Prognostic assessment of three single-nucleotide polymorphisms (GNB3 825C>T, BCL2-938C>A, MCL1-386C>G) in extrahepatic cholangiocarcinoma.
ABSTRACT Cholangiocellular carcinoma (CCA) has a devastating prognosis and markers enabling a precise prediction of the clinical outcome have long remained scarce. Recently, it has been demonstrated that genotype distribution of several single-nucleotide polymorphisms (SNPs) in genes that modulate G protein-signal transduction and apoptosis can serve as helpful predictive parameters in various carcinomas. We here aimed at extending the panel of SNPs suitable for predicting the outcome of CCA.
Forty Caucasian patients with extrahepatic CCA and 40 age- and sex-matched healthy white Caucasians were genotyped to elucidate putative associations between clinical outcome and genotypes of the three following SNPs: G protein beta 3 (GNB3) 825C>T, B-cell-lymphoma-2 (Bcl-2) -938C>A, and myeloid cell leukemia-1 (Mcl-1) -386C>G.
Patients homozygous for the C allele of the GNB3 825C>T polymorphism exhibited a significant prolonged overall survival compared with patients displaying the CT or TT genotype (median survival [months]: 31 vs. 13 vs. 7; p < .05) and also showed lower bilirubin serum levels. Additionally, the CC genotype of the BCL2-938C>A polymorphism was associated with higher GLDH serum activities (U/l; 29.8 +/- 7.1 vs. 11.4 +/- 4.3 vs. 5.6 +/- 1.7 comparing CC vs. CA vs. AA; p < .05). Genotype distributions for all SNPs were not significantly different in patients vs. controls.
GNB3 825C>T SNP may be a novel independent prognostic marker for patients suffering from extrahepatic CCA with the CC genotype to be associated with a favorable clinical outcome. Further prospective studies are needed to confirm these results and reveal additional functional SNP effects.
- SourceAvailable from: Eui Kyu Chie[Show abstract] [Hide abstract]
ABSTRACT: To analyze the outcomes of chemoradiotherapy for extrahepatic bile duct (EHBD) cancer patients who underwent R2 resection or bypass surgery and to identify prognostic factors affecting clinical outcomes, especially in terms of molecular biomarkers. Medical records of 21 patients with EHBD cancer who underwent R2 resection or bypass surgery followed by chemoradiotherapy from May 2001 to June 2010 were retrospectively reviewed. All surgical specimens were re-evaluated by immunohistochemical staining using phosphorylated protein kinase B (pAKT), CD24, matrix metalloproteinase 9 (MMP9), survivin, and β-catenin antibodies. The relationship between clinical outcomes and immunohistochemical results was investigated. At a median follow-up of 20 months, the actuarial 2-year locoregional progression-free, distant metastasis-free and overall survival were 37%, 56%, and 54%, respectively. On univariate analysis using clinicopathologic factors, there was no significant prognostic factor. In the immunohistochemical staining, cytoplasmic staining, and nuclear staining of pAKT was positive in 10 and 6 patients, respectively. There were positive CD24 in 7 patients, MMP9 in 16 patients, survivin in 8 patients, and β-catenin in 3 patients. On univariate analysis, there was no significant value of immunohistochemical results for clinical outcomes. There was no significant association between clinical outcomes of patients with EHBD cancer who received chemoradiotherapy after R2 resection or bypass surgery and pAKT, CD24, MMP9, survivin, and β-catenin. Future research is needed on a larger data set or with other molecular biomarkers.Radiation oncology journal. 12/2012; 30(4):197-204.
- [Show abstract] [Hide abstract]
ABSTRACT: Cholangiocarcinoma (CCA) cells paradoxically express the death ligand tumor necrosis factor-related apoptosis-inducing ligand (TRAIL) and thus, rely on potent survival signals to circumvent cell death by TRAIL. Hedgehog (Hh) signaling is an important survival pathway in CCA. Herein, we further examine the mechanisms whereby Hh signaling mediates apoptosis resistance in CCA, revealing a pivotal role for the cell division regulating serine/threonine kinase polo-like kinase 2 (PLK2). We employed 50 human CCA samples (25 intrahepatic and 25 extrahepatic CCA) as well as human KMCH-1, Mz-CHA-1 and HUCCT-1 CCA cells for these studies. In vivo experiments were conducted using a syngeneic rat orthotopic CCA model. In human samples, PLK1/2/3-immunoreactive cancer cells were present in the preponderance of intrahepatic and extrahepatic CCA specimens. Inhibition of Hh signaling by cyclopamine reduced PLK2 but not PLK1 or PLK3 mRNA and protein expression in vehicle- and sonic Hh (SHH)-treated CCA cells confirming our prior microarray study. PLK2 regulation by Hh signaling appears to be direct as the Hh transcription factors glioma-associated oncogene (GLI) 1 and 2 bind to the PLK2 promotor. Moreover, inhibition of PLK2 by the PLK inhibitor BI 6727 (volasertib) or PLK2 knockdown was pro-apoptotic in CCA cells. BI 6727 administration or PLK2 knockdown decreased cellular protein levels of anti-apoptotic myeloid cell leukemia-1 (Mcl-1); an effect reversed by the proteasome inhibitor MG-132. Finally, BI 6727 administration reduced Mcl-1 protein expression in CCA cells resulting in CCA cell apoptosis and tumor suppression in vivo. Conclusion: PLK2 appears to be an important mediator of Hh survival signaling. These results suggest PLK inhibitors to be of therapeutic value for the treatment of human CCA. (HEPATOLOGY 2013.).Hepatology 05/2013; · 11.19 Impact Factor
- [Show abstract] [Hide abstract]
ABSTRACT: Cholangiocarcinoma (CCA) is the second most common primary hepatic malignancy worldwide. The incidence of intrahepatic CCA is increasing, whereas that of extrahepatic CCA is decreasing. This review looks at the new advances that have been made in the management of CCA, based on a PubMed and Science Citation Index search of results from randomized controlled trials, reviews, and cohort, prospective and retrospective studies. Aggressive interventional approaches and new histopathological techniques have been developed to make a histological diagnosis in patients with high risk factors or suspected CCA. Resectability of the tumour can now be assessed using multiple radiological imaging studies; the main prognostic factor after surgery is a histologically negative resection margin. Biliary drainage and/or portal vein embolization may be performed before extended radical resection, or liver transplantation may be undertaken in combination with neoadjuvant chemotherapy or chemoradiotherapy. Though many advances have been made in the management of CCA, the standard modality of treatment has not yet been established. This review focuses on the clinical options for different stages of CCA.The Journal of international medical research 12/2013; · 1.10 Impact Factor