Carcinogenesis Advance Access published online on January 23, 2009
Carcinogenesis, doi:10.1093/carcin/bgp024
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Variants in Hormone-Related Genes and the Risk of Biliary Tract Cancers and Stones: A Population-based Study in China
1 Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA
2 Seoul National University College of Medicine, Seoul, Republic of Korea
3 Department of Epidemiology, University of Washington, Seattle, WA, USA
4 Shanghai Cancer Institute, Shanghai, China
5 Department of Pathology, MD Anderson Cancer Center, Houston, TX, USA
6 Department of Epidemiology, University of Pennsylvania, Philadelphia, PA; USA
7 Shanghai Tumor Hospital, Fudan University, Shanghai, China
8 Zhongshan Hospital, Fudan University, Shanghai, China
9 Department of Surgery, Ruijin Hospital, Shanghai Second Medical University, Shanghai, China
10 Institute of Oriental Hepatobiliary Surgery, Second Military Medical University, Shanghai, China
11 Core Genotyping Facility, National Cancer Institute, National Institutes of Health, Gaithersburg, MD, USA
Reprint requests or Correspondence to: In the U.S.A., Ann Hsing, Ph.D, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Department of Health and Human Services, 6120 Executive Blvd., EPS 5024, MSC7234, Bethesda, MD 20892-7234. Telephone: 301-496-1691; E-mail: hsinga{at}mail.nih.gov.
In Korea, Sue Kyung Park, M.D., Ph.D., Department of Preventive Medicine, Seoul National University College of Medicine, 28 Yeongeon-Dong, Jongro-Gu, Seoul 110-799, Republic of Korea; Telephone: 82-11-736-3679; Fax: 82-2-747-4830; E-mail: suepark{at}snu.ac.kr.
Biliary tract cancers, encompassing gallbladder, extrahepatic bile duct, and ampulla of Vater cancers, are uncommon but often fatal malignancies. Hormone-related factors, including parity, oral contraceptive use, obesity, and gallstones, have been implicated in the etiology of these cancers. To further clarify the role of hormones in biliary tract cancers and biliary stones, we genotyped 18 single nucleotide polymorphisms (SNPs) in 9 genes involved in steroid hormone biosynthesis, metabolism, and transport in a population-based case-control study in Shanghai, China. This study included subjects who completed an interview and provided blood, which totaled, 411 biliary tract cancer and 893 biliary stone patients, and 786 healthy Shanghai residents. The CYP1A1 IVS1 + 606 (rs2606345) T allele was associated with gallbladder (odds ratio (OR) = 2.0, 95 % CI, 1.3-3.0) and bile duct cancers (OR = 1.8, 95% CI = 1.1-3.1), while the CYP1A1 Ex7 + 131 (rs1048943) G allele was associated with ampulla of Vater cancer (OR = 2.9, 95% CI = 1.5-5.4). After taking into account multiple comparisons for SNPs within each gene, CYP1A1 was significantly associated with gallbladder (p = 0.004) and ampulla of Vater cancers (p = 0.01), but borderline with bile duct cancer (p = 0.06). The effect of CYP1A1 IVS1 + 606 on gallbladder cancer was more pronounced among non-obese (BMI <23) (OR=3.3, 95% CI = 1.8-6.1; p interaction = 0.001). Among women taking oral contraceptives, the effect of SHBG Ex8 + 6 (rs6259) on gallbladder cancer (OR = 6.7, 95% CI = 2.2-20.5; p interaction = 0.001) and stones (OR = 2.3, 95% CI = 1.1-4.9; p-interaction = 0.05) was statistically significant. Our findings suggest that common variants in hormone-related genes contribute to the risk of biliary tract cancers and stones possibly by modulating hormone metabolism.
Key Words: Biliary tract neoplasm • gallstones • genetic polymorphism • hormone biosynthesis, metabolism, and transport
Received November 16, 2008; revised January 12, 2009; accepted January 13, 2009.