Macrophage stimulating protein variation enhances the risk of sporadic extrahepatic cholangiocarcinoma.

BACKGROUND: Primary sclerosing cholangitis confers risk of cholangiocarcinoma. Here, we assessed the primary sclerosing cholangitis-associated variant rs3197999 in the MST1 gene, coding for RON receptor tyrosine kinase ligand macrophage stimulating protein, in a large European cholangiocarcinoma cohort. MATERIALS AND METHODS: 223 cholangiocarcinoma patients including three primary sclerosing cholangitis individuals and 355 cancer- and primary sclerosing cholangitis-free controls were genotyped for MST1 rs3197999. RESULTS: The cancer group departed from Hardy-Weinberg equilibrium (p = 0.022) and exhibited a trend for rs3197999 [A] overrepresentation (31% vs. 26%: p = 0.10). Homozygous rs3197999 [AA] carrier status significantly increased overall (OR = 1.97; p = 0.023) and primary sclerosing cholangitis-unrelated biliary tract cancer risk (OR = 1.84; p = 0.044), relative to homozygous common allele carriers. The association was most pronounced in patients with extrahepatic tumours. This finding was robust to multivariate analysis (p < 0.05), validating the [AA] genotype as an independent cholangiocarcinoma risk factor. CONCLUSIONS: These results suggest that the [AA] genotype of the common MST1 variant rs3197999 enhances genetic risk of sporadic extrahepatic cholangiocarcinoma irrespective of primary sclerosing cholangitis status, presumably by modulating inflammatory responses and/or altered MSP/RON signalling.

A common variant in the precursor miR-146a sequence does not predispose to cholangiocarcinoma in a large European cohort.

BACKGROUND: Micro-RNAs (miRNAs) are small, non-coding RNA species considered to fine-tune basic cellular functions by modulating target gene translation and/or mRNA stability. A common G/C polymorphism (rs2910164) in the precursor (pre-) miR-146a gene engaged in NF-κB signaling and apoptosis pathways has been reported to modulate the genetic risk of hepatocellular carcinoma by increased G-allelic production of mature miR-146a. We investigated rs2910164 in a large European-based cholangiocarcinoma (CCA) cohort. METHODS: We recruited 182 CCA patients and 350 controls in three academic medical centers. Genotyping for rs2910164 was performed by PCR-based assays with 5'-nuclease and fluorescence detection. Genotype frequencies were tested for consistency with the Hardy-Weinberg equilibrium using an exact test; allelic and genotypic differences between the patients and controls were assessed by the Chi-square test and Armitage's trend test. Exploratory subgroup analyses included gender, tumor localization (extra- versus intrahepatic CCA) and early-onset CCA. RESULTS: Genotype distributions were consistent with the Hardy-Weinberg equilibrium. No significant differences in either allele or genotype distributions were detected between the CCA and control groups or the respective subgroups investigated. However, there was a trend for a protective effect of the heterozygous single-nucleotide polymorphism state GC, as indicated by an underrepresentation in the CCA group in general (29% vs 35%; P=0.18) and, in particular, for extrahepatic tumor sites (26% vs 35%; OR=0.67; 95% CI, 0.43-1.02; P=0.065). CONCLUSIONS: Our data do not support a prominent contribution of the pre-miR-146a sequence variant in the genetic predisposition to CCA. However, current studies functionally characterizing rs2910164 have proposed that distinct repertoires of target genes are addressed by genotype-specific mature miR-146a species. Given the detected trend towards a potentially protective role of GC heterozygosity, a subtle modulation of genetic CCA risk by the pre-miR-146a GC genotype may exist and should be evaluated further.

Potential genotype-specific single nucleotide polymorphism interaction of common variation in p53 and its negative regulator mdm2 in cholangiocarcinoma susceptibility.

Aberrant cell cycle control and apoptosis deregulation are involved in biliary carcinogenesis. The tumor suppressor gene p53 and its key negative regulator murine double minute 2 (mdm2) cooperate in modulating these basic cell functions and germline p53 alteration promotes cholangiocarcinoma (CCA) formation in animal models. The potential association between common functional genetic variation in p53 (SNP72 G/C) and mdm2 (SNP309 T/G) and susceptibility to bile duct cancer, however, has not been studied. p53/SNP72 G/C (rs1042522) and mdm2/SNP309 T/G (rs2279744) were genotyped in 182 Caucasian CCA patients and 350 controls using TaqMan assays. Allelic and genotypic differences, including exploratory data analyses (according to gender, tumor localization, early onset and genotypic interactions) were compared in contingency tables using the χ(2) and Fisher's exact tests. The overall comparison of allele and genotype frequencies yielded no significant association between either SNP and CCA susceptibility. Similarly, gender- and localization-specific analyses did not reveal deviations in allelic or genotypic distributions. In carriers of the low-apoptotic p53 genotype CC, the mdm2 SNP309 T allele conferred borderline significant CCA risk [P=0.049; odds ratio (OR), 4.36; 95% CI, 0.92-20.77]. Power analysis confirmed adequate statistical power to exclude major SNP effects (each >97% for OR 1.7). Collectively, the results we obtained from the largest European CCA cohort do not support the hypothesis of a prominent role of common p53 and mdm2 variation in the genetic susceptibility to bile duct cancer. However, epistatic effects may modulate genetic CCA risk in individual subsets.

Pancreatic cancer risk variant ABO rs505922 in patients with cholangiocarcinoma.

The aim of this study was to investigate an association between the development of cholangiocarcinoma (CCA) and the ABO variant rs505922 (known to increase pancreatic cancer risk) in a large cohort of European individuals with CCA. In total, 180 individuals with CCA and 350 CCA-free controls were included. The ABO variant rs505922 was genotyped using a polymerase chain reaction-based assay. Association between this single nucleotide polymorphism (SNP) and CCA was tested in contingency tables. Neither allele distributions nor association tests and regression analysis provided evidence for an increased risk of CCA among carriers of the ABO variant (all P > 0.05). Nevertheless, we documented a deviation from Hardy-Weinberg equilibrium in the entire CCA cohort (P = 0.028) and for patients with intrahepatic (P = 0.037) but not extrahepatic tumor localization (P > 0.05). The association tests did not provide evidence for a prominent role of the investigated SNP in the genetic risk of CCA. However, Hardy-Weinberg disequilibrium in the entire cohort and the intrahepatic CCA subgroup warrants future studies investigating a potential CCA risk modulation by individual blood groups.

Survival and quality of life of cholangiocarcinoma patients: a prospective study over a 4 year period.

BACKGROUND AND AIMS: Cholangiocarcinomas (CCAs) are tumors with a poor prognosis and a lower quality of life (QoL). The aim of this study was to evaluate the survival rate and quality of life in CCA patients. METHOD: We prospectively enrolled 133 patients diagnosed with CCA in the 3rd Medical Clinic, Cluj Napoca, over a 4-year period (2005-2009). The QoL was evaluated by means of a QoL questionnaire (EORTC QLQ-C30). RESULTS: The mean age of the patients was 65 +/- 10.6 years: 55% were males. 71% of the patients had hilar tumor (Klatskin), 23% distal and 6% intrahepatic CCA (IH). Only 11.3% of the patients were eligible to receive curative treatment. The 1-year overall survival was 22.3 +/- 4.4% and the 2-year survival was 3.4 +/- 2.1%. The patients receiving metallic stents had better survival than those receiving plastic stents (40.4% vs 12.5% at 1 year, 9.1% vs 5.0% at 2 years, respectively). The 1-year survival was significantly improved for patients who underwent surgery plus adjuvant chemotherapy. The post-therapy QoL demonstrated a less improvement in Klatskin tumor patients than in patients with other types of tumors. Endoscopic palliative therapy allowed a faster community reintegration, but with variable evolution. CONCLUSIONS: The highest 2-year survival rate was 5.5%. Slightly longer survival was recorded when chemotherapy was added and also after endoscopic placement of metallic stents. Endoscopic biliary decompression improved the QoL faster than surgery.

Therapeutic approach to the malignant tumors of the biliary tract.

Cholangiocarcinomas (CCA) are malignant tumors that originate in the cholangiocytes, occur at any level of the biliary tract, are very aggressive and have a 5-year survival rate of 7-8%. Their diagnosis is late and difficult, and the prognosis is very poor. The only curative treatment of these tumors is the complete surgical resection. Signs of unresectability can be detected in most patients with CCA when establishing the diagnosis. Thus, only certain palliative measures can be employed in most cases. The ideal palliative method should be minimally invasive, accompanied by few complications, should offer an increased quality of life, require reduced hospitalization and the lowest costs. The palliative treatment of the obstructive jaundice may be achieved by means of surgical bypass, endoscopic insertion of biliary stents, percutaneous stents, transhepatic stents, photodynamic therapy and/or radio-chemotherapy.