Lipopolysaccharide-pathway proteins are associated with gallbladder cancer among adults in Shanghai, China with mediation by systemic inflammation.

PURPOSE: We examined inflammation as a mediator of associations between bacterial infection markers and gallbladder cancer (GBC). METHODS: Bacterial response proteins (lipopolysaccharide [LPS], soluble cluster of differentiation 14 [sCD14], and LPS-binding protein [LBP]) were measured in 40 GBC cases and 126 gallstone controls with data on 63 serum inflammation markers. The relationships of LPS, LBP, and sCD14 with GBC were examined by logistic regression, which also was used to evaluate whether these associations are influenced by systemic inflammation as measured by a combinatorial inflammation score. RESULTS: The third versus the first tertiles of sCD14 and of LBP were associated with an increased GBC risk (odds ratio [95% confidence interval]: 5.41 [2.00-16.75] for sCD14, and 6.49 [2.24-23.79] for LBP). sCD14 and LBP were strongly associated with inflammation score (above vs. below the median), which itself was associated with a more than 21-fold increased risk of GBC for the third versus first tertiles. Associations between GBC and sCD14 and LBP were markedly attenuated when the inflammation score was included in the model. While LPS was not associated with GBC or inflammation, only 35% of cases and 22% of controls had detectable levels. CONCLUSIONS: These findings suggest that these LPS-pathway proteins are associated with GBC via inflammation-related pathways.

Application of multiplex arrays for cytokine and chemokine profiling of bile.

BACKGROUND: Gallbladder disease is highly related to inflammation, but the inflammatory processes are not well understood. Bile provides a direct substrate in assessing the local inflammatory response that develops in the gallbladder. To assess the reproducibility of measuring inflammatory markers in bile, we designed a methods study of 69 multiplexed immune-related markers measured in bile obtained from gallstone patients. METHODS: To evaluate assay performance, a total of 18 bile samples were tested twice within the same plate for each analyte, and the 18 bile samples were tested on two different days for each analyte. We used the following performance parameters: detectability, coefficient of variation (CV), intraclass correlation coefficient (ICC), and percent agreement (concordance among replicate measures above and below detection limit). Furthermore, we examined the association of analyte levels with gallstone characteristics such as type, numbers, and size. RESULTS: All but 3 analytes (Stem Cell Factor, SCF; Thrombopoietin, TPO; sIL-1RI) were detectable in bile. 52 of 69 (75.4%) analytes had detectable levels for at least 50% of the subjects tested. The within-plate CVs were ⩽25% for 53 of 66 (80.3%) detectable analytes, and across-plate CVs were ⩽25% for 32 of 66 (48.5%) detectable analytes. Moreover, 64 of 66 (97.0%) analytes had ICC values of at least 0.8. Lastly, the percent agreement was high between replicates for all of the analytes (median; within plate, 97.2%; across plate, 97.2%). In exploratory analyses, we assessed analyte levels by gallstone characteristics and found that levels for several analytes decreased with increasing size of the largest gallstone per patient. CONCLUSIONS: Our data suggest that multiplex assays can be used to reliably measure cytokines and chemokines in bile. In addition, gallstone size was inversely related to the levels of select analytes, which may aid in identifying critical pathways and mechanisms associated with the pathogenesis of gallbladder diseases.

Variants in motilin, somatostatin and their receptor genes and risk of biliary tract cancers and stones in Shanghai, China.

Altered motility of the gallbladder can result in gallstone and cholecystitis, which are important risk factor for biliary tract cancer. Motilin (MLN) and somatostatin (SST) are known important modulators of gallbladder motility. To determine whether genetic variants in motilin, somatostatin, and their receptor genes are associated with the risk of biliary tract cancers and stones, nine tag-SNPs were determined in 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct and 53 ampulla of Vater cancer cases), 429 biliary stone cases, and 447 population controls in a population-based case-control study in Shanghai, China. We found that subjects with the MLNR rs9568169 AA genotype and SSTR5 rs169068 CC genotype were significantly associated with risk of extrahepatic bile duct cancer (OR =0.49, 95% CI: 0.27-0.89; OR =2.40, 95% CI: 1.13-5.13) compared to the major genotypes. MLN rs2281820 CT and rs3793079 AT genotypes had significantly increased risks of gallstones (OR =1.52, 95% CI: 1.06-2.18; OR =1.64, 95% CI: 1.20-2.25) compared to TT genotypes. Besides, Haplotype analysis showed that MLN T-T-T haplotype (rs2281820-rs3793079-rs2281819) had a non-significantly elevated risk of gallstone (OR =1.30, 95% CI: 0.91-1.86) compared with C-A-A haplotype. To the best of our knowledge, this is the first study to report an association between genetic polymorphisms in MLN, MLNR and their receptor genes and risk of biliary tract cancers and stones.

Variants in CCK and CCKAR genes to susceptibility to biliary tract cancers and stones: a population-based study in Shanghai, China.

BACKGROUND AND AIM: Altered motility of the gallbladder is associated with an increased risk of gallstones and can result in biliary tract cancers. Cholecystokinin (CCK) is an important modulator of gallbladder motility which functions by activating CCK type-A receptor (CCKAR). The aim of this study was to determine whether genetic variants in CCK and CCKAR are associated with the risk of biliary tract cancers and stones. METHODS: We investigated the associations between nine single nucleotide polymorphisms in CCK and CCKAR in a population-based case-control study, including 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct, and 53 ampulla of Vater cancer cases), 429 biliary stone cases, and 447 population controls in Shanghai, China. RESULTS: We found that women with the CCKAR rs1800855 AA genotype had an increased risk of gallbladder cancer (odds ratio = 2.37, 95% confidence interval (CI): 1.36-4.14) compared with subjects with the TT genotype, and remained significant after Bonferroni correction (P = 0.0056). Additionally, female carriers of the CCKAR haplotype C-T-C-T (rs2071011-rs915889-rs3822222-rs1800855) had a reduced risk of gallbladder cancer (odds ratio = 0.61, 95% confidence interval: 0.43-0.86) compared with those with the G-C-C-A haplotype; the association also remained significant after Bonferroni correction. CONCLUSIONS: These findings suggest that variants in the CCKAR gene may influence the risk of gallbladder cancer in women. Additional studies are needed to confirm our findings.

Cholesterol metabolism gene polymorphisms and the risk of biliary tract cancers and stones: a population-based case-control study in Shanghai, China.

Biliary tract cancers are rare but fatal malignancies, with increasing incidence in Shanghai, China. Gallstones, the primary risk factor for biliary tract cancer, typically result from oversaturation of cholesterol in bile. We examined the association of five variants in three lipid metabolism-related genes (CETP, ABCG8 and LRPAP1) and biliary tract cancers and stones in a population-based case-control study in Shanghai, China. We included 439 biliary tract cancer cases (253 gallbladder, 133 extrahepatic bile duct and 53 ampulla of Vater cancer cases), 429 biliary stone cases and 447 population controls. Carriers of the CG genotype of ABCG8 rs11887534 had higher risk of biliary stones [odds ratio (OR) = 2.3, 95% confidence interval (CI) 0.82-6.5), gallbladder cancer (OR = 4.3, 95% CI 1.7-10.4) and bile duct cancer (OR = 1.94, 95% CI 0.64-5.91), compared with carriers of the GG genotype. Analysis stratified by gender showed both male and female carriers of CG rs11887534 had higher risks of biliary stones and gallbladder cancer, although the association was statistically significant only for women and gallbladder cancer (OR = 6.3, 95% CI 1.86-22.3). Carriers of the ABCG8 haplotype C-C (rs4148217-rs11887534) had a 4.16-fold (95% CI 1.71-10.1) risk of gallbladder cancer compared with those carrying the C-G haplotype. Our findings suggest that ABCG8 rs11887534, identified as a gallstone risk single-nucleotide polymorphism by whole genome scan, is also associated with an increased risk of biliary tract cancer.

Androgen receptor CAG repeat length and risk of biliary tract cancer and stones.

Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, are rare but highly fatal. Gallstones represent the major risk factor for biliary tract cancer, and share with gallbladder cancer a female predominance and an association with reproductive factors and obesity. Although estrogens have been implicated in earlier studies of gallbladder cancer, there are no data on the role of androgens. Because intracellular androgen activity is mediated through the androgen receptor (AR), we examined associations between AR CAG repeat length [(CAG)(n)] and the risk of biliary tract cancers and stones in a population-based study of 331 incident cancer cases, 837 gallstone cases, and 750 controls from Shanghai, China, where the incidence rates for biliary tract cancer are rising sharply. Men with (CAG)(n) >24 had a significant 2-fold risk of gallbladder cancer [odds ratio (OR), 2.00; 95% confidence interval (CI), 1.07-3.73], relative to those with (CAG)(n) < or = 22. In contrast, women with (CAG)(n) >24 had reduced gallbladder cancer risk (OR, 0.69; 95% CI, 0.43-1.09) relative to those with (CAG)(n) < or = 22; P interaction sex = 0.01, which was most pronounced for women ages 68 to 74 (OR, 0.48; 95% CI, 0.25-0.93; P interaction age = 0.02). No associations were found for bile duct cancer or gallstones. Reasons for the heterogeneity of genetic effects by gender and age are unclear but may reflect an interplay between AR and the levels of androgen as well as estrogen in men and older women. Further studies are needed to confirm these findings and clarify the mechanisms involved.

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.

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

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.

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

Biliary tract cancers, which encompass tumors of the gallbladder, extrahepatic ducts, and ampulla of Vater, are relatively rare tumors with a high fatality rate. Other than a close link with gallstones, the etiology of biliary tract cancers is poorly understood. We conducted a population-based case-control study in Shanghai, China, to examine whether genetic variants in several DNA repair genes are associated with biliary tract cancers or biliary stones. Genomic DNA from 410 patients with biliary tract cancers (236 gallbladder, 127 bile duct, and 47 ampulla of Vater), 891 patients with biliary stones, and 786 healthy subjects randomly selected from the Shanghai population were genotyped for putative functional single nucleotide polymorphisms in four DNA repair genes (MGMT, RAD23B, CCNH, and XRCC3). Of the five single nucleotide polymorphisms examined, only one (MGMT EX5-25C>T, rs12917) was associated with biliary tract cancer. Independent of gallstones, subjects carrying the CT genotype of the MGMT EX5-25C>T marker had a significantly reduced risk of gallbladder cancer [odds ratio (OR), 0.63; 95% confidence interval (95% CI), 0.41-0.97; P = 0.02] and nonsignificant reduced risks of bile duct (OR, 0.61; 95% CI, 0.35-1.06) and ampulla of Vater (OR, 0.85; 95% CI, 0.39-1.87) cancers. However, this marker was not associated with biliary stones, and the other markers examined were not significantly associated with either biliary tract cancers or stones. Findings from this population-based study in Shanghai suggest that MGMT gene variants may alter susceptibility to biliary tract cancer, particularly gallbladder cancer. Confirmation in future studies, however, is required.

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.

Biliary tract cancer and stones in relation to chronic liver conditions: A population-based study in Shanghai, China.

Biliary tract cancers are relatively rare but fatal tumors. Apart from a close link with gallstones and cholangitis, risk factors for biliary tract cancer are obscure. Chronic liver conditions, including liver cirrhosis, have been linked to a higher risk of biliary tract cancer. In a population-based case-control study conducted in Shanghai, China, we investigated the relationships of a history of chronic hepatitis and liver cirrhosis as well as a family history of liver cancer with biliary tract cancer risk. The study included 627 patients with biliary tract cancers (368 gallbladder, 191 bile duct and 68 ampulla of Vater), 1,037 patients with biliary stones (774 gallbladder stones and 263 bile duct stones) and 959 healthy subjects randomly selected from the population. Bile duct cancer was associated with self-reports of chronic liver conditions, including a history of chronic hepatitis (OR = 2.0, 95% CI 0.9-4.4), liver cirrhosis (OR = 4.7, 95% CI 1.9-11.7) and a family history of primary liver cancer (OR = 2.0, 95% CI 1.0-3.9). The excess risk persisted after adjustment for gallstones and were more pronounced among subjects without gallstones (OR = 5.0, 95% CI 1.3-20.0 and OR = 4.9, 95% 2.0-12.2, respectively). History of liver conditions was also associated with an excess of biliary stones (OR = 1.9, 95% CI 1.2-3.0). No association was found for cancers of the gallbladder and ampulla of Vater. A history of chronic hepatitis and cirrhosis may be risk factors for extraheptic bile duct cancer. Given that chronic infection with hepatitis B virus (HBV) is the most common cause of liver disease in China, serologic markers of HBV need to be measured in future studies to examine the link between HBV and bile duct cancer.

Tea drinking and the risk of biliary tract cancers and biliary stones: a population-based case-control study in Shanghai, China.

Biliary tract cancers, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, are rare but highly fatal malignancies. Apart from gallstones, etiologic factors for biliary tract cancer are not clearly defined. Several epidemiologic studies have suggested that consumption of tea, especially green tea, is protective against a variety of cancers, including gastrointestinal malignancies. As part of a large population-based case-control study of biliary tract disease in Shanghai, China, we evaluated the effects of tea consumption on the risk of biliary tract cancers and biliary stones. The study included 627 incident cases with biliary tract cancer, 1,037 cases with biliary stones and 959 randomly selected controls. Study subjects were interviewed to ascertain data on demographic, medical and dietary factors, including tea consumption. Forty-one percent of the controls were ever tea drinkers, defined as those who consumed at least 1 cup of tea per day for at least 6 months. After adjustment for age, education and body mass index, among women, ever tea drinkers had significantly reduced risks of biliary stones (OR = 0.73, 95% CI = 0.54-0.98) and gallbladder cancer (OR = 0.56, 95% CI = 0.38-0.83). The inverse relationship between tea consumption and gallbladder cancer risk was independent of gallstone disease. Among men, tea drinkers were more likely to be cigarette smokers, and the risk estimates were generally below 1.0, but were not statistically significant. Further studies are needed to confirm these results in other populations and clarify the hormonal and other mechanisms that may be involved.

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.

CYP17 MspA1 polymorphism and risk of biliary tract cancers and gallstones: a population-based study in Shanghai, China.

Biliary tract cancers, encompassing cancers of the gallbladder, extrahepatic bile duct and ampulla of Vater, are rare but highly fatal malignancies. Other than gallstones, little is known about the risk factors for biliary tract cancers. Endogenous estrogens are thought to play a role in the etiology of gallstones and gallbladder cancer, since both conditions predominate in females and are associated with parity and obesity. In view of reports linking the CYP17 MspA1 polymorphism to high circulating levels of estrogens and a predisposition to other hormonally related cancers, we examined the relationship between CYP17 MspA1 variants and risk of biliary disease in a population-based case-control study in Shanghai. The study included 446 cancer cases (254 gallbladder, 139 extrahepatic bile duct, 53 ampullary cancers), 929 biliary stone cases (691 gallbladder, 238 bile duct) and 818 population controls. Genomic DNA from peripheral blood lymphocytes was used for genotyping. Relative to those with the A2/A2 genotype, A1 carriers (A1/A1 and A1/A2 genotypes) had an increased risk of gallbladder cancer (odds ratio (OR) = 1.5, 95% confidence interval (CI) = 1.1-2.1). In addition, women with the A1 allele and high parity (> or =3) had a 3-fold risk of gallbladder cancer (OR = 3.3, 95% CI = 1.6-6.9), compared to those with the A2/A2 genotype and lower parity, with the highest risk seen for those also having biliary stones (OR = 4.6, 95% CI = 1.8-11.7, P(interaction) = 0.04). The A1 allele was not associated with a higher risk of gallstones except among those with body mass index (BMI) greater than 25 kg/m2 (OR = 3.1, 95% CI = 2.0-4.8, P(interaction) = 0.02) and among those with a history of diabetes (OR = 2.5, 95% CI = 1.4-4.3, P interaction = 0.09). No clear relation was seen between the CYP17 polymorphism and cancers of the bile duct or ampulla of Vater. The association of the CYP17 MspA1 polymorphism with an increased risk of gallbladder cancer, as well as biliary stones among overweight and diabetic individuals, suggests an interplay between genetic and hormonal risk factors in gallbladder disease.

Aspirin use and risk of biliary tract cancer: a population-based study in Shanghai, China.

The association of gallbladder and bile duct cancers with gallstones, cholecystitis, and cholangitis suggest that chronic inflammation contributes to the carcinogenic process. However, the effect of nonsteroidal anti-inflammatory drugs, such as aspirin, on biliary tract cancer has not been well studied. In a population-based case-control study conducted in Shanghai, China, we examined the relationship between aspirin use and the risk of biliary disease. A total of 627 patients with biliary tract cancer, including cancers of the gallbladder (n = 368), extrahepatic bile duct (n = 191), and ampulla of Vater (n = 68); 1,037 patients with biliary stones; and 958 healthy adults were included in the study. Self-reported data on aspirin use was collected from study participants by in-person interview. The prevalence of aspirin use was low, with 5.7% of the population controls being regular users. After controlling for age, sex, education, and biliary stone status, aspirin use was associated with a reduced risk of gallbladder cancer [odds ratio (OR), 0.37; 95% confidence interval (CI), 0.17-0.88]. An inverse relationship was also observed for frequency and duration of use and with younger age when starting use. In addition, there was a nonsignificant reduction in the risk of bile duct (OR, 0.48; 95% CI, 0.19-1.19) and ampullary cancers (OR, 0.22; 95% CI, 0.03-1.65) associated with aspirin use, whereas no clear association was seen with biliary stones (OR, 0.92; 95% CI, 0.59-1.44). Further studies of biliary tract cancer in other populations are needed to confirm these results and to elucidate the mechanisms that underlie the reduced risk associated with use of aspirin and possibly other nonsteroidal anti-inflammatory drugs.

[A survey on the diagnosis and treatment of biliary tract cancers in Shanghai].

OBJECTIVE: To survey the status of diagnosis and treatment of biliary tract cancer in Shanghai. METHODS: A clinical epidemiology investigation was carried out on 658 new cases of biliary duct cancers aged 35-74, that registered between June 1997 and May 2001 in urban Shanghai. Clinical findings were collected in 390 gallbladder cancer, 195 bile duct cancer and 73 ampullary cancer. RESULTS: Biliary tract cancers mainly occurred in elderly patients. Ratio of males to female was 1:2.61 in gallbladder cancer, while bile duct cancer and ampullary cancer were slightly more common in men. Association with gallstones was 68.5%, 43.1% and 22.4% for gallbladder cancer, bile duct cancer and ampullary cancer, respectively. Diagnostic accuracy rate of B-ultrasonography was 63.1% in gallbladder cancer. Incidental gallbladder cancer accounted for 20%, while stage IVA and IVB patients reached up to 43.6%. Misdiagnosis rate was still high in bile duct cancer and ampullary cancer, it was 19.1% and 47.1% respectively. In addition, most patients presented jaundice at diagnosis. 69 cases (18.2%) of gallbladder cancer, 50 cases (25.6%) of bile duct cancer and 54 cases (74%) of ampullary cancer underwent radical resection, the 1-, 3- and 5-year survival rates were 58.5%, 42.8% and 40.7%, 58%, 28.3% and 11.1%, 81.5%, 39.2% and 26.9%, respectively. 79 patients with bile duct cancer underwent palliative drainage, and most cases died within 1 year. Metal endo-prostheses or plastic stents were placed into the biliary tract in 38 patients. The median survival was about 7 months. CONCLUSIONS: It is difficult to make early diagnosis of biliary tract cancers. Standardization of the operation for gallbladder cancer must be respected. Surgical exploration should be undertaken when a bile duct cancer is suspected and there are no contraindications to surgery. Pancreatoduodenectomy should be recommended for ampullary cancer.

Alteration in N -acetylglucosaminyltransferase activities and glycan structure in tissue and bile glycoproteins from extrahepatic bile duct carcinoma.

The activities of three N -acetylglucosaminyltransferases (GnT)-III, IV and V, as well as the structural alterations of N-glycans on the glycoproteins in cancer tissues and bile specimens from 28 cases of extrahepatic bile duct carcinoma (EBDC) were compared with those from 18 cases of benign biliary duct diseases (BBDD). GnT activities were determined with fluorescence-labeled substrate using a HPLC method. It was found that GnT-III and GnT-V activities in EBDC were increased to 3.14 and 15.96 times respectively of the mean BBDD values, but GnT-IV remained unchanged. The activity of GnT-V was correlated with the grade of differentiation and TMN stage of EBDC. The up-regulation of GnT-III resulted in the increased bisecting-GlcNAc on the N-glycans of glycoproteins in cancer tissues and a 201 kDa bile glycoprotein when analyzed with HRP-labeled E(4)-PHA. The increased GnT-V activity led to the elevation of the beta1,6GlcNAc branch (or antennary number) on the N-glycans in cancer tissue glycoproteins and 201, 163, 122 kDa proteins in the bile as probed with HRP-labeled DSA. These findings suggest that the alteration in GnT activities may be involved in the malignant transformation and development of EBDC, resulting in the aberrant glycosylation of some tissue and bile proteins. The latter was expected to be used in the clinical diagnosis and prognosis evaluation in EBDC patients.

Correlation of glycosyltransferases mRNA expression in extrahepatic bile duct carcinoma with clinical pathological characteristics.

BACKGROUND: The incidence of extrahepatic bile duct carcinoma (EBDC) has been increasing, especially in aged people, but the glycobiology of the tumor is not elucidated. In this study we investigated the expressions of three glycosyltransferases in 35 patients with EBDC and 35 patients with benign biliary duct disease (BBDD) as well as their clinicopathological significance. METHOD: The patients were divided into several subgroups by tumor differentiation, TNM stage, and invasion by the standards recommended by UICC. Tumor samples were immediately frozen in liquid nitrogen after resection, followed by mRNA determination of enzymes in the tissue using a mRNA selective reverse trancriptase-polymerase chain reaction kit. The mRNA levels of different groups were semi-quantitatively compared. RESULTS: The mRNA levels of N-acetylglucosaminyltransferase V (GnT-V) and a subtype of alpha 2,3 sialyltransferases for N-glycans, ST3Gal-III were elevated 7.75 and 5.39 times in EBDC as compared with BBDD, respectively, and they were correlated to several clinicopathological factors including tumor advancement, differentiation, metastasis, and invasiveness. The mRNA expression of another sialyltransferase, ST6Gal-I, was also 0.63-fold higher in EBDC than in BBDD, but not involved in the clinicopathological characteristics. CONCLUSION: The elevated expression of these three glycosyltransferases can be considered as an important molecular event in the occurrence and progression of EBDC.