ABSTRACT
Expression of ATP-binding cassette B5 (ABCB5) has been demonstrated to confer chemoresistance, enhance cancer stem cell properties and associate with poor prognosis in hepatocellular carcinoma (HCC). The aim of this study was to evaluate the genetic variations of ABCB5 in HCC patients with reference to healthy individuals and the clinicopathological significance. A pilot study has examined 20 out of 300 pairs HCC and paralleled blood samples using conventional sequencing method to cover all exons and exon/intron regions to investigate whether there will be novel variant sequence and mutation event. A total of 300 HCC and 300 healthy blood DNA samples were then examined by Sequenom MassARRAY genotyping and pyrosequencing for 38 SNP and 1 INDEL in ABCB5. Five novel SNPs were identified in ABCB5. Comparison of DNA from blood samples of HCC and healthy demonstrated that ABCB5 SNPs rs75494098, rs4721940 and rs10254317 were associated with HCC risk. Specific ABCB5 variants were associated with aggressive HCC features. SNP rs17143212 was significantly associated with ABCB5 expression level. Nonetheless, the paralleled blood and tumour DNA sequences from HCC patients indicated that ABCB5 mutation in tumours was not common and corroborated the TCGA data sets. In conclusion, ABCB5 genetic variants had significant association with HCC risk and aggressive tumour properties.
Subject(s)
ATP Binding Cassette Transporter, Subfamily B/genetics , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Animals , Asian People/genetics , Carcinoma, Hepatocellular/ethnology , DNA, Neoplasm/genetics , Disease-Free Survival , Exons/genetics , Genetic Predisposition to Disease , Genotype , Humans , INDEL Mutation , Introns/genetics , Kaplan-Meier Estimate , Liver Neoplasms/ethnology , Mutation , Neoplasms/genetics , Pilot Projects , Polymorphism, Single Nucleotide , Proportional Hazards Models , RNA, Messenger/biosynthesis , RNA, Neoplasm/biosynthesis , Risk , Sequence Alignment , Sequence Homology, Nucleic Acid , Species Specificity , Vertebrates/geneticsABSTRACT
BACKGROUND: Recurrent pyogenic cholangitis (RPC) is a known risk factor for intrahepatic cholangiocarcinoma (ICC), whether it represents a poor prognostic factor remains controversial. The aim of this study was to investigate the post-hepatectomy oncological outcomes of patients with ICC and coexisting RPC. METHOD: A retrospective analysis with propensity score matching (PSM) was performed for comparison between ICC patient with and without RPC. RESULTS: There were 143 patients with ICC with a median follow-up of 21 months. RPC was diagnosed in 18% of patients. The time from RPC diagnosis to ICC diagnosis was 137(47-481) months. The 3-year disease-free (DFS) and overall survival for the whole population was 34% and 43% respectively. Preoperative child score, elevated carcinoembryonic antigen, presence of microvascular invasion, multiple tumours, presence of postoperative complications and RPC were independent factors for DFS and OS. After PSM, 60 ICC patients who did not have RPC were compared with 20 ICC patients with RPC. Patients with RPC had significantly worse median DFS (10 vs 23 months, P = 0.020) and OS (15 vs 45 months, P = 0.004) when compared to the patients without RPC. CONCLUSION: RPC represents a poor prognostic factor affecting outcomes after hepatectomy for patients with ICC.
Subject(s)
Bile Duct Neoplasms/surgery , Cholangiocarcinoma/surgery , Cholangitis/complications , Hepatectomy , Adult , Aged , Aged, 80 and over , Bile Duct Neoplasms/complications , Bile Duct Neoplasms/diagnostic imaging , Cholangiocarcinoma/complications , Cholangiocarcinoma/diagnostic imaging , Cholangitis/diagnosis , Disease-Free Survival , Female , Hepatectomy/adverse effects , Humans , Male , Middle Aged , Postoperative Complications/etiology , Propensity Score , Recurrence , Retrospective Studies , Risk Assessment , Risk Factors , Time FactorsABSTRACT
OBJECTIVE: We investigated the mutational landscape of mammalian target of rapamycin (mTOR) signalling cascade in hepatocellular carcinomas (HCCs) with chronic HBV background, aiming to evaluate and delineate mutation-dependent mechanism of mTOR hyperactivation in hepatocarcinogenesis. DESIGN: We performed next-generation sequencing on human HCC samples and cell line panel. Systematic mutational screening of mTOR pathway-related genes was undertaken and mutant genes were evaluated based on their recurrence. Protein expressions of tuberous sclerosis complex (TSC)1, TSC2 and pRPS6 were assessed by immunohistochemistry in human HCC samples. Rapamycin sensitivity was estimated by colony-formation assay in HCC cell lines and the treatment was further tested using our patient-derived tumour xenograft (PDTX) models. RESULTS: We identified and confirmed multiple mTOR components as recurrently mutated in HBV-associated HCCs. Of significance, we detected frequent (16.2%, n=18/111) mutations of TSC1 and TSC2 genes in the HCC samples. The spectrum of TSC1/2 mutations likely disrupts the endogenous gene functions in suppressing the downstream mTOR activity through different mechanisms and leads to more aggressive tumour behaviour. Mutational disruption of TSC1 and TSC2 was also observed in HCC cell lines and our PDTX models. TSC-mutant cells exhibited reduced colony-forming ability on rapamycin treatment. With the use of biologically relevant TSC2-mutant PDTXs, we demonstrated the therapeutic benefits of the hypersensitivity towards rapamycin treatment. CONCLUSIONS: Taken together, our findings suggest the significance of previously undocumented mutation-dependent mTOR hyperactivation and frequent TSC1/2 mutations in HBV-associated HCCs. They define a molecular subset of HCC having genetic aberrations in mTOR signalling, with potential significance of effective specific drug therapy.
Subject(s)
Antibiotics, Antineoplastic/therapeutic use , Carcinoma, Hepatocellular/genetics , Liver Neoplasms/genetics , Sirolimus/therapeutic use , TOR Serine-Threonine Kinases/metabolism , Tumor Suppressor Proteins/genetics , Adult , Aged , Animals , Antibiotics, Antineoplastic/pharmacology , Axin Protein/genetics , Carcinoma, Hepatocellular/chemistry , Carcinoma, Hepatocellular/metabolism , Cell Line, Tumor , Cell Proliferation/drug effects , Cell Proliferation/genetics , DNA Mutational Analysis , DNA-Binding Proteins , Female , Humans , Liver Neoplasms/chemistry , Liver Neoplasms/metabolism , Male , Mice , Middle Aged , Mutation Rate , Neoplasm Transplantation , Nuclear Proteins/genetics , Signal Transduction , Sirolimus/pharmacology , Transcription Factors/genetics , Tuberous Sclerosis Complex 1 Protein , Tuberous Sclerosis Complex 2 Protein , Tumor Stem Cell Assay , Tumor Suppressor Protein p53/genetics , Tumor Suppressor Proteins/analysis , Young Adult , beta Catenin/geneticsABSTRACT
BACKGROUND: This study aims to assess if radiofrequency ablation (RFA) has any oncological superiority over transarterial chemoembolization (TACE) on post-hepatectomy recurrence. METHODOLOGY: From 2002 to 2011, 60.15% of 823 patients developed recurrence after hepatectomy for Hepatocellular carcinoma (HCC). 102 patients with recurrence underwent RFA (n = 42) or TACE (n = 60) for tumor size ≤5 cm and number of lesion ≤3 when tumors were not resectable or transplantable. Those with renal impairment, portal vein thrombosis and poor liver reserve were excluded. Primary outcome was overall survival, which was determined using log-rank test and Kaplan Meier plots performed. Categorical data were analyzed using Chi-square test and continuous variable were analyzed using Mann-U Whitney test. RESULTS: Demographics and primary tumor characteristics were similar in both groups (p > 0.05). Overall survival after initial hepatectomy and salvage treatment for recurrence was similar (p > 0.05) in both groups with 5-year OS after salvage treatment for RFA and TACE at 24.1% and 25.7%, respectively. For patients with second recurrence after salvage treatment, an interchangeable treatment strategy of RFA and TACE conferred a better survival outcome than a stand-alone treatment with RFA or TACE (p < 0.05). CONCLUSIONS: RFA and TACE may be equally effective for intrahepatic recurrence after hepatectomy when tumor size is ≤5 cm and ≤3 lesion when re-resection or salvage transplantation is not considered feasible.
