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. Author manuscript; available in PMC: 2019 Mar 1.
Published in final edited form as: Cancer Epidemiol Biomarkers Prev. 2018 Jan 16;27(3):348–351. doi: 10.1158/1055-9965.EPI-17-1003

Family history of cancer and risk of biliary tract cancers: results from the Biliary Tract Cancers Pooling Project

Alison L Van Dyke 1,*, Margaret S Langhamer 1,2,*, Bin Zhu 1, Ruth M Pfeiffer 1, Demetrius Albanes 1, Gabriella Andreotti 1, Laura E Beane Freeman 1, Andrew T Chan 3, Neal D Freedman 1, Susan M Gapstur 2,4, Graham G Giles 5,6, Francine Grodstein 7, Linda M Liao 1, Juhua Luo 8, Roger L Milne 5,6, Kristine R Monroe 9, Marian L Neuhouser 10, Jenny N Poynter 11, Mark P Purdue 1, Kim Robien 12, Catherine Schairer 1, Rashmi Sinha 1, Stephanie Weinstein 1, Xuehong Zhang 13, Jessica L Petrick 1, Katherine A McGlynn 1, Peter T Campbell 4, Jill Koshiol 1
PMCID: PMC5835211  NIHMSID: NIHMS933707  PMID: 29339358

Abstract

Background

Although some familial cancer syndromes include biliary tract cancers (BTCs) (cancers of the gallbladder, intrahepatic and extrahepatic bile ducts, and ampulla of Vater), the few studies that have examined the relationships between family history of cancer (FHC) and BTCs have reported inconclusive findings. The objective of this study was to investigate the associations of FHC with risk of BTC in the Biliary Tract Cancers Pooling Project (BiTCaPP).

Methods

We used Cox proportional hazards regressions models to estimate HRs and 95% confidence intervals for associations between FHC (any, 1st degree, in female relative, in male relative, relative with gastrointestinal cancer, and relative with hormonally-related cancer) and BTC risk by anatomic site within the biliary tract, adjusting for sex and race/ethnicity. Sensitivity analyses were conducted that restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy.

Results

Data on FHC were available from 12 prospective studies within BiTCaPP, which collectively contributed 2,246 cases (729 gallbladder, 345 intrahepatic and 615 extrahepatic bile duct, and 385 ampulla of Vater cancers) with 21,706,107 person-years of follow-up. A marginal, inverse association between FHC and gallbladder cancer was driven to the null when analysis was restricted to studies reporting cholecystectomy data and to people without a history of cholecystectomy. FHC was not associated with risk of BTC at the other anatomic sites.

Conclusions

These findings do not support an association between FHC and BTCs.

Impact

In a study of 1.5 million people, FHC is not a risk factor for BTCs.

Keywords: Biliary Tract, Cancer, Family History, Risk, Pooling Project

Introduction

Biliary tract cancers (BTCs), including gallbladder (GBC), intrahepatic (IHBDC) and extrahepatic (EHBDC) bile duct, and ampulla of Vater (AVC) cancers, have a poor prognosis (1). Previous studies found associations of familial cancer syndromes (familial adenomatous polyposis, Lynch syndrome, neurofibromatosis type 1) with BTC risk, suggesting they may have a heritable component (2).

While some studies suggest a higher risk of BTCs among individuals with a family history of cancer (FHC) compared to people without a FHC, most studies examined BTCs combined (3) or only at one anatomic site (4–6) or had small numbers of cases (3, 5–8). Also, it is unknown whether family history of gastrointestinal or hormonally-dependent cancers is associated with BTCs. We investigated associations of type of FHC with risk of BTC by anatomic site.

Materials and Methods

The Biliary Tract Cancers Pooling Project (BiTCaPP) combines data from 28 prospective studies involving over 2.8 million people. The National Cancer Institute has Office of Human Subjects Research Protection exemption for BiTCaPP. Contributing studies received institutional review board approval prior to data collection; participants gave written informed consent.

FHC was available from 12 BiTCaPP studies (Table 1) and was harmonized as: any FHC, first degree FHC, cancer history in a female relative, cancer history in a male relative, family history of gastrointestinal cancers (colorectum, esophagus, small intestine, stomach, liver, biliary tract, pancreas), and family history of hormonally-related cancers (breast, ovarian, prostate, endometrial/uterine). Exclusions were prevalent disease at baseline, missing person time, age at baseline, or case/non-case status and age <18 years at baseline.

Table 1.

Participant characteristics by study included in family history of cancers and biliary tract cancers in the BiTCaPPa,b

Study Follow-Up Period Sample Sizec N (% of Pooled) GBC N IHBDC N EHBDC N AVC N Women % Age Mean (SD) Non-Hispanic White % Cholecystectomy % Gallstones %
AARP 1995-2011 547,369 (36) 213 150 219 147 40 62 (5) 93 14 10
AgHealth 1993-2013 43,934 (3) 6 8 5 3 47 47 (12) 98 N/C N/C
ATBC 1985-2010 20,438 (1) 14 20 30 12 0 57 (5) 100 5 6
BCDDP 1980-1998 47,008 (3) 11 5 7 8 100 62 (8) 88 N/C 22
CPS-II NC 1992-2011 155,091 (10) 70 59 51 36 53 63 (6) 98 13 12
HPFS 1986-2012 51,395 (3) 11 8 23 10 0 54 (10) 97 3 1
IWHS 1986-2013 37,663 (2) 69 17 27 12 100 62 (4) 99 N/C N/C
MCCS 1990-2009 39,695 (3) 35 20 22 6 59 55 (9) 100 8 9
MEC 1993-2010 190,565 (12) 111 N/A 110 64 55 60 (9) 25 6 7
NHS 1976-2012 100,693 (7) 54 17 34 18 100 47 (7) 94 8 2
PLCO 1993-2009 148,086 (10) 46 19 50 34 51 63 (5) 89 N/C 12
WHI 1993-2014 158,969 (10) 89 22 37 35 100 63 (7) 83 13 16
Total 1,540,906 729 345 615 385 56 60 (8) 84 10 10
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a

Studies were conducted in the United States, except for ATBC (Finland) and MCCS (Australia). ATBC and WHI were randomized controlled trials; PLCO was a cancer screening trial. The remaining studies contributing to BiTCaPP were prospective cohort studies.

b

Data are missing for the following variables: race/ethnicity (N=11,145), cholecystectomy (N=319,423), gallstones (N=18,916).

c

Sample sizes presented are figures after people are excluded who were missing family history of any cancer (N=66,887), had prevalent disease (person time ≤0) or missing person time (N=30,706), and/or age at baseline <18 (N=166) or missing age at baseline (N=37).

Abbreviations: NIH-AARP Diet & Health Study (AARP), Agricultural Health Study (AgHealth), Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study (ATBC), ampulla of Vater cancer (AVC), Biliary Tract Cancers Pooling Project (BiTCaPP), Breast Cancer Detection Demonstration Project (BCDDP), Cancer Prevention Study II Nutrition Cohort (CPS-II NC), extrahepatic bile duct cancer (EHBDC), gallbladder cancer (GBC), Health Professionals Follow-Up Study (HPFS), intrahepatic bile duct cancer (IHBDC), Iowa Women’s Health Study (IWHS), Melbourne Collaborative Cohort Study (MCCS), Multiethnic Cohort Study (MEC), Nurses’ Health Study (NHS), not available from study (N/A), not collected (N/C), Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial (PLCO), standard deviation (SD), Women’s Health Initiative (WHI).

Relationships between FHC and baseline characteristics were examined using χ2 tests for categorical variables and t-tests for continuous variables. We used Cox proportional hazards regression models with age as the time scale and left truncation at recruitment to estimate HRs and 95% confidence intervals (CI) for associations between FHC and BTCs, adjusting for sex and race/ethnicity, with baseline hazard stratified by study. Analyses were repeated restricting to studies reporting cholecystectomy and to people without a history of cholecystectomy. To address concerns that FHC may be associated with history of cholecystectomy, and thereby bias results toward the null, we evaluated these relationships using logistic regression adjusting for baseline age, sex, and race/ethnicity. All tests were two-sided (α=0.05) and conducted using SAS software (Version 9.3, Cary, NC).

Results

Data were available for over 1.5 million people (58% of BiTCaPP) and 21,706,107 person-years (Table 1). Participants averaged 60 years-old at baseline and were mostly non-Hispanic white with slightly more women than men (Table 1). Compared with people without a FHC, people with a FHC were more likely to be women (59 vs. 53%, P<0.0001) and non-Hispanic white (87 vs. 79%, P<0.0001) and to have a college education (68 vs. 60%, P<0.0001). Differences in baseline age [mean (standard deviation) for with FHC vs. without FHC, P-value: 61 (8) vs. 60 (9), <0.0001] and history of diabetes or gallstones (with FHC vs. without FHC, P-value: 8 vs. 9%, <0.0001 for diabetes and 10 vs. 9%, <0.0001 for gallstones) between people with and without any FHC were statistically significant, but too small to be clinically meaningful. People with any FHC more frequently reported a cholecystectomy history [odds ratio (95% CI): 1.20 (1.18-1.21)].

FHC was not associated with IHBDC or EHBDC (Table 2). FHC was marginally, inversely associated with overall GBC, but the association was null after restricting to people who had not had a cholecystectomy. Having a relative with a hormonally-related cancer was marginally and inversely associated with AVC risk.

Table 2.

Family history of cancer and risk of biliary tract cancers: pooled HR estimates from the BiTCaPP

Biliary Tract Cancer Site
IHBDCa,b EHBDCa,b AVCa,b GBC
FHC Variable Overall
(12 Studies)a,b 		Restricted to Studies with Cholecystectomy Data
(8 Studies)b,c 		Restricted to People Not Reporting a Cholecystectomy
(8 Studies)b,d
Any FHCe  
Non-Cases: n (%) 808,883 (60) 891,352 (58) 891,469 (58) 891,292 (58) 754,710 (60) 689,897 (60)
Cases: n (%) 206 (60) 337 (55) 220 (58) 397 (55) 339 (57) 322 (56)
HR (95% CI) 0.96 (0.77-1.19) 0.92 (0.78-1.08) 0.95 (0.77-1.18) 0.82 (0.71-0.96) 0.89 (0.75-1.05) 0.89 (0.75-1.05)
1st Degree FHC 
Non-Cases: n (%) 701,678 (52) 784,163 (51) 784,264 (51) 784,128 (51) 662,945 (53) 607,264 (52)
Cases: n (%) 183 (54) 298 (49) 197 (52) 333 (46) 295 (50) 279 (49)
HR (95% CI) 0.97 (0.78-1.20) 0.90 (0.77-1.06) 0.99 (0.80-1.21) 0.82 (0.71-0.95) 0.89 (0.75-1.04) 0.88 (0.75-1.04)
Female Relative with Cancer
Non-Cases: n (%) 524,406 (39) 534,426 (35) 534,508 (35) 534,381 (35) 448,724 (36) 408,640 (35)
Cases: n (%) 128 (37) 211 (35) 129 (34) 256 (35) 206 (35) 195 (34)
HR (95% CI) 0.89 (0.71-1.12) 1.09 (0.91-1.31) 0.97 (0.77-1.21) 0.96 (0.82-1.13) 0.99 (0.82-1.19) 1.00 (0.83-1.21)
Male Relative with Cancer
Non-Cases: n (%) 408,907 (31) 422,675 (28) 422,724 (28) 422,660 (28) 386,177 (31) 353,196 (31)
Cases: n (%) 107 (31) 150 (25) 101 (27) 165 (23) 156 (27) 147 (26)
HR (95% CI) 0.92 (0.72-1.16) 0.86 (0.70-1.04) 0.91 (0.72-1.16) 0.81 (0.67-0.97) 0.86 (0.71-1.04) 0.87 (0.71-1.06)
Relative with GI Cancer
Non-Cases: n (%) 225,826 (18) 264,067 (18) 264,120 (18) 264,053 (18) 222,961 (19) 200,930 (18)
Cases: n (%) 58 (19) 113 (19) 60 (17) 127 (19) 107 (19) 101 (19)
HR (95% CI) 0.96 (0.72-1.28) 1.03 (0.83-1.27) 0.85 (0.64-1.13) 0.99 (0.82-1.21) 0.97 (0.78-1.20) 0.97 (0.78-1.21)
Relative with Hormonally-Related Cancer
Non-Cases: n (%) 376,622 (30) 414,250 (28) 414,317 (28) 414,224 (28) 338,764 (28) 306,277 (28)
Cases: n (%) 83 (26) 151 (26) 84 (23) 177 (26) 145 (26) 137 (26)
HR (95% CI) 0.85 (0.66-1.10) 0.94 (0.78-1.13) 0.77 (0.60-0.99) 0.84 (0.70-0.99) 0.87 (0.72-1.05) 0.87 (0.71-1.06)
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a

Adjusted for sex and race/ethnicity without restrictions.

b

The baseline hazard was adjusted by including study in the strata statement.

c

Adjusted for sex, race/ethnicity and restricted to the 8 studies reporting history of cholecystectomy (AARP, ATBC, CPS-II NC, HPFS, MCCS, MEC, NHS, and WHI) without restricting to people who did not report a history of cholecystectomy.

d

Adjusted for sex, race/ethnicity and restricted to people who did not report a history of cholecystectomy (8 studies).

e

Any FHC includes data on second degree family history of cancer, which was available for BCDDP, IWHS, NHS, and WHI.

Abbreviations: ampulla of Vater cancer (AVC), Biliary Tract Cancers Pooling Project (BiTCaPP), confidence interval (CI), extrahepatic bile duct cancer (EHBDC), family history of cancer (FHC), gallbladder cancer (GBC), intrahepatic bile duct cancer (IHBDC).

Discussion

In the largest study to date, we examined associations of FHC and BTC risk by anatomic site. We observed no association of FHC with IHBDC or EHBDC and marginal, inverse associations with GBC and with AVC. To address the concern that associations of FHC with GBC may reflect informative censoring by cholecystectomy rather than a true association, we restricted FHC-GBC analyses to studies reporting cholecystectomy and to people not reporting a history of a cholecystectomy, which drove associations between FHC and GBC to the null. The association between family history of hormonally-related cancer (upper CI of 0.99) and AVC may represent a false positive finding among many comparisons.

While most previous studies reported FHC associated with higher risk of BTCs overall (3), GBC (4, 5, 7), EHBDC or IHBDC (6, 7), or AVC (7), one study using FHC from the Utah pedigree database reported statistically nonsignificant, lower risks of BTCs with FHC (8). BiTCaPP was also predominantly comprised of non-Hispanic whites from the U.S. It is possible that the association of FHC with BTC risk may vary by population. Thus, FHC still may be an important predictor of BTC risk outside of the United States. Misclassification of self-reported FHC is possible but likely nondifferential.

In the largest prospective study, we found no associations between FHC and BTC risk. These results provide no support to the hypothesis that having a FHC is associated with higher BTC risk. As we were unable to examine associations of family history of BTCs with BTCs, the results do not preclude this potential association.

Acknowledgments

The authors thank the participants, investigators, study coordinators, data managers and other research staff of the studies contributing family history of cancer data to BiTCaPP. We also thank Eric Boyd with Information Management Services (Calverton, Maryland) for his contribution to data harmonization.

The content is solely the responsibility of the authors and does not necessarily represent the official views of the National Institutes of Health.

For NIH-AARP, the acknowledgement statement is on the following website: https://dietandhealth.cancer.gov/acknowledgement.html.

The Melbourne Collaborative Cohort Study was made possible by the contributions of many people, including the original investigators, the recruiting teams, and the many thousands of Melbourne residents who participated in the study.

We would like to thank the participants and staff of the Nurses’ Health Study and the Health Professionals Follow-up Study 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, WY. The authors assume full responsibility for analyses and interpretation of these data.

For a list of the investigators who have contributed to the Women’s Health Initiative science, please visit the following website: http://www.whi.org/researchers/Documents%20%20Write%20a%20Paper/WHI%20Investigator%20Short%20List.pdf)

Grant Support:

  • This work and the following coauthors were supported by the Intramural Research Program (IRP) of the National Institutes of Health (NIH), National Cancer Institute (NCI), Division of Cancer Epidemiology and Genetics (A.L. Van Dyke, M.S. Langhamer, B. Zhu, R.M. Pfeiffer, D. Albanes, G. Andreotti, L.E. Beane Freeman, N.D. Freedman, L. Liao, M.P. Purdue, C. Schairer, R. Sinha, S. Weinstein, J.L. Petrick, K.A. McGlynn, J. Koshiol).

  • The Agricultural Health Study is funded by the IRP of the NIH, NCI (Z01 P010119).

  • The NIH-AARP Diet and Health Study is supported by the IRP of DCEG at NCI, part of the NIH.

  • The Alpha-Tocopherol, Beta-Carotene Cancer Prevention (ATBC) Study is supported by the Intramural Research Program of the U.S. NCI, NIH, and by U.S. Public Health Service contract HHSN261201500005C from the NCI, Department of Health and Human Services.

  • The Breast Cancer Detection and Demonstration Project (BCDDP) is supported by the IRP of NCI, NIH and the American Cancer Society.

  • The American Cancer Society funded the Cancer Prevention Studies (CPS), including the CPS-II Nutrition Cohort, as well as S.G. Gapstur and P.T. Campbell.

  • The Health Professionals Follow-up Study: Prospective Studies of Diet and Cancer in Men and Women, A.T. Chan, and X. Zhang were supported by the EGRP, DCCPS, NCI (CA055075),

  • The Iowa Women’s Health Study, K. Robien, and J. Poynter were funded through the Epidemiology and Genomics Research Program (EGRP), Division of Cancer Control and Population Sciences (DCCPS) at NCI (CA039742).

  • The Melbourne Collaborative Cohort Study, G. Giles, and R. Milne were funded by Vic-Health, Cancer Council Victoria, and by Australian National Health and Medical Research Council grants 209057 and 396414. Cases and their vital status were ascertained through the Victorian Cancer Registry and the Australian Institute of Health and Welfare, including the National Death Index and the Australian Cancer Database.

  • Understanding Ethnic Differences in Cancer: The Multiethnic Cohort Study and K.R. Monroe received funding from the NCI (U01 CA164973).

  • The Nurses’ Health Study I: Dietary and Hormonal Determinants of Cancer in Women and F. Grodstein received funding through the EGRP, DCCPS, NCI (CA087969 and CA049449).

  • NCI funded the Prostate, Lung, Colorectal, and Ovarian Cancer Screening Trial through contracts.

  • The Women’s Health Initiative, M.L. Neuhouser, and J. Luo are funded by the National Heart, Lung, and Blood Institute, NCI, NIH, U.S. Department of Health and Human Services through contracts HHSN268201600018C, HHSN268201600001C, HHSN268201600002C, HHSN268201600003C, and HHSN268201600004C.

  • A.T. Chan also received funding from the National Institute of Diabetes and Digestive and Kidney Diseases, NIH (K24 DK098311) and from NCI, NIH (R01 CA137178, R01 CA202704, and R01 CA176272).

Abbreviations List

AARP

NIH-AARP Diet and Health Study

AgHealth

Agricultural Health Study

ATBC

Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study

AVC

ampulla of Vater cancer

BCDDP

Breast Cancer Detection Demonstration Project

BiTCaPP

Biliary Tract Cancers Pooling Project

BTC

biliary tract cancer

CI

confidence interval

CPS-II NC

Cancer Prevention Study II Nutrition Cohort

EHBDC

extrahepatic bile duct cancer

FHC

family history of cancer

GBC

gallbladder cancer

HPFS

Health Professionals Follow-Up Study

IHBDC

intrahepatic bile duct cancer

IRB

institutional review board

IWHS

Iowa Women’s Health Study

MCCS

Melbourne Collaborative Cohort Study

MEC

Multiethnic Cohort Study

NHS

Nurses’ Health Study

PLCO

Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial

SD

standard deviation

WHI

Women’s Health Initiative

Footnotes

Conflict of Interest: The authors declare no potential conflicts of interest.

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