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Biliary tract cancers are rare but highly fatal with poorly understood etiology. Identifying potentially modifiable risk factors for these cancers is essential for prevention. Here we estimated the relationship between adiposity and cancer across the biliary tract, including cancers of the gallbladder (GBC), intrahepatic bile ducts (IHBDC), extrahepatic bile ducts (EHBDC), and the ampulla of Vater (AVC). We pooled data from 27 prospective cohorts with over 2.7 million adults. Adiposity was measured using baseline body mass index (BMI), waist circumference, hip circumference, waist-to-hip, and waist-to-height ratios. HRs and 95% confidence intervals (95% CI) were estimated using Cox proportional hazards models adjusted for sex, education, race, smoking, and alcohol consumption with age as the time metric and the baseline hazard stratified by study. During 37,883,648 person-years of follow-up, 1,343 GBC cases, 1,194 EHBDC cases, 784 IHBDC cases, and 623 AVC cases occurred. For each 5 kg/m2 increase in BMI, there were risk increases for GBC (HR = 1.27; 95% CI, 1.19-1.36), IHBDC (HR = 1.32; 95% CI, 1.21-1.45), and EHBDC (HR = 1.13; 95% CI, 1.03-1.23), but not AVC (HR = 0.99; 95% CI, 0.88-1.11). Increasing waist circumference, hip circumference, waist-to-hip ratio, and waist-to-height ratio were associated with GBC and IHBDC but not EHBDC or AVC. These results indicate that adult adiposity is associated with an increased risk of biliary tract cancer, particularly GBC and IHBDC. Moreover, they provide evidence for recommending weight maintenance programs to reduce the risk of developing these cancers. SIGNIFICANCE: These findings identify a correlation between adiposity and biliary tract cancers, indicating that weight management programs may help minimize the risk of these diseases.
Characteristic bile duct and gut microbiota have been identified in patients with chronic biliary tract disease. This study aimed to characterize the fecal and bile microbiota in biliary tract cancer (BTC) patients and their relationship. Patients with BTC (n = 30) and benign biliary disease (BBD) without cholangitis (n = 11) were included. Ten healthy, age-matched subjects were also recruited for fecal microbiota comparison. The fecal and bile duct microbiotas were analyzed by sequencing the 16S rRNA gene V3-V4 region. Live bacteria were obtained in the bile from three BTC patients by culture, and metagenomics-based identification was performed. Linear discriminant analysis effect size showed a higher Enterobacteriaceae abundance and a lower Clostridia abundance, including that of Faecalibacterium and Coprococcus, in the BTC patients than in the other subjects. Ten of 17 operational taxonomic units (OTUs) assigned to Enterobacteriaceae in the bile were matched with the OTUs found in the BTC subject fecal samples. Furthermore, a bile-isolated strain possessed the carcinogenic bacterial colipolyketide synthase-encoding gene. Enterobacteriaceae was enriched in the BTC feces, and more than half of Enterobacteriaceae in the bile matched that in the feces at the OTU level. Our data suggests that fecal microbiota dysbiosis may contribute to BTC onset.
Biliary cancers are highly aggressive tumors that are often diagnosed an advanced disease stage and have a poor outcome with systemic therapy. Recent efforts towards molecular characterization have identified a subset of biliary patients that have HER2/neu amplification or mutation. HER2/neu amplification is associated with response to HER2/neu-directed therapy in breast and gastric cancers. However, the efficacy of HER2/neu-targeted therapy in biliary cancers is unknown.
Purpose: To analyze human and bacteria proteomic profiles in bile, exposed to a tumor vs. non-tumor microenvironment, in order to identify differences between these conditions, which may contribute to a better understanding of pancreatic carcinogenesis. Patients and Methods: Using liquid chromatography and mass spectrometry, human and bacterial proteomic profiles of a total of 20 bile samples (7 from gallstone (GS) patients, and 13 from pancreatic head ductal adenocarcinoma (PDAC) patients) that were collected during surgery and taken directly from the gallbladder, were compared. g:Profiler and KEGG (Kyoto Encyclopedia of Genes and Genomes) Mapper Reconstruct Pathway were used as the main comparative platform focusing on over-represented biological pathways among human proteins and interaction pathways among bacterial proteins. Results: Three bacterial infection pathways were over-represented in the human PDAC group of proteins. IL-8 is the only human protein that coincides in the three pathways and this protein is only present in the PDAC group. Quantitative and qualitative differences in bacterial proteins suggest a dysbiotic microenvironment in the PDAC group, supported by significant participation of antibiotic biosynthesis enzymes. Prokaryotes interaction signaling pathways highlight the presence of zeatin in the GS group and surfactin in the PDAC group, the former in the metabolism of terpenoids and polyketides, and the latter in both metabolisms of terpenoids, polyketides and quorum sensing. Based on our findings, we propose a bacterial-induced carcinogenesis model for the biliary tract. Conclusion: To the best of our knowledge this is the first study with the aim of comparing human and bacterial bile proteins in a tumor vs. non-tumor microenvironment. We proposed a new carcinogenesis model for the biliary tract based on bile metaproteomic findings. Our results suggest that bacteria may be key players in biliary tract carcinogenesis, in a long-lasting dysbiotic and epithelially harmful microenvironment, in which specific bacterial species' biofilm formation is of utmost importance. Our finding should be further explored in future using in vitro and in vivo investigations.
Background: The genomic spectrum of biliary tract carcinoma (BTC) has been characterized and is associated with distinct anatomic and etiologic subtypes, yet limited studies have linked genomic alterations with personalized therapies in BTC patients. Methods: This study analyzed 803 patients with BTC:164 with gallbladder cancer, 475 with intrahepatic cholangiocarcinoma (ICC) and 164 with extrahepatic cholangiocarcinoma. We determined genomic alterations, mutational signatures related to etiology and histopathology and prognostic biomarkers. Personalized targeted therapies for patients harboring potentially actionable targets (PATs) were investigated. Results: The median tumor mutation burden (TMB) was 1.23 Mut/Mb, with 4.1% of patients having hypermutated BTCs. Unlike the results obtained from the Western population, the most frequently altered cancer-related genes in our cohort included TP53 (53%), KRAS (26%), ARID1A (18%), LRP1B (14%) and CDKN2A (14%). Germline mutations occurred mostly in DNA damage repair genes. Notably, 35.8% of the ICCs harbored aristolochic acid related signatures and an elevated TMB. TP53 and KRAS mutations and amplified 7q31.2 were demonstrated to negatively affect patient prognosis. Moreover, 19 genes were proposed to be PATs in BTCs, with 25.4% of patients harboring these PATs. Forty-six patients received PAT-matched targeted therapies, achieving a 26.1% objective response rate; the median progression-free survival (PFS) was 5.0 months, with 56.8% of patients obtaining PFS benefits. Conclusions: Extensive genomic diversity and heterogeneity were observed among BTC patients, with contributions according to potential etiology exposures, anatomical subtypes and clinicopathological characteristics. We also demonstrated that patients with refractory BTCs who have PATs can derive considerable benefit from receiving a matched therapy, initiating further prospective clinical trials guided by molecular profiling among this aggressive cancer.
Trends in biliary tract cancer incidence rates have increased in Shanghai, China. These trends have coincided with economic and developmental growth, as well as a shift in dietary patterns to a more Westernized diet. To examine the effect of dietary changes on incident disease, we evaluated associations between diet and biliary tract cancers amongst men and women from a population-based case-control study in Shanghai, China. Biliary tract cancer cases were recruited from 42 collaborating hospitals in urban Shanghai, and population-based controls were randomly selected from the Shanghai Household Registry. Food frequency questionnaire data were available for 225 gallbladder, 190 extrahepatic bile duct, and 68 ampulla of Vater cancer cases. A total of 39 food groups were created and examined for associations with biliary tract cancer. Interestingly, only four food groups demonstrated a suggested association with gallbladder, extrahepatic bile duct, or ampulla of Vater cancers. The allium food group, consisting of onions, garlic, and shallots showed an inverse association with gallbladder cancer (OR: 0.81, 95% CI: 0.68-0.97). Similar trends were seen in the food group containing seaweed and kelp (OR: 0.79, 95% CI: 0.67-0.96). In contrast, both preserved vegetables and salted meats food groups showed positive associations with gallbladder cancer (OR:1.27, 95% CI: 1.06-1.52; OR: 1.18, 95% CI: 1.02-1.37, respectively). Each of these four food groups showed similar trends for extrahepatic bile duct and ampulla of Vater cancers. The results of our analysis suggest intake of foods with greater anti-inflammatory properties may play a role in decreasing the risk of biliary tract cancers. Future studies should be done to better understand effects of cultural changes on diet, and to further examine the impact diet and inflammation have on biliary tract cancer incidence.
Currently, there is no validated therapeutic target for biliary tract cancer (BTC). This study aimed to investigate the pre-clinical and clinical implication of HER2 as a therapeutic target in BTC. We established two novel HER2-amplified BTC cell lines, SNU-2670 and SNU-2773, from gallbladder cancer patients. SNU-2670 and SNU-2773 cells were sensitive to trastuzumab, dacomitinib, and afatinib compared with nine HER2-negative BTC cell lines. Dacomitinib and afatinib led to G1 cell cycle arrest in SNU-2773 cells and apoptosis in SNU-2670 cells. Furthermore, dacomitinib, afatinib, and trastuzumab showed synergistic cytotoxicity when combined with some cytotoxic drugs including gemcitabine, cisplatin, paclitaxel, and 5-fluorouracil. In a SNU-2670 mouse xenograft model, trastuzumab demonstrated a good anti-tumor effect as a monotherapy and in combination with gemcitabine increasing apoptosis. In our clinical data, 13.0% of patients with advanced BTC were defined as HER2-positive. Of these, three patients completed HER2-targeted chemotherapy. Two of them demonstrated a partial response, and the other one showed stable disease for 18 weeks. In summary, these pre-clinical and clinical data suggest that HER2 could be a therapeutic target, and that a HER2-targeting strategy should be developed further in patients with HER2-positive advanced BTC.
The poor prognosis of malignant biliary diseases is partially caused by their difficult early diagnosis. Therefore, many patients are only diagnosed at advanced stages. This study aimed to improve diagnosis by clarifying the differences in the duodenal juice metabolomes of benign and malignant biliary diseases. From October 2021 to January 2023, duodenal juice was obtained from 67 patients with suspected biliary diseases who required endoscopic ultrasonography and endoscopic retrograde cholangiography for diagnosis/treatment. The samples metabolomes were analyzed via nuclear magnet resonance spectroscopy using an 800-MHz spectrometer. Metabolomes of malignant and benign diseases were then compared, and multivariate analysis was performed to determine the relevant factors for malignancy/benignancy. For benignancy, no significant predictors were observed. For malignancy, acetone was a significant predictor, with higher concentrations in the malignant group than in the benign group. Regarding the receiver operating characteristic curve analysis for biliary tract carcinoma diagnosis, the predictive value of acetone in duodenal juice was comparable with serum CA19-9 levels (area under the curve: 0.7330 vs. 0.691, p = 0.697). In conclusion, duodenal juice metabolomics is a feasible method that is available for differential diagnosis in the biliary disease field.
Biliary tract cancers (BTCs) are rare and heterogeneous group of tumors classified anatomically into intrahepatic and extrahepatic bile ducts and gallbladder adenocarcinomas. Patient-derived tumor cell (PDC) models with genome analysis can be a valuable platform to develop a method to overcome the clinical barrier on BTCs.
Biliary tract cancers (BTCs), including cholangiocarcinoma and gallbladder cancer, are a relatively rare group of cancers with a poor prognosis. Over the past decade, the utilization of next-generation sequencing has led to the identification of multiple actionable somatic aberrations in BTCs. Subsequently, new therapies have been created to target these molecular alterations and have been incorporated into clinical practice. In this review, we outline therapies that have been previously studied, and those that are under investigation, to target genomic alterations with the goal of improving survival in patients with advanced disease.
Cholangiocarcinoma (CCA) results from the malignant transformation of cholangiocytes. Primary sclerosing cholangitis (PSC) and primary biliary cholangitis (PBC) are chronic diseases in which cholangiocytes are primarily damaged. Although PSC is an inflammatory condition predisposing to CCA, CCA is almost never found in the autoimmune context of PBC. Here, we hypothesized that PBC might favor CCA immunosurveillance. In preclinical murine models of cholangitis challenged with syngeneic CCA, PBC (but not PSC) reduced the frequency of CCA development and delayed tumor growth kinetics. This PBC-related effect appeared specific to CCA as it was not observed against other cancers, including hepatocellular carcinoma. The protective effect of PBC was relying on type 1 and type 2 T cell responses and, to a lesser extent, on B cells. Single-cell TCR/RNA sequencing revealed the existence of TCR clonotypes shared between the liver and CCA tumor of a PBC host. Altogether, these results evidence a mechanistic overlapping between autoimmunity and cancer immunosurveillance in the biliary tract.
Biliary tract cancer (BTC) is clinically and pathologically heterogeneous and responds inadequately to treatment. A small section of patients develop resectable disease, although the relapse rates are high; the benefits of adjuvant capecitabine chemotherapy for BTC are now understood, and gemcitabine-based combination chemotherapy is the first line of therapeutic strategy for BTC; however, alternative therapy for BTC is not known. Genomic profiling can provide detailed information regarding the carcinogenesis, identification, and therapy for BTC. Currently, confirmed restorative targets for BTC are lacking. In this review, we aimed to analyze the preclinical and clinical implications of a spectrum of genomic alterations associated with new potentially remedial targets. We focused on eight draggable genes for BTC, which were described as having evidence of therapeutic impact (evidence level 2A-3B) based on the clinical practice guidance for next-generation sequencing in cancer diagnosis and treatment; these include ERBB2, NTRK1, RNF43, CDK6, CDKN2B, FGFR2, IDH1, and IDH2. Moreover, some of the BTC present microsatellite instability, hypermutation, and germline variants, which we also reviewed. Finally, we discussed the therapeutic options based on the next-generation sequencing findings in BTC. Studies have demonstrated that BTC includes subgroups with individually distinct driver mutations, most of which will be targeted with new treatment plans.
Biliary tract cancers (BTCs) are rare with poor prognosis. Due to the advent of genomic sequencing, new data have emerged regarding the molecular makeup of this disease. To add to the complexity, various subtypes also harbor a varied genetic composition. The commonly mutated genes associated with this cancer are KRAS, EGFR, IDH, FGFR and BAP1. Various clinical studies are looking at targeting these genetic mutations. Another therapeutic area of note is the potential for the use of immunotherapy in patients with BTC. Although BTC may be a result of chronic inflammation, this does not necessarily translate into increased immunogenicity. This literature review discusses the diverse molecular and immune-related pathways in patients with BTC and their potential therapeutic implications.
Bile pigment, bilirubin, and biliverdin concentrations may change as a results of biliary tract cancer (BTC) altering the mechanisms of radical oxidation and heme breakdown. We explored whether changes in bile pigment components could help distinguish BTC from benign biliary illness by evaluating alterations in patients with BTC. We collected bile fluid from 15 patients with a common bile duct stone (CBD group) and 63 individuals with BTC (BTC group). We examined the bile fluid's bilirubin, biliverdin reductase (BVR), heme oxygenase (HO-1), and bacterial taxonomic abundance. Serum bilirubin levels had no impact on the amounts of bile HO-1, BVR, or bilirubin. In comparison to the control group, the BTC group had considerably higher amounts of HO-1, BVR, and bilirubin in the bile. The areas under the curve for the receiver operating characteristic curve analyses of the BVR and HO-1 were 0.832 (p<0.001) and 0.891 (p<0.001), respectively. Firmicutes was the most prevalent phylum in both CBD and BTC, according to a taxonomic abundance analysis, however the Firmicutes/Bacteroidetes ratio was substantially greater in the BTC group than in the CBD group. The findings of this study showed that, regardless of the existence of obstructive jaundice, biliary carcinogenesis impacts heme degradation and bile pigmentation, and that the bile pigment components HO-1, BVR, and bilirubin in bile fluid have a diagnostic significance in BTC. In tissue biopsies for the diagnosis of BTC, particularly for distinguishing BTC from benign biliary strictures, bile pigment components can be used as additional biomarkers.
Gemcitabine‑based chemotherapy is one of the most effective and commonly used chemotherapeutic regimens for biliary tract cancer (BTC). However, development of resistance to this drug limits its efficacy. The present study aimed to explore the effects of midkine (MDK) on the resistance of BTC cells to gemcitabine. Cell viability and proliferation were measured by a Cell Counting Kit‑8 assay and 5‑ethynyl‑2'‑deoxyuridine staining, respectively. Western blot analysis was used to detect the expression of E‑cadherin and vimentin. The results indicated that BTC cell lines were more resistant to gemcitabine plus MDK compared with gemcitabine alone. In terms of the underlying mechanism, MDK promoted the epithelial to mesenchymal transition (EMT) of BTC cells and the enhancing effect of MDK on gemcitabine resistance was abrogated when the EMT was blocked with small interfering (si)RNA targeting Twist. In addition, MDK promoted the expression of Notch‑1, while knockdown of Notch‑1 by siRNA blocked the EMT process in the BTC cell lines. Taken together, these results indicated that MDK promoted gemcitabine resistance of BTC through inducing EMT via upregulating Notch‑1. It was suggested that inhibition of the EMT is a promising strategy to overcome MDK‑induced drug resistance.
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