Opisthorchis viverrini-related cholangiocarcinoma (CCA), a fatal bile duct cancer, is a major public health concern in areas endemic for this parasite. We report here whole-exome sequencing of eight O. viverrini-related tumors and matched normal tissue. We identified and validated 206 somatic mutations in 187 genes using Sanger sequencing and selected 15 genes for mutation prevalence screening in an additional 46 individuals with CCA (cases). In addition to the known cancer-related genes TP53 (mutated in 44.4% of cases), KRAS (16.7%) and SMAD4 (16.7%), we identified somatic mutations in 10 newly implicated genes in 14.8-3.7% of cases. These included inactivating mutations in MLL3 (in 14.8% of cases), ROBO2 (9.3%), RNF43 (9.3%) and PEG3 (5.6%), and activating mutations in the GNAS oncogene (9.3%). These genes have functions that can be broadly grouped into three biological classes: (i) deactivation of histone modifiers, (ii) activation of G protein signaling and (iii) loss of genome stability. This study provides insight into the mutational landscape contributing to O. viverrini-related CCA.
"Targeting specific molecular pathways holds promise for advanced gallbladder cancer therapy. Cancer Treat Rev (2015), http://dx.doi.org/10.1016/j.ctrv.2015.01.003 similar to lithiasis-related GBC   . This similarity in carcinogenesis may be attributed to the chronic presence of a ''foreign'' body observed in these two anatomically associated cancers. "
[Show abstract][Hide abstract] ABSTRACT: Gallbladder cancer is the most common and aggressive malignancy of the biliary tract. The complete surgical resection is the only potentially curative approach in early stage; however, most cases are diagnosed in advanced stages and the response to traditional chemotherapy and radiotherapy is extremely limited, with modest impact in overall survival. The recent progress in understanding the molecular alterations of gallbladder cancer has shown great promise for the development of more effective treatment strategies. This has mainly resulted from the identification of molecular alterations in relevant intracellular signaling pathways — Hedgehog, PI3K/AKT/mTOR, Notch, ErbB, MAPK and angiogenesis— which are potential tailored targets for gallbladder cancer patients. This review discusses the recent remarkable progress in understanding the molecular alterations that represent novel prognosis molecular markers and therapeutic targets for gallbladder cancer, which will provide opportunities for research and for developing innovative strategies that may enhance the benefit of conventional chemotherapy, or eventually modify the fatal natural history of this orphan disease.
Cancer Treatment Reviews 01/2015; 41(3). DOI:10.1016/j.ctrv.2015.01.003 · 7.59 Impact Factor
"Although many frequently mutated genes have been identified in cholangiocarcinoma, such as TP53 (37–44%) and KRAS (17–54%) (4), none of these signature genes have become targets of therapy. Sequencing efforts are continuously conducted in order to generate in-depth information with regard to the somatic alterations in ICC. "
[Show abstract][Hide abstract] ABSTRACT: Intrahepatic cholangiocarcinoma (ICC) is the second most common primary liver cancer with poor responsiveness to existing drug therapies. Therefore, novel treatment strategies against ICC are required to improve survival. The aim of this study was to demonstrate the role of fused-in-glioblastoma-c-ros-oncogene1 (FIG-ROS) fusion gene in ICC. ROS was positively expressed in ICC tissues and HUCCT1 cells. Plasmids expressing ROS- and FIG-specific shRNAs were constructed and transfected into HUCCT1 cells. The results showed that single transfection of ROS- or FIG-specific shRNA inhibited HUCCT1 cell proliferation, colony formation, cell cycle progression, migration and invasion, while inducing apoptosis. Moreover, the co-inhibition of ROS- and FIG-specific shRNA exhibited stronger effects on HUCCT1 cell proliferation, apoptosis, colony formation, cell cycle progression, migration and invasion, when compared to single inhibition of ROS and FIG. Furthermore, findings of this study suggested that the AKT signaling pathway was involved in the ROS-FIG-mediated biological processes of HUCCT1 cells. In summary, the results suggest that FIG-ROS plays an oncogenic role in ICC. Additionally, ROS1-6290 and FIG-363 segments may become effective therapeutic targets for ICC harboring ROS-FIG fusion protein.
International Journal of Molecular Medicine 06/2014; 34(3). DOI:10.3892/ijmm.2014.1823 · 2.09 Impact Factor
"In another study vandetanib, a partial EGFR inhibitor, suppressed growth of TKKK (KRAS WT) BTC cell line, while HuCCT (KRAS mutant) required 10 times the amount of drug for similar effect (Yoshikawa et al, 2009). KRAS mutations are found in 3–50% of tumours depending on tumour location and methodology used to evaluate for mutations in different studies (Suto et al, 2000; Rashid et al, 2002; Ong et al, 2012). The most recent report suggests that KRAS mutations are most common in extrahepatic tumours and that rates for intrahepatic cancers are on the lower end of this spectrum at 9–22% (Voss et al, 2013). "
[Show abstract][Hide abstract] ABSTRACT: Background:
Current data suggest that platinum-based combination therapy is the standard first-line treatment for biliary tract cancer. EGFR inhibition has proven beneficial across a number of gastrointestinal malignancies; and has shown specific advantages among KRAS wild-type genetic subtypes of colon cancer. We report the combination of panitumumab with gemcitabine (GEM) and oxaliplatin (OX) as first-line therapy for KRAS wild-type biliary tract cancer.
Patients with histologically confirmed, previously untreated, unresectable or metastatic KRAS wild-type biliary tract or gallbladder adenocarcinoma with ECOG performance status 0–2 were treated with panitumumab 6 mg kg−1, GEM 1000 mg m−2 (10 mg m−2 min−1) and OX 85 mg m−2 on days 1 and 15 of each 28-day cycle. The primary objective was to determine the objective response rate by RECIST criteria v.1.1. Secondary objectives were to evaluate toxicity, progression-free survival (PFS), and overall survival.
Thirty-one patients received at least one cycle of treatment across three institutions, 28 had measurable disease. Response rate was 45% and disease control rate was 90%. Median PFS was 10.6 months (95% CI 5–24 months) and median overall survival 20.3 months (95% CI 9–25 months). The most common grade 3/4 adverse events were anaemia 26%, leukopenia 23%, fatigue 23%, neuropathy 16% and rash 10%.
The combination of gemcitabine, oxaliplatin and panitumumab in KRAS wild type metastatic biliary tract cancer showed encouraging efficacy, additional efforts of genetic stratification and targeted therapy is warranted in biliary tract cancer.
British Journal of Cancer 06/2014; 111(3). DOI:10.1038/bjc.2014.343 · 4.84 Impact Factor
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