Carcinogenesis Advance Access originally published online on January 23, 2009
Carcinogenesis 2009 30(4):606-614; 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 Department of Health and Human Services, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, 6120 Executive Boulevard, EPS 5024, MSC 7234, Bethesda, MD 20892-7234, USA
2 Department of Preventive Medicine, Seoul National University College of Medicine, 28 Yeongeon-Dong, Jongro-Gu, Seoul 110-799, Republic of Korea
3 Department of Epidemiology, University of Washington, Seattle, WA 98195, USA
4 Shanghai Cancer Institute, Shanghai, China
5 Department of Pathology, MD Anderson Cancer Center, Houston, TX 77030, USA
6 Department of Epidemiology, University of Pennsylvania, Philadelphia, PA 19104, USA
7 Shanghai Tumor Hospital
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 20892, USA
* To whom correspondence should be addressed. Tel: +1 301 496 1691; Fax: +1 301 402 0916; Email: hsinga{at}mail.nih.gov
Correspondence may also be addressed to Sue Kyung Park. Tel: +82 11 736 3679; Fax: +82 2 747 4830; Email: 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 nine 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% confidence interval (CI), 1.3–3.0] and bile duct cancers (OR = 1.8, 95% CI = 1.1–3.1), whereas 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 (body mass index < 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.
Abbreviations: BMI, body mass index; CI, confidence interval; 2-OH-E2, 2-hydroxy-estradiol; OC, oral contraceptives; OR, odds ratio; SHBG, sex hormone-binding globulin; SNP, single-nucleotide polymorphisms
Received November 16, 2008; revised January 12, 2009; accepted January 13, 2009.