Risk Of Bile Duct Cancer Research Articles

Genetics of primary sclerosing cholangitis and pathophysiological implications.

Primary sclerosing cholangitis (PSC) is a chronic disease leading to fibrotic scarring of the intrahepatic and extrahepatic bile ducts, causing considerable morbidity and mortality via the development of cholestatic liver cirrhosis, concurrent IBD and a high risk of bile duct cancer. Expectations have been high that genetic studies would determine key factors in PSC pathogenesis to support the development of effective medical therapies. Through the application of genome-wide association studies, a large number of disease susceptibility genes have been identified. The overall genetic architecture of PSC shares features with both autoimmune diseases and IBD. Strong human leukocyte antigen gene associations, along with several susceptibility genes that are critically involved in T-cell function, support the involvement of adaptive immune responses in disease pathogenesis, and position PSC as an autoimmune disease. In this Review, we survey the developments that have led to these gene discoveries. We also elaborate relevant interpretations of individual gene findings in the context of established disease models in PSC, and propose relevant translational research efforts to pursue novel insights.

Exogenous estrogen and the risk of biliary tract cancer – a population-based study in a cohort of Swedish men treated for prostate cancer

Background: To assess the role of exogenous estrogen in the etiology of biliary tract cancer, a nationwide population-based cohort study in Sweden was performed. Methods: The study included all men in Sweden with prostate cancer diagnosed in 1961–2008. Due to treatment standards, patients diagnosed in 1961–1980 were considered more exposed to estrogen, while those diagnosed in 1981–2008 were regarded less exposed. Standardized incidence ratios (SIRs) with 95% confidence intervals (CIs) were calculated to estimate the risk of biliary tract cancer in cohort members compared to the corresponding Swedish male population. Results: After 849 307 person-years of follow-up in 203 131 prostate cancer patients, there were 41 incident gallbladder cancers and 36 cancers of the extra-hepatic bile ducts. In overall, there were no apparent differences in the risk of gallbladder cancer or bile duct cancer between patients diagnosed in 1961–1980 and patients diagnosed in 1981–2008. However, in patients diagnosed in 1961–1980, there was a statistically non-significant increased risk of gallbladder cancer (SIR 1.34; 95% CI 0.71–2.29) and extra-hepatic bile duct cancer (SIR 1.20; 95% CI 0.55–2.28) > 5 years of follow-up after the prostate cancer diagnosis. No such association was found for patients diagnosed in 1981–2008. Sensitivity analyses excluding prostate cancer patients exposed to potential confounding factors did not change the SIRs. Conclusions: Long exposure to high doses of exogenous estrogen might increase the risk of biliary tract cancer. However, any potential excess risk of bile duct cancer resulted by prolonged exposure to high doses of exogenous estrogen seems to be small.

Decreased risk of cholangiocarcinogenesis following repeated cycles of Opisthorchis viverrini infection-praziquantel treatment: Magnetic Resonance Imaging (MRI) and histopathological study in a hamster model

It has been suggested that repeated infection of Opisthorchis viverrini followed by repeated treatment with praziquantel (PZQ) increases risk of development of cholangiocarcinoma (CCA). Evidence for the prediction has accumulated based on findings of indirect approaches involving molecular changes and epidemiological trends. By contrast, here we directly monitored the impact of repeated liver fluke infection and treatment with PZQ on cholangiocarcinogenesis in a rodent model of human opisthorchiasis, using magnetic resonance imaging (MRI) and histopathology. Twenty five Syrian golden hamsters were assigned to five treatment groups: 1) infection with O. viverrini (OV group), 2) treatment with the carcinogen N-nitrosodimethylamine (NDMA) at 12.5ppm (DMN), 3) O. viverrini infection in tandem with NDMA (OD), 4) O. viverrini infection, NDMA, and treatment with PZQ (ODP), and 5) uninfected, untreated control. The repeated infections were established by intragastric inoculation of 50 metacercariae of O. viverrini to the OV, OD and ODP hamsters at weeks 0, 5 and 10. PZQ at 300mg/kg body weight was given to each hamster of the ODP group on weeks 4, 9 and 13 (four weeks after each infection). Imaging by MRI was undertaken on weeks 5, 10 and 14 (i.e. one week after each PZQ treatment). MRI revealed that the ODP hamsters did not develop CCA, whereas necropsy at week 40 revealed CCA in hamsters of the OD and DMN groups. Findings for histopathology and for proliferating cell nuclear antigen index conformed to the MRI findings. In overview, and notwithstanding that the immune response of individual hosts may play roles in cholangiocarcinogenesis, three cycles of the infection with O. viverrini followed treatment of the infection with PZQ did not increase the risk of bile duct cancer in this hamster model of liver fluke infection-induced CCA.

Risk of bile duct cancer among printing workers exposed to 1,2-dichloropropane and/or dichloromethane.

We conducted a retrospective cohort study to examine the risk of bile duct cancer among current and former workers in the offset color proof printing department at a printing company in Osaka, Japan. Standardized incidence ratios (SIRs) between January 1, 1985, and December 31, 2012, were estimated for the cumulative years of exposure to two chemicals, dichloromethane (DCM) and 1,2-dichloropropane (1,2-DCP), using the national incidence level as a reference. In addition, we examined risk patterns by the calendar year in which observation started. Among 106 workers with a total of 1,452.4 person-years of exposure, 17 bile duct cancer cases were observed, resulting in an estimated overall SIR of 1,132.5 (95% confidence interval (CI): 659.7-1,813.2). The SIR was 1,319.9 (95% CI: 658.9-2,361.7) for those who were exposed to both DCM and 1,2-DCP, and it was 1,002.8 (95% CI: 368.0-2,182.8) for those exposed to 1,2-DCP only. SIRs tended to increase according to years of exposure to 1,2-DCP but not DCM when a 5-year lag time was assumed. The SIRs were higher for the cohorts in which observation started in 1993-2000, particularly in cohorts in which it started in 1996-1999, compared with those in which it started before or after 1993-2000. We observed an extraordinarily high risk of bile duct cancer among the offset color proof printing workers. Elevated risk may be related to cumulative exposure to 1,2-DCP, but there remains some possibility that a portion of the risk is due to other unidentified substances.

Prevalence of Bile Duct Cancer among Printing Industry Workers in Comparison with Other Industries

The aim of this study was to assess the risk of developing bile duct cancer among workers in the other printing industry in comparison with workers in all industries in general. Prevalence of bile duct cancer was compared between workers in the printing industry and age-standardized controls in all other industries using the claims database of the Japan Health Insurance Association, which insures workers of small-medium sized employers of all industries. Young (aged 30-49) male workers in the printing industry showed an elevated but insignificant standardized prevalence rate ratio (SPRR) for bile duct cancer in comparison with workers in all other industries (SPRR: 1.78; 95%CI: 0.63-5.00). The risk was higher for intrahepatic bile duct cancer but remained insignificant (SPRR: 3.03; 95%CI: 0.52-17.56). The sharply elevated risk of bile duct cancer observed among proof-printing workers of a printing factory in Osaka may not be generalizable to workers in the printing industry nationwide.

A common variant at the TERT-CLPTM1L locus modulates genetic risk of bile duct cancer

Background & Aim: Risk genes for bile duct cancer (BDC) are poorly defined (Höblinger A, Curr Opin Gastroenterol 2008). In a recent genome-wide association (GWA) study, the common variants at the TERT-CLPTM1L locus [telomerase reverse transcriptase (TERT), cisplatin resistance related protein CRR9p (CLPTM1L)]rs401681 and rs2736098, potentially affecting telomere length, have been implicated in the genetic predisposition to multiple solid tumors, however, not including cholangiocarcinoma (Rafnar T, Nat Genet 2008). In this study, we assessed these variants in a large European BDC cohort.

Abstract 5750: Reproductive factors and risks of biliary tract cancers and stones: population-based study in Shanghai, China

Abstract Biliary tract cancers, encompassing tumors arising from the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are relatively uncommon but highly fatal. Higher parity has been linked to increased risks of gallbladder cancer and gallstones, but the effects of other reproductive factors are less clear. Thus, we examined the association between reproductive factors and the risks of biliary tract cancers and biliary stones among women in a population-based case-control study in Shanghai, China. A total of 361 incident biliary tract cancer cases (269 gallbladder and 92 extrahepatic bile duct), 647 biliary stone cases, and 586 healthy women randomly selected from the population were included. High parity, early age at first birth, and late age at menarche contributed to a higher risk of gallbladder cancer risk, particularly among women with associated biliary stones. Among women with stones, those who had 4 or more children and had their first child before the age of 23 had a 3.3-fold (95% CI 1.06-10.03) risk of gallbladder cancer, while those with menarche at 16 years or later had a 4.0-fold (95% CI 1.19-13.58) risk. Among parous women, breastfeeding was associated with a reduced risk of bile duct cancer (OR=0.40, 95% CI 0.20-0.81). In contrast, menopausal status, age at menopause, duration of menstruation, and oral contraceptive use were not associated with biliary tract cancer risk. No association was found between biliary stones and any of the reproductive factors examined. Our results provide further support for a role of reproductive factors, especially high parity and late age at menarche, in the development of gallbladder cancer among women with biliary stones. Citation Format: {Authors}. {Abstract title} [abstract]. In: Proceedings of the 101st Annual Meeting of the American Association for Cancer Research; 2010 Apr 17-21; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2010;70(8 Suppl):Abstract nr 5750.

Fasciola hepatica infection in a 65-year-old woman

Fascioliasis is an infectious disease caused by fasciola or liver fluke. Humans are accidental hosts to these flatworms. The World Health Organisation considers fascioliasis an important human parasitic disease. In Europe, Australia and Northern America, the disease is rare, but should have a high index of suspicion in patients who have lived in or travelled to endemic areas. Although it can be self-limiting, fascioliasis is associated with an increased risk of bile duct cancer. Before a clear-cut diagnosis is made using ELISA-based arrays, radiologic studies can provide the clinician with a number of suggestive features, thereby avoiding the need for liver biopsy or even surgery, which have nowadays become obsolete for the diagnosis of fascioliasis. We provide an overview of the major radiologic hallmarks and we demonstrate the role of iron-oxide enhanced MRI.

Polymorphisms of estrogen receptors and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China

Biliary tract cancer encompasses tumors of the gallbladder, bile duct and ampulla of Vater. Gallbladder cancer is more common in women, whereas bile duct cancer is more common in men, suggesting that sex hormones may play a role in the etiology of these cancers. The intracellular action of estrogens is regulated by the estrogen receptor (ESR); thus, we examined the role of common genetic variants in ESR genes on the risk of biliary tract cancers and stones in a population-based case-control study in Shanghai, China (411 cancer cases, 895 stone cases and 786 controls). We genotyped six single-nucleotide polymorphisms (SNPs), four in ESR1 (rs2234693, rs3841686, rs2228480 and rs1801132) and two in ESR2 (rs1256049 and rs4986938). In all participants, the ESR1 rs1801132 (P325P) G allele was associated with excess risks of bile duct [odds ratio (OR) = 1.7, 95% confidence interval (CI) 1.1-2.8] and ampulla of Vater cancers (OR = 2.1, 95% CI 0.9-4.9) compared with the CC genotype. The association with bile duct cancer was apparent among men (OR = 2.8, 95% CI 1.4-5.7) but not among women (P-heterogeneity = 0.01). Also, the ESR2 rs4986938 (38 bp 3' of STP) GG genotype was associated with a higher risk of bile duct cancer (OR = 3.3, 95% CI 1.3-8.7) compared with the AA genotype, although this estimate was based on a small number of subjects. None of the other SNPs examined was associated with biliary tract cancers or stones. False discovery rate-adjusted P-values were not significant (P > 0.1). No association was found for ESR1 haplotype based on four SNPs. These preliminary results suggest that variants in ESR genes could play a role in the etiology of biliary tract cancers, especially bile duct cancer in men.

Nanotechnology-Related Environment, Health, and Safety Research

We were very interested to read the article by Schmidt (2009) about the increasing number of nanomaterials and their potential effects. We were especially interested in the similarities between carbon nanotubes and chrysotile asbestos fibers. The widespread use of asbestos-like substances with similar putative carcinogenic potential could result in the development of other unexpected types of cancer. The potential carcinogenic risk of nano-materials that are structurally similar to asbestos and have been used in many industrial fields in the last few years has been highlighted by Carter (2008). Some studies conducted in animal models suggest that nanomaterials cause free radical–mediated cellular DNA damage and consequently have an asbestos-like carcinogenic action (Poland et al. 2008). In addition to mesothelioma (the typical cancer index of exposure) or lung cancer, asbestos can cause other types of cancer. On the basis of our clinical experience, we hypothesize that at least a portion of bile ducts cancers (i.e., cholangiocarcinomas) are caused by exposure to this known carcinogenic agent. From 2002 to 2008 we treated 258 patients with cholangiocarcinoma at our institute. Over the previous year, we carefully interviewed 66 consecutive patients using a standardized questionnaire asking about their exposure to asbestos and other known risk factors linked to bile duct carcino genesis (Khan et al. 2008). We collected each patient’s remote, recent, and occupational clinical history. In addition to the association with known risk factors for the onset of cholangiocarcinoma, we assessed occupational or household exposure to asbestos in 24 patients, 10 of whom did not have other certain risk factors (Table 1; Brandi et al. 2008). Table 1 Characteristics of patients. Asbestos fibers cause cancer through chronic inflammation, amplifying the production of oxygen radicals, cytokines, growth factors, and proinflammatory factors responsible for both impaired antioxidant and control cell proliferation and apoptosis mechanisms in target cells (Manning et al. 2002). In contrast with findings for pleural mesothelioma, the association between exposure to asbestos and the development of other tumors, such as gastrointestinal and bile duct cancers, has not been univocally demonstrated (Gamble 1994). The putative increased risk of bile duct cancer in subjects exposed to asbestos may be due to different mechanisms. The asbestos fibers cross the alveolar barrier by inhalation or penetrate the gastrointestinal mucosa by ingestion. They then reach the interstitial environment and circulatory system through lymphatic vessels and are finally delivered to all tissues, namely the liver and bile ducts (Miserocchi et al. 2008), where they may start a malignant transformation process (Wingren 2004). In addition, asbestos fibers may reach the bile ducts through the papilla of Vater from the intestinal lumen by retrograde reflux, as do bacteria, and remain in the gallbladder for a long time. In the near future we may have to consider asbestos as another factor accounting for the etiopathogenesis of cholangiocarcinomas that may explain the otherwise mysterious increasing incidence of intrahepatic cholangio carcinomas in Western countries.

Variants in inflammation genes and the risk of biliary tract cancers and stones: a population-based study in China.

To evaluate the role of chronic inflammation in the development of gallstones and biliary tract cancer, we examined the risk associated with 62 single nucleotide polymorphisms (SNPs), in 22 inflammation-related genes, in a population-based case-control study conducted in Shanghai, China, where the incidence of biliary tract cancer has been increasing in recent decades. The study included 411 cases with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct, and 47 ampulla of Vater), 895 with biliary stones, and 786 controls randomly selected from the population. Unconditional logistic regression was used to calculate odds ratios and 95% confidence intervals for the association of individual SNPs and haplotypes with biliary stones and biliary tract cancer. Of the 62 SNPs examined, 14 were related to the risk of biliary cancer and stones. Specifically, variants in the IL8, IL8RB, RNASEL, and NOS2 genes were associated with biliary stones, whereas VEGF variants were associated with gallbladder cancer. Of the 10 genes with multiple SNPs from which we inferred haplotypes, only one IL8RB haplotype, consisting of 3 SNPs (rs2230054, rs1126579, and rs1126580), was associated with the risk of bile duct cancer (P = 0.003) and biliary stones (P = 0.02), relative to the most frequent haplotype. In summary, common variants in genes that influence inflammatory responses may predispose to gallstones and biliary tract cancer, suggesting the need for future studies into the immunologic and inflammatory pathways that contribute to biliary diseases, including cancer.

Polymorphisms of Genes in the Lipid Metabolism Pathway and Risk of Biliary Tract Cancers and Stones: A Population-Based Case-Control Study in Shanghai, China

Biliary tract cancers, encompassing the gallbladder, extrahepatic bile duct, and ampulla of Vater, are uncommon yet highly fatal malignancies. Gallstones, the primary risk factor for biliary cancers, are linked with hyperlipidemia. We examined the associations of 12 single nucleotide polymorphisms of five genes in the lipid metabolism pathway with the risks of biliary cancers and stones in a population-based case-control study in Shanghai, China. We included 235 gallbladder, 125 extrahepatic bile duct, and 46 ampulla of Vater cancer cases, 880 biliary stone cases, and 779 population controls. Subjects completed an in-person interview and gave blood. Genotyping was conducted by TaqMan assay using DNA from buffy coats. The effects of APOE IVS1+69 (rs440446) and APOB IVS6+360C>T (rs520354) markers were limited to men. Men carrying the G allele of APOE IVS1+69 had a 1.7-fold risk of stones [95% confidence interval (95% CI), 1.2-2.4], a 1.8-fold risk of gallbladder cancer (95% CI, 1.0-3.3), a 3.7-fold risk of bile duct cancer (95% CI, 2.0-7.0), and a 4-fold risk of ampullary cancer (95% CI, 1.4-12.4). Male carriers of the T allele of APOB IVS6+360C>T had a 2-fold risk of bile duct cancer (95% CI, 1.2-3.4). The APOB T-T haplotype (APOB IVS6+360C>T, EX4+56C>T) was associated with a 1.6-fold risk of bile duct cancer (95% CI, 1.1-2.3). Male and female carriers of the T allele of LDLR IVS9-30C>T (rs1003723) had a 1.5-fold risk of bile duct cancer. Our findings suggest that gene variants in the lipid metabolism pathway contribute to the risk of biliary tract stones and cancers, particularly of the bile duct.

Serum lipid levels and the risk of biliary tract cancers and biliary stones: A population‐based study in China

Biliary tract cancers, encompassing the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. Gallstones, the predominant risk factor for biliary cancers, are linked with hyperlipidemia. As part of a population-based case-control study conducted in Shanghai, China, we examined the associations of serum lipid levels with biliary stones and cancers. We included 460 biliary cancer cases (264 gallbladder, 141 extrahepatic bile duct, and 55 ampulla of Vater), 981 biliary stone cases and 858 healthy individuals randomly selected from the population. Participants completed an in-person interview and gave overnight fasting blood samples. Participants in the highest quintile of triglycerides (>/=160 mg/dl) had a 1.4-fold risk of biliary stones (95% CI = 1.1-1.9), a 1.9-fold risk of gallbladder cancer (95% CI = 1.3-2.8), and a 4.8-fold risk of bile duct cancer (95% CI = 2.8-8.1), compared to the reference group (third quintile: 90-124 mg/dl). Participants in the lowest quintile of high-density lipoprotein (HDL) (<30 mg/dl) had a 4.2-fold risk of biliary stones (95% CI = 3.0-6.0), an 11.6-fold risk of gallbladder cancer (95% CI = 7.3-18.5), and a 16.8-fold risk of bile duct cancer (95% CI = 9.1-30.9), relative to the reference group (third quintile: 40-49 mg/dl). In addition, total cholesterol, low-density lipoprotein (LDL) and apolipoprotein A (apo A) were inversely associated with biliary stones; whereas low levels as well as high levels of total cholesterol, LDL, apo A and apolipoprotein B (apo B) were associated with excess risks of biliary tract cancers. Our findings support a role for serum lipids in gallstone development and biliary carcinogenesis.

Selected base excision repair gene polymorphisms and susceptibility to biliary tract cancer and biliary stones: a population-based case-control study in China

Base excision repair (BER) corrects DNA damage caused by oxidative stress and chronic inflammation, putative risk factors for cancer. To understand the relationship between genetic variation in BER genes and risk of biliary tract cancer and biliary stones, we examined non-synonymous polymorphisms in three key BER genes-x-ray repair cross-complementing group 1 (XRCC1) (R194W, rs1799782; R280H, rs25489 and R399Q, rs25487), apurinic/apyrimidinic endonuclease (APEX1) (D148E, rs3136820) and 8-oxoguanine DNA glycosylase (OGG1) (S326C, rs1052133), in a population-based study of 411 biliary tract cancer cases (237 gallbladder, 127 bile duct and 47 ampulla of Vater), 891 biliary (gallbladder or bile duct) stone cases and 786 population controls conducted in Shanghai, China. Compared with subjects carrying the XRCC1 194RR genotype, those with the WW genotype had a 1.9-fold risk of bile duct cancer [odds ratio (OR) = 1.9, 95% confidence interval (CI) = 1.1-3.5, P(trend) = 0.03], and compared with subjects carrying the XRCC1 280RR genotype, those with the XRCC1 280H allele had a 50% reduced risk of bile duct cancer (OR = 0.5, 95% CI = 0.3-0.9, P(trend) = 0.05). The effect of the R280H polymorphism persisted (P(trend) = 0.03), when all three XRCC1 polymorphisms were jointly considered in the model, a finding supported by the haplotype results (covariate-adjusted global permutation P = 0.03). We also found an inverse association between the APEX1 148E allele and gallbladder stones (P(trend) = 0.03), but no association for the OGG1 polymorphism. This study suggests that genetic variants in XRCC1 and APEX1 may alter susceptibility to biliary tract cancer and stones. Further studies are required to confirm the reported associations.

Prostaglandin-endoperoxide synthase 2 ( PTGS2 ) gene polymorphisms and risk of biliary tract cancer and gallstones: a population-based study in Shanghai, China

There is evidence that chronic inflammation predisposes to biliary tract cancer and that use of non-steroidal anti-inflammatory drugs (NSAIDs) is protective. Although the mechanisms by which NSAIDs lower cancer risk remain unclear, NSAIDs reduce prostaglandin production by blocking prostaglandin-endoperoxide synthase 2 (PTGS2, commonly known as COX-2), an enzyme induced by proinflammatory stimuli that is often overexpressed in malignant tissue. Since variants in the PTGS2 gene may modify the expression or function of its encoded enzyme to modulate the inflammatory response in the biliary tract, we examined the associations of eight PTGS2 polymorphisms (-645C-->T; Ex3 -8G-->C; IVS5 -275T-->G; IVS7 +111T-->C; Ex10 +127T-->C; Ex10 +686 --->ATTAT-->TTATA; Ex10 +837T-->C; Ex10 -90C-->T) with biliary tract cancer and stones in a population-based case-control study conducted in Shanghai, China. Genotyping was performed for 411 patients with biliary tract cancer (237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater), 895 patients with biliary stones (673 gallbladder, 222 bile duct), and 786 healthy individuals randomly selected from the population. Significant associations were seen only between the Ex10 +837T-->C marker and bile duct cancer risk. Relative to individuals with the TT genotype, those carrying the C allele (TC or CC genotype) had a 1.8-fold (95% confidence interval: 1.2-2.7) risk of bile duct cancer. Inferred haplotypes including this risk-conferring allele were also associated with increased bile duct cancer risk of similar magnitude. Our results suggest that a common PTGS2 variant increases bile duct cancer risk. Further investigation is needed to confirm and extend our findings in studies of biliary tract cancer that more comprehensively examine PTGS2 and other inflammation-related genes.

Precancerous conditions of biliary tract cancer in patients with pancreaticobiliary maljunction: reappraisal of nationwide survey in Japan.

It is widely known that pancreaticobiliary maljunction (PBM), an anomalous arrangement of the pancreaticobiliary ductal system, is frequently associated with biliary tract cancer in patients with or without bile duct dilatation. In 1985, we surveyed patients with PBM who had been operated on at 133 Japanese institutions. A close relationship was shown between biliary tract carcinogenesis and PBM, according to the type of maljunction and age distribution: PBM patients with cystic dilatation had a high risk of bile duct cancer, even in those who were young (aged less than 20 years); the incidence of gallbladder cancer increased markedly in PBM patients over 40 years old with cystic dilatation, while it gradually increased with age in the PBM patients without cystic dilatation. Therefore, we recommend surgical treatment for patients with PBM even if they have no symptoms.