• biomarkers
• carcinoma
• epigenomics
• gallbladder neoplasms
• genetic markers
• genomics
• local
• neoplasm recurrence
• prognosis
• tumor

• COX2
• aspirin
• cancer survival
• genes
• mechanism
• pathway
• proteins

Glioblastoma is one of the most aggressive and deadliest malignant tumors. Acquired resistance decreases the effectiveness of bevacizumab in glioblastoma treatment and thus increases the mortality rate in patients with glioblastoma. In this study, the potential targets of pentagamavunone-1 (PGV-1), a curcumin analog, were explored as a complementary treatment to bevacizumab in glioblastoma therapy.

Target prediction, data collection, and analysis were conducted using the similarity ensemble approach (SEA), SwissTargetPrediction, STRING DB, and Gene Expression Omnibus (GEO) datasets. Gene ontology and Kyoto Encyclopedia of Genes and Genomes (KEGG) pathway enrichment analysis were conducted using Webgestalt and DAVID, respectively. Hub genes were selected based on the highest degree scores using the CytoHubba. Analysis of genetic alterations and gene expression as well as Kaplan–Meier survival analysis of selected genes were conducted with cBioportal and GEPIA. Immune infiltration correlations between selected genes and immune cells were analyzed with database TIMER 2.0.

We found 374 targets of PGV-1, 1139 differentially expressed genes (DEGs) from bevacizumab-resistant-glioblastoma cells. A Venn diagram analysis using these two sets of data resulted in 21 genes that were identified as potential targets of PGV-1 against bevacizumab resistance (PBR). PBR regulated the metabolism of xenobiotics by cytochrome P450. Seven potential therapeutic PBR, namely GSTM1, AKR1C3, AKR1C4, PTGS2, ADAM10, AKR1B1, and HSD17B110 were found to have genetic alterations in 1.2%–30% of patients with glioblastoma. Analysis using the GEPIA database showed that the mRNA expression of ADAM10, AKR1B1, and HSD17B10 was significantly upregulated in glioblastoma patients. Kaplan–Meier survival analysis showed that only patients with low mRNA expression of AKR1B1 had significantly better overall survival than the patients in the high mRNA group. We also found a correlation between PBR and immune cells and thus revealed the potential of PGV-1 as an immunotherapeutic agent via targeting of PBR.

This study highlighted seven PBR, namely, GSTM1, AKR1C3, AKR1C4, PTGS2, ADAM10, AKR1B1, and HSD17B110. This study also emphasized the potential of PBR as a target for immunotherapy with PGV-1. Further validation of the results of this study is required for the development of PGV-1 as an adjunct to immunotherapy for glioblastoma to counteract bevacizumab resistance.

• ADAM10, a disintegrant and metalloproteinase 10
• AKRs, Aldo keto reductases
• Bevacizumab resistance
• Bioinformatics
• CAFs, Cancer-associated fibroblasts
• COX-2, cyclooxigenase-2
• DEGs, differentially expressed genes
• DT, Direct targets of PGV-1
• GSTM1, glutathione S-transferase mu 1
• GSTP1, glutathione S-transferase Pi-1
• Glioblastoma
• HSD17B10, Human type 10 17beta-hydroxysteroid dehydrogenase
• Immunotherapy
• KEGG, Kyoto Encyclopedia of Genes and Genomes
• PBR, potential therapeutic target genes of PGV-1 against bevacizumab resistance glioblastoma
• PGV-1
• PGV-1, Pentagamavunon-1
• PTGS2, prostaglandin-endoperoxide synthase 2
• ROS, reactive oxygen species
• SEA, Similarity ensemble approach
• Target prediction
• VEGF, vascular endothelial growth factor
• Webgestalt, WEB-based GEne SeT AnaLysis Toolkit

• Cholangiocarcinoma
• Liver transplantation
• Neoadjuvant chemoradiotherapy
• Primary sclerosing cholangitis

• biomarkers
• diagnosis
• gallbladder cancer
• genetic susceptibility
• patient stratification
• prognosis
• treatment selection

• 825510 European Union's Horizon 2020 Research and Innovation Programme (ESCALON)
• 1170893 Fondo Nacional de Desarrollo Científico y Tecnológico (FONDECYT)

• ABCB4 mutation
• Cholangiocarcinoma
• LPAC syndrome
• QPCR
• UDCA therapy

• Aged
• Animals
• Bile Duct Neoplasms/etiology
• Bile Duct Neoplasms/pathology
• Bile Duct Neoplasms/surgery
• Cholangiocarcinoma/etiology
• Cholangiocarcinoma/pathology
• Cholangiocarcinoma/surgery
• Fatal Outcome
• Humans
• Male
• Opisthorchiasis/complications
• Opisthorchiasis/diagnosis
• Opisthorchiasis/epidemiology
• Opisthorchiasis/pathology
• Opisthorchis
• Siberia/epidemiology

• Cancer
• Candidate gene
• Gallbladder
• Genome wide association
• Germline
• Mutations
• Next generation sequencing
• Somatic

• Biliary Tract Neoplasms/genetics
• Biliary Tract Neoplasms/pathology
• Gallbladder Neoplasms/genetics
• Gallbladder Neoplasms/pathology
• Genetic Predisposition to Disease
• Genome-Wide Association Study
• Germ-Line Mutation/genetics
• High-Throughput Nucleotide Sequencing
• Humans

Aspirin has been revealed to probably decrease the risk of cholangiocarcinoma (CCC), which, nevertheless, is of controversy. To this end, a systematic review and meta-analysis was performed to investigate the above-described association.

We thoroughly searched PubMed, EMBASE, and ISI Web of Science for relevant studies published prior to October 2017, followed by random-effects model for calculation of pooled ORs and corresponding 95% CIs. Additionally, subgroup and sensitivity analyses were carried out to confirm whether the outcomes were stable.

Nine articles, consisting of 12,535 CCC patients and 92,97,450 healthy controls, were enrolled in this study. We demonstrated a significantly decreased risk of CCC in those using aspirin, with studies being heterogeneous (OR=0.69; CI=0.43–0.94; I2=97.4%). Moreover, this relationship was detected only in case-control studies (OR=0.65; 95% CI=0.38–0.93), rather than cohort studies (OR=0.94; 95% CI=0.70–1.27). Besides, in separated analysis of intrahepatic CCC and extrahepatic CCC, aspirin was more strongly correlated with a declined risk of intrahepatic CCC (OR=0.33, 95% CI=0.26–0.39; I2=93.6%) than the risk of extrahepatic CCC (OR=0.56, 95% CI=0.41–0.73; I2=0%).

Collectively, the aspirin administration was correlated with a significant 31% decreased risk of CCC, particularly in the intrahepatic CCC.

• aspirin
• biliary tract neoplasms
• cholangiocarcinoma
• meta-analysis

Numerous studies have investigated the relationship between COX-2 8473 T > C polymorphism and cancer susceptibility, however, the results remain controversial. Therefore, we carried out the present meta-analysis to obtain a more accurate assessment of this potential association.

In this meta-analysis, 79 case-control studies were included with a total of 38,634 cases and 55,206 controls. We searched all relevant articles published in PubMed, EMBASE, OVID, Web of Science, CNKI and Wanfang Data, till September 29, 2017. The pooled odds ratios (ORs) with 95% confidence intervals (CIs) were used to evaluate the strength of the association. We performed subgroup analysis according to ethnicity, source of controls, genotyping method and cancer type. Moreover, Trial sequential analysis (TSA) was implemented to decrease the risk of type I error and estimate whether the current evidence of the results was sufficient and conclusive.

Overall, our results indicated that 8473 T > C polymorphism was not associated with cancer susceptibility. However, stratified analysis showed that the polymorphism was associated with a statistically significant decreased risk for nasopharyngeal cancer and bladder cancer, but an increased risk for esophageal cancer and skin cancer. Interestingly, TSA demonstrated that the evidence of the result was sufficient in this study.

No significant association between COX-2 8473 T > C polymorphism and cancer risk was detected.

The online version of this article (10.1186/s12885-018-4753-3) contains supplementary material, which is available to authorized users.

• 8473 T > C polymorphism
• COX-2 gene
• Cancer
• Meta-analysis
• Risk

• Ampulla of vater carcinoma (AVC)
• Biomarker
• Mutation
• Prognosis

• Cholangiocarcinoma
• cells of origin
• classifications
• inflammation
• molecular profiling
• stem cells

Gallbladder cancer is a malignancy of biliary tract which is infrequent in developed countries but common in some specific geographical regions of developing countries. Late diagnosis and deprived prognosis are major problems for treatment of gallbladder carcinoma. The dramatic associations of this orphan cancer with various genetic and environmental factors are responsible for its poorly defined pathogenesis. An understanding to the relationship between epidemiology, molecular genetics and pathogenesis of gallbladder cancer can add new insights to its undetermined pathophysiology. Present review article provides a recent update regarding epidemiology, pathogenesis, and molecular genetics of gallbladder cancer. We systematically reviewed published literature on gallbladder cancer from online search engine PubMed (http://www.ncbi.nlm.nih.gov/pubmed). Various keywords used for retrieval of articles were Gallbladder, cancer Epidemiology, molecular genetics and bullion operators like AND, OR, NOT. Cross references were manually searched from various online search engines (http://www.ncbi.nlm.nih.gov/pubmed,https://scholar.google.co.in/, http://www.medline.com/home.jsp). Most of the articles published from 1982 to 2015 in peer reviewed journals have been included in this review.

• Gallbladder cancer
• Epidemiology
• Molecular genetics
• Pathogenesis

• Biomarkers, Tumor/genetics
• DNA Methylation
• Epigenesis, Genetic
• Gallbladder Neoplasms/epidemiology
• Gallbladder Neoplasms/genetics
• Gallbladder Neoplasms/pathology
• Gene Expression Regulation, Neoplastic
• Genetic Predisposition to Disease
• Humans
• Loss of Heterozygosity
• Microsatellite Instability
• Molecular Epidemiology
• Mutation
• Phenotype
• Risk Factors

• Inflammation
• Social genomics
• Stress

• Diagnosis and management
• Intrahepatic cholangiocarcinoma
• Practice guidelines

• Bile Duct Neoplasms/diagnosis
• Bile Duct Neoplasms/epidemiology
• Bile Duct Neoplasms/therapy
• Bile Ducts, Intrahepatic
• Cholangiocarcinoma/diagnosis
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/therapy
• Evidence-Based Medicine/standards
• Gastroenterology/standards
• Global Health
• Humans
• Practice Guidelines as Topic

• Aetiology
• Chronic inflammation
• Gallbladder cancer
• Pathogenesis

• neoplasm
• non-genomic factor
• β-adrenergic antagonism
• β-adrenergic blocker

Genetic variants in inflammation-related genes have been associated with biliary stones and biliary tract cancers in previous studies.

To follow-up on these findings, we examined 35 single nucleotide polymorphism (SNPs) in 5 genes related to inflammation (IL8, NFKBIL, RNASEL, TNF, and VEGFA) in 456 participants with incident biliary tract cancer cases (262 gallbladder, 141 extrahepatic bile duct, 53 ampulla of Vater), 982 participants with biliary stones, and 860 healthy controls in a population–based case–control study in Shanghai, China.

Suggestive associations were observed for SNPs in VEGFA with biliary stones, IL8 with gallbladder and ampulla of Vater cancers, and RNASEL with ampulla of Vater cancer (false discovery rate≤0.2).

These findings provide additional support for the role of inflammation in biliary stones and biliary tract cancer risk and need further validation.

• gallbladder cancer
• polymorphism
• review
• cancer
• meta-analysis

• Gallbladder Neoplasms/genetics
• Gene Expression Profiling
• Genetic Predisposition to Disease
• Polymorphism, Genetic
• Risk Factors

• Z99 HG999999 Intramural NIH HHS

• Bile Duct Neoplasms/epidemiology
• Bile Ducts, Intrahepatic
• Cholangiocarcinoma/classification
• Cholangiocarcinoma/epidemiology
• Cholangiocarcinoma/etiology
• Cholangitis, Sclerosing/complications
• Choledochal Cyst/complications
• Humans
• Parasitic Diseases/complications
• Risk Factors

• K24 DK078154 NIDDK NIH HHS
• P30 DK056338 NIDDK NIH HHS
• T32 DK083266 NIDDK NIH HHS
• T32 DK083266-01A1 NIDDK NIH HHS

• Alleles
• Apoptosis/genetics
• Case-Control Studies
• Cyclooxygenase 2/genetics
• DNA Repair/genetics
• Gallbladder Neoplasms/epidemiology
• Gallbladder Neoplasms/genetics
• Gallbladder Neoplasms/pathology
• Genes, Neoplasm
• Genetic Predisposition to Disease
• Humans
• India/epidemiology
• Inflammation/genetics
• Polymorphism, Genetic

Cyclooxygenase-2 (COX-2) is up-regulated in several types of cancer, and it is hypothesized that COX-2 expression may be genetically influenced. Here, we evaluate the association between single-nucleotide polymorphisms (SNPs) in the COX-2 gene (PTGS2) and the occurrence of breast cancer among Brazilian women.

The study was conducted prospectively in two steps: First, we screened the promoter region and three fragments of the 3'-untranslated region of PTGS2 from 67 healthy Brazilians to identify SNPs and to select those with a minor allele frequency (MAF) of at least 0.10. The MAF of these selected SNPs was further characterized in 402 healthy volunteers to evaluate potential differences related to heterogeneous racial admixture and to estimate the existence of linkage disequilibrium among the SNPs. The second step was a case-control study with 318 patients and 273 controls designed to evaluate PTGS2 genotype- or haplotype-associated risk of breast cancer.

The screening analysis indicated nine SNPs with the following MAFs: rs689465 (0.22), rs689466 (0.15), rs20415 (0.007), rs20417 (0.32), rs20419 (0.015), rs5270 (0.02), rs20424 (0.007), rs5275 (0.22) and rs4648298 (0.01). The SNPs rs689465, rs689466, rs20417 and rs5275 were further studied: Their genotypic distributions followed Hardy-Weinberg equilibrium and the MAFs were not affected by gender or skin color. Strong linkage disequilibrium was detected for rs689465, rs20417 and rs5275 in the three possible pairwise combinations. In the case-control study, there was a significant increase of rs5275TC heterozygotes in cases compared to controls (OR = 1.44, 95% CI = 1.01-2.06; P = 0.043), and the haplotype formed by rs689465G, rs689466A, rs20417G and rs5275C was only detected in cases. The apparent association with breast cancer was not confirmed for rs5275CC homozygotes or for the most frequent rs5275C-containing haplotypes.

Our results indicate no strong association between the four most frequent PTGS2 SNPs and the risk of breast cancer.

Biliary tract cancers (BTCs) are lethal malignancies currently lacking satisfactory methods for early detection and accurate diagnosis. Surface-enhanced laser desorption/ionization time-of-flight mass spectrometry (SELDI-TOF-MS) is a promising diagnostic tool for this disease. In this pilot study, sera samples from 50 BTCs and 30 cholelithiasis patients as well as 30 healthy subjects from a population-based case-control study were randomly grouped into training set (30 BTCs, 20 cholelithiasis and 20 controls), duplicate of training set, and blind set (20 BTCs, 10 cholelithiasis and 10 controls); all sets were analyzed on Immobilized Metal Affinity Capture ProteinChips via SELDI-TOF-MS. A decision tree classifier was built using the training set and applied to all test sets. The classification tree constructed with the 3,400, 4,502, 5,680, 7,598, and 11,242 mass-to-charge ratio (m/z) protein peaks had a sensitivity of 96.7% and a specificity of 85.0% when comparing BTCs with non-cancers. When applied to the duplicate set, sensitivity was 66.7% and specificity was 70.0%, while in the blind set, sensitivity was 95.0% and specificity was 75.0%. Positive predictive values of the training, duplicate, and blind sets were 82.9%, 62.5% and 79.2%, respectively. The agreement of the training and duplicate sets was 71.4% (Kappa = 0.43, u = 3.98, P < 0.01). The coefficient of variations based on 10 replicates of one sample for the five differential peaks were 15.8–68.8% for intensity and 0–0.05% for m/z. These pilot results suggest that serum protein profiling by SELDI-TOF-MS may be a promising approach for identifying BTCs but low assay reproducibility may limit its application in clinical practice.

• R01 CA080180 NCI NIH HHS

• Aged
• Biliary Tract Neoplasms/etiology
• Biliary Tract Neoplasms/genetics
• Body Mass Index
• Estrogen Receptor alpha/genetics
• Estrogen Receptor beta/genetics
• Female
• Gallstones/etiology
• Gallstones/genetics
• Humans
• Male
• Middle Aged
• Polymorphism, Single Nucleotide
• Risk

• ZIA CP010158 Intramural NIH HHS
• N01-CO-12400 NCI NIH HHS

Cholangiocarcinoma (CCA) is a devastating cancer arising from the neoplastic transformation of the biliary epithelium. It is characterized by a progressive increase in incidence and prevalence. The only curative therapy is radical surgery or liver transplantation but, unfortunately, the majority of patients present with advanced stage disease, which is not amenable to surgical therapies. Recently, proposed serum and bile biomarkers could help in the screening and surveillance of categories at risk and in diagnosing CCA at an early stage. The molecular mechanisms triggering neoplastic transformation and growth of biliary epithelium are still undefined, but significant progress has been achieved in the last few years. This review deals with the most recent advances on epidemiology, biology, and clinical management of CCA.

• Cholangiocarcinoma
• Cholangiocytes
• Growth factors
• Proliferation
• Apoptosis

• Case-Control Studies
• Cyclooxygenase 2/genetics
• Female
• Gallbladder Neoplasms/genetics
• Genetic Predisposition to Disease
• Genotype
• Humans
• India
• Male
• Middle Aged
• Polymorphism, Genetic
• Risk

• gallbladder cancer
• gallstones
• mapuche
• typhoid
• genetics

• Chile/epidemiology
• Female
• Gallbladder Neoplasms/mortality
• Humans
• Male
• Risk Factors

• ZIA CP010158 Intramural NIH HHS

• biliary tract cancers
• gallbladder
• extrahepatic bile duct
• ampulla of vater
• dna repair
• polymorphism
• china

• Adult
• Aged
• Asian People/genetics
• Biliary Tract Neoplasms/epidemiology
• Biliary Tract Neoplasms/genetics
• Case-Control Studies
• Chi-Square Distribution
• China/epidemiology
• Cyclin H
• Cyclins/genetics
• DNA Modification Methylases/genetics
• DNA Repair/genetics
• DNA Repair Enzymes/genetics
• DNA-Binding Proteins/genetics
• Female
• Genetic Predisposition to Disease
• Genetic Variation
• Genotype
• Humans
• Logistic Models
• Male
• Middle Aged
• Polymorphism, Single Nucleotide/genetics
• Risk Factors
• Tumor Suppressor Proteins/genetics

• ZIA CP010158 Intramural NIH HHS

• gallstones
• biliary tract cancer
• inflammation
• genetic susceptibility

• Biliary Tract Neoplasms/epidemiology
• Biliary Tract Neoplasms/genetics
• China
• Humans
• Inflammation/genetics
• Polymorphism, Single Nucleotide
• Population Surveillance
• Risk Factors

• N01 CO012400 NCI NIH HHS
• ZIA CP010158 Intramural NIH HHS
• N01-CO-12400 NCI NIH HHS

Biliary tract cancer, encompassing tumors of the gallbladder, extrahepatic bile ducts and ampulla of Vater, is a rare but highly fatal malignancy. Obesity and gallstones, both related to insulin resistance, are linked to an elevated risk of biliary cancer. The peroxisome proliferator-activated receptors (PPARs) and the retinoid X receptors (RXRs), expressed in adipose tissue, play a key role in the regulation of obesity-related insulin sensitivity, thus genetic variants of these two receptor genes may be related to biliary cancer and stones. We examined the associations of seven single-nucleotide polymorphisms in the PPAR-γ, PPAR-δ, RXR-α, RXR-β and INS genes with biliary cancer and stones in a population-based case–control study in Shanghai, China. We included 237 gallbladder, 127 extrahepatic bile duct and 47 ampulla of Vater cancer cases, 895 stone cases and 786 population controls. Relative to individuals with the RXR-β C51T (rs2076310) CC genotype, those having the TT genotype had a 1.6-fold risk for bile duct cancer [odds ratio (OR) = 1.67; 95% confidence interval (CI) = 0.99–2.84], with a more pronounced association among men (OR = 2.30; 95% CI = 1.14–4.65; P interaction = 0.07). This marker was also associated with a higher risk of gallstones among subjects with a higher body mass index (BMI) (≥23 kg/m²) (OR = 1.80; 95% CI = 1.09–2.94), although the interaction with BMI was not statistically significant (P interaction = 0.28). No association was found between other variants and biliary cancers and stones. Results from this population-based study suggest that certain genetic variants involved in the regulation of obesity-related insulin sensitivity may increase susceptibility to bile duct cancer and gallstones.

• Animals
• Bile Acids and Salts/metabolism
• Cholesterol, Dietary/adverse effects
• Dietary Fats/adverse effects
• Fatty Acid Synthases/genetics
• Fatty Acids/administration & dosage
• Fatty Acids/biosynthesis
• Fatty Acids, Unsaturated/administration & dosage
• Humans
• Neoplasms/etiology
• Neoplasms/genetics
• Oxidation-Reduction
• PPAR gamma/metabolism
• Phytanic Acid/adverse effects
• Protein Prenylation
• Racemases and Epimerases/genetics
• Signal Transduction
• Vitamin D/therapeutic use

• P01CA106742 NCI NIH HHS
• R01CA107668 NCI NIH HHS
• R01CA114017 NCI NIH HHS
• R01CA114104 NCI NIH HHS
• R01CA115958 NCI NIH HHS

We conducted a population-based study of 627 patients with biliary tract cancers (368 of gallbladder, 191 bile duct, and 68 ampulla of Vater), 1037 with biliary stones, and 959 healthy controls randomly selected from the Shanghai population, all personally interviewed. Gallstone status was based on information from self-reports, imaging procedures, surgical notes, and medical records. Among controls, a transabdominal ultrasound was performed to detect asymptomatic gallstones. Gallstones removed from cancer cases and gallstone patients were classified by size, weight, colour, pattern, and content of cholesterol, bilirubin, and bile acids. Of the cancer patients, 69% had gallstones compared with 23% of the population controls. Compared with subjects without gallstones, odds ratios associated with gallstones were 23.8 (95% confidence interval (CI), 17.0–33.4), 8.0 (95% CI 5.6–11.4), and 4.2 (95% CI 2.5–7.0) for cancers of the gallbladder, extrahepatic bile ducts, and ampulla of Vater, respectively, persisting when restricted to those with gallstones at least 10 years prior to cancer. Biliary cancer risks were higher among subjects with both gallstones and self-reported cholecystitis, particularly for gallbladder cancer (OR=34.3, 95% CI 19.9–59.2). Subjects with bile duct cancer were more likely to have pigment stones, and with gallbladder cancer to have cholesterol stones (P<0.001). Gallstone weight in gallbladder cancer was significantly higher than in gallstone patients (4.9 vs 2.8 grams; P=0.001). We estimate that in Shanghai 80% (95% CI 75–84%), 59% (56–61%), and 41% (29–59%) of gallbladder, bile duct, and ampulla of Vater cancers, respectively, could be attributed to gallstones.

• biliary tract cancer
• cholelithiasis
• familial aggregation
• genetic susceptibility
• china

• Adult
• Aged
• Biliary Tract Neoplasms/epidemiology
• Case-Control Studies
• China
• Family Health
• Female
• Gallstones/epidemiology
• Gallstones/genetics
• Humans
• Male
• Middle Aged
• Risk Factors

• ZIA CP010158 Intramural NIH HHS

• Adolescent
• Alleles
• Asthma/genetics
• Case-Control Studies
• Child
• Child, Preschool
• China/epidemiology
• Cyclooxygenase 2/genetics
• Genotype
• Humans
• Hypersensitivity, Immediate/genetics
• Immunoglobulin E/blood
• Membrane Proteins/genetics
• Molecular Epidemiology
• Polymorphism, Single Nucleotide
• Predictive Value of Tests
• Respiratory Function Tests

• Algorithms
• Case-Control Studies
• Cholelithiasis/genetics
• Environment
• Genetics, Population
• Humans
• Linear Models
• Models, Genetic
• Polymorphism, Single Nucleotide/genetics
• Regression Analysis