Family history of gallstones and the risk of biliary tract cancer and gallstones: A population-based study in Shanghai, China

Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, DHHS, Bethesda, MD 20852, USA.
International Journal of Cancer (Impact Factor: 5.01). 08/2007; 121(4):832-8. DOI: 10.1002/ijc.22756
Source: PubMed

ABSTRACT 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.

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    • "Moreover, an increased number, volume, weight, cholesterol type and long-standing carriage of gallstones are also associated with a high risk for GBC. Subjects with gallstones but no family history of gallstones have a 21-fold risk, while those with both gallstones and a positive family history have a 57-fold risk (Hsing et al., 2007). In 1924, Leitch studied gallbladder carcinogenesis by introducing human gallstones, glass pebbles and pitch pellets into the gallbladder of guinea pigs. "
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    ABSTRACT: Gallbladder cancer (GBC) is a deadly biliary neo-plasia with marked ethnic and geographical distribution. The prognosis of GBC is often dismal due to late diagnosis and lack of effective therapeutic options. The main risk factor for GBC is gallstone carriage over long periods of time, which leads to persistent damage and chronic inflammation. This condition promotes genetic/epigenetic alterations and the progressive impairment of the epithelial architecture, mainly through a metaplasia–dysplasia–carcinoma sequence. New molecular alterations have been identified that may help improve the clinical management of patients through the application of more specific therapies. The application of new DNA sequencing technologies is making it possible to catalogue the spectrum of genetic alterations that charac-terise GBC and is aiding in the understanding of the biology behind gallbladder carcinogenesis. Here, a stepwise model of morphogenetic progression from inflammatory to neoplastic tissues is proposed based on currently available evidence. Epidemiology Gallbladder cancer (GBC) is an infrequent neoplasm with marked ethnic and geographical variations. High incidence rates occur in South American natives, particularly from Andean regions. Other high-risk areas are India, Pakistan and Eastern Europe. The high incidences observed in American natives suggest a considerable genetic component in the development of this disease, along with an important environmental influence, including diet and lifestyle (Stinton and Shaffer, 2012). GBC affects women 2–6 times more frequently than men, and its incidence increases progressively with age in both sexes. Although GBC is uncommon in most Western regions, for some countries, such as Chile and Bolivia, this disease is a public health problem. GBC is often diagnosed late when the disease is at advanced stages mainly due to its anatomical location and vague symptoms overlapped with gallstone disease. The overall mean survival rate for patients with advanced GBC is 6 months, with a 5-year survival rate of 5% (Stinton and Shaffer, 2012). Treatment of advanced GBC involves chemotherapeutic agents such as gem-citabine and 5-fluorouracil; however, these drugs extend the life of patients only a few weeks. Therefore, there is an urgent need to identify potential new therapeutic targets for GBC treatment. The most important risk factor for GBC is gallstones, present in over 95% of patients with chronic cholecystitis and 85–95% of patients with GBC (Roa et al., 1996, 2014b). In most regions with a high incidence of GBC, a high incidence of gallstone disease is also observed. However, around 10–25% of patients with GBC have no cholelithiasis and, importantly, only 1–3% of patients with gallstones will develop GBC. Other important risk factors are obesity, female gender, biliary infections and an anomalous pancreatobiliary ductal junction (Goldin and Roa, 2009). Gallstones >3 cm in size carry a 10-fold increased risk for GBC compared to smaller stones. Moreover, an increased eLS
    eLS, 03/2015; Wiley & Sons., ISBN: 9780470015902
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    • "The study protocol was approved by the Institutional Review Boards of the US National Cancer Institute (NCI) and the Shanghai Cancer Institute (SCI). Details of the study have been reported elsewhere (Hsing et al, 1998, 2007a, b, c, d). Patients with primary biliary cancer (ICD-9, 156) newly diagnosed between June 1997 and May 2001 were identified through a rapid-reporting system established between the Shanghai Cancer Institute and 42 collaborating hospitals in urban Shanghai. "
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    ABSTRACT: Though obesity is an established risk factor for gall bladder cancer, its role in cancers of the extrahepatic bile ducts and ampulla of Vater is less clear, as also is the role of abdominal obesity. In a population-based case-control study of biliary tract cancer in Shanghai, China, odds ratios (ORs) and 95% confidence intervals (CIs) were calculated for biliary tract cancer in relation to anthropometric measures, including body mass index (BMI) at various ages and waist-to-hip ratio (WHR), adjusting for age, sex, and education. The study included 627 patients with biliary tract cancer (368 gall bladder, 191 bile duct, 68 ampulla of Vater) and 959 healthy subjects randomly selected from the population. A higher BMI at all ages, including early adulthood (ages 20-29 years), and a greater WHR were associated with an increased risk of gall bladder cancer. A high usual adult BMI (>or=25) was associated with a 1.6-fold risk of gall bladder cancer (95% CI 1.2-2.1, P for trend <0.001). Among subjects without gallstones, BMI was also positively associated with gall bladder cancer risk. Regardless of BMI levels, increasing WHR was associated with an excess risk of gall bladder cancer risk, with those having a high BMI (>or=25) and a high WHR (>0.90) having the highest risk of gall bladder cancer (OR=12.6, 95% CI 4.8-33.2), relative to those with a low BMI and WHR. We found no clear risk patterns for cancers of the bile duct and ampulla of Vater. These results suggest that both overall and abdominal obesity, including obesity in early adulthood, are associated with an increased risk of gall bladder cancer. The increasing prevalence of obesity and cholesterol stones in Shanghai seems at least partly responsible for the rising incidence of gall bladder cancer in Shanghai.
    British Journal of Cancer 09/2008; 99(5):811-5. DOI:10.1038/sj.bjc.6604616 · 4.82 Impact Factor
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    ABSTRACT: Gallbladder cancer (GBC) is an uncommon disease in most developed countries, with the exception of some geographical areas. The highest gallbladder cancer incidence rates have been reported in women from North India (21.5/100,000), Chile (18.1/100,000), Pakistan (13.8/100,000), and Ecuador (12.9/100,000). High incidences have also been found in Korea and Japan and some central and eastern European countries such as Poland, the Czech Republic, and Slovakia [1, 2]. GBC is up to three times higher among women than men in most countries and up to six times in select populations [1, 3].
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