 (95% CI6)n (%)OR6 (95% CI6)n (%)OR6 (95% CI6)
  • 1

    All population controls compared to bile duct and ampulla vater cancer cases.

  • 2

    Population controls without cholesectomy compared to gallbadder cancer cases.

  • 3

    Population controls without biliary stones compared to biliary stone cases.

  • 4

    Includes gallstone and bile duct stone cases.

  • 5

    Adjusted for age, gender, education, smoking, alcohol drinking and BMI.

  • 6

    Adjusted for age, gender and gallstones.

  • 7

    At least one affected first-degree relative, i.e. parent, sibling, offspring.

  • 8

    Among subjects with at least one sibling.

  • 9

    Among subjects with at least one brother.

  • 10

    Among subjects with at least one sister.

  • 11

    Among subjects with at least one offspring.

  • 12

    Among subjects with at least one son.

  • 13

    Among subjects with at least one daughter.

All subjects959 (100.0)902 (100.0)735 (100.0)1037 (100.0)368 (100.0)191 (100.0)68 (100.0)
Family history of gallstones7
No868 (90.5)820 (90.9)667 (90.7)792 (76.4)1.0297 (80.7)1.0162 (84.8)1.058 (85.3)1.0
Yes
 Reported family history of gallstones91 (9.5)82 (9.1)68 (9.3)245 (23.6)2.8 (2.1–3.8)71 (19.3)2.1 (1.4–3.3)29 (15.2)1.5 (0.9–2.5)10 (14.7)1.5 (0.7–3.2)
 Family history of cholecystectomy49 (5.1)43 (4.8)4 (0.5)64 (6.2)3.3 (2.0–5.6)36 (9.8)1.4 (1.0–1.8)11 (5.8)0.9 (0.7–1.4)6 (8.8)1.3 (0.8–2.0)
 1 relative with a history of gallstones84 (8.8)77 (8.5)33 (4.5)118 (11.4)1.7 (1.4–2.1)62 (16.8)2.1 (1.3–3.3)24 (12.6)1.4 (0.8–2.4)7 (10.3)1.2 (0.5–2.8)
 >1 relative with a history of gallstones7 (0.7)5 (0.6)64 (8.7)181 (17.5)2.3 (1.7–3.1)9 (2.4)1.7 (0.8–3.3)5 (2.6)1.5 (0.8–2.9)3 (4.4)2.5 (1.2–5.3)
 Male relative with a history of gallstones25 (2.6)23 (2.5)20 (2.7)86 (8.3)3.3 (1.9–5.5)22 (6.0)2.4 (1.1–5.3)11 (5.8)2.4 (1.1–5.6)3 (4.4)1.8 (0.5–6.8)
 Female relative with a history of gallstones70 (7.3)62 (6.9)50 (6.8)189 (18.2)3.0 (2.1–4.2)51 (13.9)1.9 (1.2–3.2)20 (10.5)1.2 (0.7–2.2)8 (11.8)1.6 (0.7–3.6)
 Parent with a history of gallstones33 (3.4)31 (3.4)29 (3.9)97 (9.4)2.1 (1.3–3.3)18 (4.9)2.2 (1.0–4.8)11 (5.8)1.7 (0.8–3.8)1 (1.5)
   Father8 (0.8)7 (0.8)6 (0.8)18 (1.7)1.5 (0.6–3.9)3 (0.8)2.3 (0.5–11.8)5 (2.6)2.6 (0.7–9.4)0 (0.0)
   Mother25 (2.6)24 (2.7)23 (3.1)82 (7.9)2.3 (1.4–3.8)15 (4.1)2.2 (0.9–5.2)7 (3.7)1.5 (0.6–3.9)1 (1.5)
 Sibling with a history of gallstones837 (4.1)33 (3.9)24 (3.4)128 (13.2)4.0 (2.5–6.4)26 (7.6)1.6 (0.8–3.1)17 (9.6)1.9 (0.9–3.7)8 (12.9)2.8 (1.2–6.8)
   Brother910 (1.3)10 (1.3)8 (1.3)51 (5.9)5.0 (2.3–10.8)9 (3.0)1.6 (0.5–5.2)5 (3.1)3.0 (0.9–9.9)3 (5.5)4.3 (1.1–17.4)
   Sister1028 (3.6)24 (3.3)16 (2.7)87 (10.4)3.9 (2.2–6.9)17 (6.0)1.4 (0.6–3.2)13 (8.3)1.6 (0.7–3.3)6 (10.9)2.6 (0.9–7.0)
 Offspring with a history of gallstones1124 (2.6)20 (2.3)17 (2.4)56 (5.7)3.6 (2.0–6.3)31 (8.7)2.9 (1.4–6.2)4 (2.2)0.9 (0.3–2.8)1 (1.5)
   Son127 (0.9)6 (0.8)6 (1.0)22 (2.9)3.5 (1.4–8.8)10 (3.2)4.0 (1.0–15.7)1 (0.7)0 (0.0)
   Daughter1318 (2.5)15 (2.2)12 (2.2)38 (5.2)3.6 (1.9–7.2)21 (7.0)2.4 (1.0–5.8)3 (2.0)0.8 (0.2–2.9)1 (1.8)
Reported spouse with history of gallstones8
  No814 (86.0)768 (86.3)624 (85.8)750 (73.0)1.0284 (77.8)1.0146 (77.2)1.058 (85.3)1.0
  Yes51 (5.4)49 (5.5)43 (5.9)47 (4.6)1.0 (0.6–1.6)15 (4.1)1.0 (0.5–2.1)16 (8.5)2.0 (1.0–3.8)1 (1.5)
   Among male subjects23 (6.3)21 (6.0)20 (6.5)30 (7.8)1.6 (0.9–2.9)7 (7.1)1.7 (0.5–5.4)13 (13.4)3.3 (1.4–7.5)1 (2.7)
   Among female subjects28 (4.8)28 (5.2)23 (5.5)17 (2.6)0.6 (0.3–1.1)8 (3.0)0.7 (0.3–1.9)3 (3.3)0.8 (0.2–2.9)0 (0.0)

A family history of gallstones was also associated with a significantly increased risk of biliary tract cancer (Table II). After adjustment for age, gender, BMI, and gallstones, subjects with a family history of gallstones had a risk of 2.1-fold for gallbladder cancer (95% CI 1.4–3.3), 1.5-fold for bile duct cancer (95% CI 0.9–2.5) and 1.5-fold for ampulla of Vater cancer (95% CI 0.7–3.2). When the analysis was restricted to subjects whose relatives had gallstones treated with cholecystectomy, the excess risks persisted for all subsites of biliary cancer and for subjects with 2 or more family members having gallstones, but was statistically significant only for gallbladder cancer (OR = 1.4, 95% CI = 1.0–1.8). The effect of a family history of gallstones on gallbladder cancer risk was more pronounced for women (OR = 2.9, 95% CI = 1.9–4.5) than men (OR = 1.8, 95% CI = 0.9–3.4), although there was no significant interaction between gender and family history of gallstones (p for interaction = 0.23). We did not observe a difference in risk estimates between men and women for bile duct cancer, and there were too few ampulla of Vater cancer cases to evaluate risk by gender. Regardless of the type of relative, family history of gallstones was associated with higher risks of biliary tract cancers. For gallbladder cancer the risk was highest for subjects having an offspring with stones (OR = 2.9, 95% CI 1.4–6.2), particularly for those having an affected son (OR = 4.0, 95% CI 1.0–15.7). A history of gallstones among spouses was associated only with a higher risk of bile duct cancer among male subjects (OR = 3.3, 95% CI 1.4–7.5).

Table III shows the combined effect of having gallstones and a positive family history of gallstones on biliary tract cancer risk. Compared with subjects without either gallstones or a reported family history, those with gallstones but no family history had a 21-fold risk of gallbladder cancer (95% CI 14.8–30.1), while those with both gallstones and a family history had a 57-fold risk (95% CI 30.2–110.5). Regardless of BMI, diabetes, or hypertension, a family history of gallstones was associated with an increased risk of gallbladder cancer (data not shown). Similar risk patterns were seen for cancers of the bile duct and ampulla of Vater, with the highest risk among those with both stones and a positive family history.

Table III. Odds Ratios (ORs) and Confidence Intervals (95% CI) for Biliary Tract Cancers in Relation to Family History of Gallstones and Gallstone Status
Family history of gallstones and gallstone status among subjectsControl subjectsBiliary tract cancer
All1Without cholecys tectomy2Gallbladder cancerBile duct cancerAmpulla of Vater cancer
n (%)n (%)n (%)OR3 (95% CI3)n (%)OR3 (95% CI3)n (%)OR3 (95% CI3)
  • 1

    Population controls compared with bile duct and ampulla vater cancer cases.

  • 2

    Pupulation controls without cholesectomy compared with gallbadder cancer cases.

  • 3

    Adjusted for age and gender.

Total959 (100.0)902 (100.0)368 (100.0)191 (100.0)68 (100.0)
Family history(−), Gallstones(−)667 (69.6)667 (73.9)52 (14.1)1.055 (28.8)1.028 (41.2)1.0
Family history(+), Gallstones(−)68 (7.1)68 (7.5)8 (2.2)1.4 (0.6−3.1)9 (4.7)1.4 (0.6−2.9)4 (5.9)1.4 (0.5−4.2)
Family history(−), Gallstones(+)201 (21.0)153 (17.0)245 (66.6)21.1 (14.8–30.1)107 (56.0)7.6 (5.2–11.1)30 (44.1)4.0 (2.3–7.0)
Family history(+), Gallstones(+)23 (2.4)14 (1.6)63 (17.1)57.7 (30.2–110.5)20 (10.5)11.9 (6.0–23.5)6 (8.8)6.8 (2.5–18.4)
 p interaction   0.18 0.94 0.77

Discussion

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

In this population-based study in Shanghai, China, a family history of gallstones was associated with a 2.8-fold risk of biliary stones and a 2-fold risk of biliary tract cancer, regardless of the number and type of first-degree relatives having gallstones. For gallbladder cancer, subjects with gallstones alone had a 21-fold risk, while those with both gallstones and a positive family history had a 57-fold risk. No association was found for gallstones among spouses.

The excess risk of biliary stones associated with a family history of gallstones is consistent with several previous studies in various population groups.21, 22, 23, 24 Reasons for the much higher risk (4- to 5-fold) seen for subjects with a sibling or child having gallstones are unclear, but may be related in part to difficulty in recalling parents' gallstone histories or to detection bias among siblings. Although gallstones are more common in women than in men, the risk of gallstones related to a positive family history did not vary by gender, with a similar magnitude of risk regardless of whether the gallstones occurred in male or female relatives.

The 2-fold risk of biliary tract cancer associated with a family history of gallstones was independent of gallstone status among subjects, and is consistent with risks reported in previous studies from various population groups, including the U.S., Japan, Mexico and Bolivia,12, 25 providing further support for the role of genetic susceptibility in both gallstones and biliary tract cancer. Although the risk of biliary tract cancer associated with a personal history of gallstones was elevated in our study, with odds ratios of 25, 8 and 5 for cancers of the gallbladder, bile duct and ampulla of Vater, respectively, the risk of biliary tract cancer associated with a family history of gallstones persisted after adjustment for gallstone status among study subjects. Although females are more likely to develop gallbladder cancer as well as stones our study indicated that gender did not modify the association between a family history of gallstones and biliary tract cancer.

The very high risk (57-fold) of gallbladder cancer associated with a personal history combined with a family history of gallstones suggests an interactive effect, although it was not statistically significant (p for interaction = 0.18). This effect was not observed for cancers of the bile duct and ampulla of Vater, perhaps related to the smaller sample sizes or the lower risks associated with stones for these cancer subsites. In our study, it was difficult to evaluate the risk of gallbladder cancer in relation to family history of gallstones in the absence of gallstones among study subjects, since nearly 84% of the cancer cases had gallstones and only 2.2% of the cases with a family history of gallstones did not have gallstones.

The underlying mechanism for the familial tendency to gallstone disease may be related to genetic susceptibility or shared lifestyle or metabolic factors. Although the association appeared independent of risk factors for gallstones, such as obesity and diabetes, it is difficult to tease apart genetic and lifestyle factors, given the likelihood of gene-environment interaction. For example, lipid levels in serum and bile affect the risk of gallstones, and are influenced by variants of genes in the lipid metabolism pathway26, 27, 28, 29 as well as lifestyle factors, such as obesity and diet.30 In addition, preliminary studies suggest susceptibility genes in the lipid metabolism pathway, including the LDLR, LPL and APOE genes.25, 31, 32 The role of genetic susceptibility is supported by our finding that biliary stones were not associated with gallstone history in spouses, although we cannot rule out the potential effect of early-life exposures. Further work is needed to identify the genetic and other mechanisms responsible for the lithogenic bile reported in high risk populations such as native Americans.

Similarly, it is unclear why a family history of gallstones further increases the risk of gallbladder cancer in our study. In addition to gallstones, the risk factors for gallbladder cancer, such as obesity, insulin resistance, high-fat or high-caloric diet and altered lipid metabolism tend to run in families8, 9, 12, 32 (Hsing AW, Rashid A, Sakoda L, Deng J, Han T, Wang BS, Shen MC, Fraumeni JF Jr., Gao YT. Gallstones and the risk of biliary tract cancer: a population-based study. Br J Cancer, Submitted for publication). We were unable to tease apart these factors, since gallstones and gallbladder cancer share similar risk factors, and we did not have lifestyle information from family members.

A number of strengths and limitations of the study should be noted. Given the high case ascertainment (>95%) and response rates (>85%), selection and survival biases were minimal. Also, the rigorous pathology and clinical confirmation of biliary tract cancer and stone diagnoses among cases minimized misclassification of outcome. This is one of the few studies of biliary tract cancer to have complete assessment of gallstone status among cancer cases and controls, which permitted an assessment of the family history of gallstones while controlling for subjects' gallstone status. Since the family history of gallstones was based on self-reported data and was not confirmed by medical records, some misclassification of family history of gallstones was possible. However, when the analysis was limited to relatives who had a cholecystectomy, the association between family history of gallstones and biliary tract cancer persisted. History of cholecystectomy is likely to underestimate the true prevalence of gallstones in family members in both cases and controls, since patients with gallstones are not necessarily treated with surgery. It is possible that given the strong association between gallstones and gallbladder cancer, relatives of cancer cases might be more knowledgeable or concerned about gallstone status, thereby increasing the likelihood of stone detection in family members. However, this bias should be minimal, since the diagnosis of gallstones in family members occurred prior to the diagnosis of cancer in study subjects, although some degree of recall bias among cases is possible. Underreporting of gallstones in family members because of asymptomatic gallstones is possible but is likely to be small, since only 6% of the controls who underwent abdominal ultrasound had silent gallstones. In addition, this misclassification is unlikely to be differential in cases and controls. Because of small numbers, we had limited statistical power to evaluate bile duct and ampulla of Vater cancers, or to test for interactions between family histories and other conditions.

In summary, data from this population-based study of biliary tract cancer indicate that a family history of gallstones among first-degree blood relatives augments the risk of biliary stones as well as biliary tract cancer risk. These results suggest that genetic factors or shared environment may increase the familial tendency to gallstones and biliary tract cancer. The clustering of both conditions in families provides an opportunity for epidemiologic studies incorporating genomic and metabolic approaches to clarify the genetic and other pathways involved in the development of biliary stones and cancer.

Acknowledgements

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References

We thank Ms. Jiarong Cheng, Ms. Lu Sun, Mr. Kai Wu, Ms. Enju Liu and the staff at the Shanghai Cancer Institute for data collection, specimen collection and processing; collaborating hospitals and surgeons for data collection; local pathologists for pathology review; Ms. Lisa McFarland, Ms. Shelley Niwa, Ms. Kathy Hurt-Mullen, Ms. Sara Glashofer, Ms. Nancy Odaka, Ms. John Heinrich and Ms. Linda Lannom of Westat for data preparation and management; and Ms. Janis Koci of the Scientific Applications International Corporation for management of the biological samples.

References

  1. Top of page
  2. Abstract
  3. Materials and methods
  4. Results
  5. Discussion
  6. Acknowledgements
  7. References
  • 1
    Hsing AW, Rashid A, Devesa SS, Fraumeni JF,Jr. Biliary tract cancer. In: SchottenfeldD, FraumeniJF,Jr, eds. Cancer epidemiology and prevention, 3rd edn. Oxford University Press: New York, 2006. 787800.
  • 2
    Ries LA. SEER cancer statistics review, 1975–2000. National Cancer Institute: Bethesda, MD, 2003. Available at http://seer.cancer.gov/csr/1975_2000.
  • 3
    Hsing AW, Gao YT, Devesa SS, Jin F, Fraumeni JF,Jr. Rising incidence of biliary tract cancers in Shanghai, China. Int J Cancer 1998; 75: 36870.
  • 4
    Lazcano-Ponce EC, Miquel JF, Munoz N, Herrero R, Ferrecio C, Wistuba II, Alonso de Ruiz P, Aristi Urista G, Nervi F. Epidemiology and molecular pathology of gallbladder cancer. CA Cancer J Clin 2001; 51: 34964.
  • 5
    Scott TE, Carroll M, Cogliano FD, Smith BF, Lamorte W. A case-control assessment of risk factors for gallbladder carcinoma. Dig Dis Sci 1999; 44: 161925.
  • 6
    Rios-Dalenz J, Takabayashi A, Henson DE, Strom BL, Soloway RD. Cancer of the gallbladder in Bolivia: suggestions concerning etiology. Am J Gastroenterol 1985; 80: 3715.
  • 7
    Nervi F, Duarte I, Gomez G, Rodriguez G, Del Pino G, Ferrerio O, Covarrubias C, Valdivieso V, Torres MI, Urzua A. Frequency of gallbladder cancer in Chile, a high-risk area. Int J Cancer 1988; 41: 65760.
  • 8
    Zatonski WA, La Vecchia C, Przewozniak K, Maisonneuve P, Lowenfels AB, Boyle P. Risk factors for gallbladder cancer: a polish case-control study. Int J Cancer 1992; 51: 70711.
  • 9
    Sarin SK, Negi VS, Dewan R, Sasan S, Saraya A. High familial prevalence of gallstones in the first-degree relatives of gallstone patients. Hepatology 1995; 22: 13841.
  • 10
    Kratzer W, Kachele V, Mason RA, Hill V, Hay B, Haug C, Adler G, Beckh K, Muche R. Gallstone prevalence in Germany: the Ulm Gallbladder Stone Study. Dig Dis Sci 1998; 43: 128591.
  • 11
    Miquel JF, Covarrubias C, Villaroel L, Mingrone G, Greco AV, Puglielli L, Carvallo P, Marshall G, Del Pino G, Nervi F. Genetic epidemiology of cholesterol cholelithiasis among Chilean Hispanics, Amerindians, and Maoris. Gastroenterology 1998; 115: 93746.
  • 12
    Strom BL, Soloway RD, Rios-Dalenz JL, Rodriguez-Martinez HA, West SL, Kinman JL, Polansky M, Berlin JA. Risk factors for gallbladder cancer. An international collaborative case-control study. Cancer 1995; 76: 174756.
  • 13
    Rashid A, Ueki T, Gao YT, Houlihan PS, Wallace C, Wang BS, Shen MC, Deng J, Hsing AW. K-ras mutation, p53 overexpression, and microsatellite instability in biliary tract cancers: a population-based study in China. Clin Cancer Res 2002; 8: 315663.
  • 14
    Ueki T, Hsing AW, Gao YT, Wang BS, Shen MC, Cheng J, Deng J, Fraumeni JF,Jr, Rashid A. Alterations of p16 and prognosis in biliary tract cancers from a population-based study in China. Clin Cancer Res 2004; 10: 171725.
  • 15
    Wang BS, Qin J, Deng J, Zhang BH, Han TQ, Shen MC, Rashid A, Hsing AW, Gao YT. A survey on the diagnosis and treatment of biliary tract cancers in Shanghai. Zhonghua Wai Ke Za Zhi 2005; 43: 4559.
  • 16
    Liu E, Sakoda LC, Gao YT, Rashid A, Shen MC, Wang BS, Deng J, Han TQ, Zhang BH, Fraumeni JF,Jr, Hsing AW. Aspirin use and risk of biliary tract cancer: a population-based study in Shanghai, China. Cancer Epidemiol Biomarkers Prev 2005; 14: 131518.
  • 17
    Sakoda LC, Gao YT, Chen BE, Chen J, Rosenberg PS, Rashid A, Deng J, Shen MC, Wang BS, Han TQ, Zhang BH, Cohen-Webb H, et al. Prostaglandin-endoperoxide synthase 2 (PTGS2) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China. Carcinogenesis 2006; 27: 12516.
  • 18
    Hou L, Xu J, Gao YT, Rashid A, Zheng SL, Sakoda LC, Shen MC, Wang BS, Deng J, Han TQ, Zhang BH, Meyers DA, et al. CYP17 MspA1 polymorphism and risk of biliary tract cancers and gallstones: a population-based study in. Shanghai. China. Int J Cancer 2005; 118: 284753.
  • 19
    Zhang XH, Andreotti G, Gao YT, Deng J, Liu E, Rashid A, Wu K, Sun L, Sakoda LC, Cheng JR, Shen MC, Wang BS, et al. Tea drinking and the risk of biliary tract cancers and biliary stones: a population-based case-control study in Shanghai, China. Int J Cancer 2006; 118: 308994.
  • 20
    Hsing AW, Gao YT, McGlynn K, Niwa S, Wang BS, Zhang M, Shen MC, Zhang BH, Deng J, Fraumeni JF,Jr, Rashid A. Biliary tract cancer and stones in relation to liver cirrhosis and family history of liver cancer: a population-based study in Shanghai, China. Int J Cancer 2007; 120: 19815.
  • 21
    Pazzi P, Scagliarini R, Sighinolfi D, Govoni M, La Corte R, Gullini S. Nonsteroidal antiinflammatory drug use and gallstone disease prevalence: a case-control study. Am J Gastroenterol 1998; 93: 14204.
    Direct Link:
  • 22
    Zhuang X, Li L. A case-control study of gallstone disease in female population in Taicang. Zhonghua Liu Xing Bing Xue Za Zhi 2000; 21: 447.
  • 23
    Nakeeb A, Comuzzie AG, Martin L, Sonnenberg GE, Swartz-Basile D, Kissebah AH, Pitt HA. Gallstones: genetics versus environment. Ann Surg 2002; 235: 8429.
  • 24
    Salinas G, Velasquez C, Saavedra L, Ramirez E, Angulo H, Tamayo JC, Orellana A, Huivin Z, Valdivia C, Rodriguez W. Prevalence and risk factors for gallstone disease. Surg Laparosc Endosc Percutan Tech 2004; 14: 2503.
  • 25
    Juvonen T. Pathogenesis of gallstones. Scand J Gastroenterol 1994; 29: 57782.
  • 26
    Brown MS, Goldstein JL. A receptor-mediated pathway for cholesterol homeostasis. Science 1986; 232: 3447.
  • 27
    Lusis AJ. Genetic factors affecting blood lipoproteins: the candidate gene approach. J Lipid Res 1988; 29: 397429.
  • 28
    Ko CW, Lee SP. Gallstone formation. Local factors. Gastroenterol Clin North Am 1999; 28: 99115.
  • 29
    Mahley RW, Rall SC,Jr. Apolipoprotein E: far more than a lipid transport protein. Annu Rev Genomics Hum Genet 2000; 1: 50737.
  • 30
    Ye SQ, Kwiterovich POJr. Influence of genetic polymorphisms on responsiveness to dietary fat and cholesterol. Am J Clin Nutr 2000; 72(5 Suppl): 1275S1284S.
  • 31
    Singh MK, Pandey UB, Ghoshal UC, Srivenu I, Kapoor VK, Choudhuri G, Mittal B. Apolipoprotein B-100 XbaI gene polymorphism in gallbladder cancer. Hum Genet 2004; 114: 2803.
  • 32
    Kato K, Akai S, Tominaga S, Kato I. A case-control study of biliary tract cancer in Niigata Prefecture, Japan. Jpn J Cancer Res 1989; 80: 9328.