Elucidating the molecular basis of hepatocellular carcinoma (HCC) is crucial to developing targeted diagnostics and therapies for this deadly disease. The landscape of somatic genomic rearrangements ...(GRs), which can lead to oncogenic gene fusions, remains poorly characterized in HCC. We have predicted 4314 GRs including large-scale insertions, deletions, inversions and translocations based on the whole-genome sequencing data for 88 primary HCC tumor/non-tumor tissues. We identified chromothripsis in 5 HCC genomes (5.7%) recurrently affecting chromosomal arms 1q and 8q. Albumin (ALB) was found to harbor GRs, deactivating mutations and deletions in 10% of cohort. Integrative analysis identified a pattern of paired intra-chromosomal translocations flanking focal amplifications and asymmetrical patterns of copy number variation flanking breakpoints of translocations. Furthermore, we predicted 260 gene fusions which frequently result in aberrant over-expression of the 3′ genes in tumors and validated 18 gene fusions, including recurrent fusion (2/88) of ABCB11 and LRP2.
•We performed WGS of 88 HCC tumor and non-tumor pairs and predicted 4,314 somatic genomic rearrangement events including 260 gene fusions.•We identified chromothripsis affecting 6% of the hepatocellular carcinoma cohort.•We identified a recurrent gene fusion, ABCB11-LRP2, in 2% of the cohort.•We found genomic alterations affecting ALB (serum albumin) in 10% of the cohort.•Our analysis revealed genomic rearrangements as potential causal mechanisms underlying focal amplifications of the CCND1/FGF19 locus.
Hepatocellular carcinoma (HCC) is a heterogeneous and highly aggressive malignancy, for which there are no effective cures. Identification of a malignant stemlike subtype of HCC may offer patients ...with a dismal prognosis a potential targeted therapy using c-MET and Wnt pathway inhibitors. MicroRNAs (miRNAs) show promise as diagnostic and prognostic tools for cancer detection and stratification. Using a TRE-c-Met-driven transgenic HCC mouse model, we identified a cluster of 23 miRNAs that is encoded within the Dlk1-Gtl2 imprinted region on chromosome 12qF1 overexpressed in all of the isolated liver tumors. Interestingly, this region is conserved among mammalian species and maps to the human DLK1-DIO3 region on chromosome 14q32.2. We thus examined the expression of the DLK1-DIO3 miRNA cluster in a cohort of 97 hepatitis B virus-associated HCC patients and identified a subgroup (n = 18) of patients showing strong coordinate overexpression of miRNAs in this cluster but not in other cancer types (breast, lung, kidney, stomach, and colon) that were tested. Expression levels of imprinted gene transcripts from neighboring loci in this 14q32.2 region and from a subset of other imprinted sites were concomitantly elevated in human HCC. Interestingly, overexpression of the DLK1-DIO3 miRNA cluster was positively correlated with HCC stem cell markers (CD133, CD90, EpCAM, Nestin) and associated with a high level of serum α-fetoprotein, a conventional biomarker for liver cancer, and poor survival rate in HCC patients. In conclusion, our findings suggest that coordinate up-regulation of the DLK1-DIO3 miRNA cluster at 14q32.2 may define a novel molecular (stem cell-like) subtype of HCC associated with poor prognosis.
Summary
Background
Hepatocellular carcinoma (HCC) cells are auxotrophic for arginine, depletion of which leads to tumour regression. The current study evaluated safety, pharmacokinetics (PK)/ ...pharmacodynamics (PD) parameters, and potential anti-tumor activity of pegylated recombinant human arginase 1 (peg-rhArg1) in advanced HCC patients.
Methods
Eligibility criteria included advanced HCC with measurable lesions, Child-Pugh A or B, and adequate organ function. Initial single IV bolus was followed by weekly doses of peg-rhArgI escalated from 500 U/kg to 2500 U/kg in a 3 + 3 design.
Results
Fifteen patients were enrolled at weekly doses of 500 U/kg (
n
= 3), 1000 U/kg (
n
= 3), 1600 U/kg (
n
= 3) and 2500 U/kg (
n
= 6). The median age was 57 years (33–74); 87% were hepatitis B carriers and 47% had prior systemic treatment. The most commonly reported drug-related non-haematological adverse events (AEs) were diarrhea (13.3%), abdominal discomfort (6.7%) and nausea (6.7%). No drug-related haematological AEs were seen. Only 1 of the six patients that received 2500U/kg peg-rhArg1 experienced DLT (grade 4 bilirubin elevation) and thus the maximum tolerated dose was 2500 U/kg. PK and PD analysis indicated that peg-rhArg1 was efficacious in inducing arginine depletion in a dose-dependent manner. Adequate arginine depletion dose was achieved in the 1,600–2,500 U/kg range and therefore the optimal biological dose was at 1600 U/kg, which was chosen as the recommended dose. The best response was stable disease for >8 weeks in 26.7% of the enrolled patients.
Conclusion
Peg-rhArg1 has manageable safety profile and preliminary evidence of activity in advanced HCC patients.
HYPOTHESIS Hepatic resection improves quality of life (QOL) in patients with resectable hepatocellular carcinoma (HCC). DESIGN A prospective longitudinal study. SETTING A university teaching ...hospital. PATIENTS Sixty-six consecutive patients undergoing resection of HCC, and 10 patients with unresectable HCC found after surgical exploration who were subsequently treated with transarterial chemoembolization (control group). MAIN OUTCOME MEASURE Serial measurements of preoperative and postoperative QOL using the Functional Assessment of Cancer Therapy–General (FACT-G) Questionnaire for up to 2 years after surgery (at 3, 6, 9, 12, 18, and 24 months). RESULTS Among the 66 patients with resectable HCC, the mean postoperative QOL scores at 3 months after surgery were significantly higher than the mean preoperative QOL scores in domains related to physical, social, and emotional well-being and relationship with physicians. The mean total QOL score increased from 83.5 (SD, 9.4) before surgery to 94.1 (SD, 7.7) at 3 months after surgery (P<.001). No significant change of QOL scores at 3 months after surgery was observed in the control group. Twenty patients in the resected group died of early recurrence within 2 years after surgery, but their mean postoperative QOL scores remained higher than the preoperative QOL scores for most assessment times. In contrast, in the control group, the mean total QOL scores became significantly lower than the preoperative scores, starting 9 months after surgery. Forty-six patients in the resected group completed all QOL assessments. At all postoperative assessments, their mean QOL scores were higher than preoperative scores. Recurrence developed in 13 of the 46 patients within the 2-year study, and there was significant deterioration of QOL over time among these 13 (P<.001), whereas no significant change in QOL over time was observed among the 33 recurrence-free patients. Of various clinicopathologic factors, only advanced pTNM stage was significantly predictive of deterioration of QOL over time after resection of HCC. CONCLUSIONS Hepatic resection results in significant enhancement of QOL in patients with HCC. Development of recurrence is the main factor leading to deterioration in QOL over time after resection of HCC.Arch Surg. 2001;136:693-699-->
HYPOTHESIS Major hepatic resection for hepatocellular carcinoma (HCC) is associated with high operative morbidity and mortality, especially in patients with underlying chronic liver disease. The ...present study evaluated the factors associated with increased operative risks in patients who underwent extended right-sided hepatic resection for HCC. DESIGN Retrospective study. SETTING Tertiary referral center. PATIENTS A retrospective study was performed on 172 patients who underwent extended right-sided hepatic resection of more than 4 Couinaud segments for HCC during a 16-year period (January 1, 1989, to December 31, 2004) to evaluate the clinical factors associated with operative morbidity and mortality. MAIN OUTCOME MEASURE Risk factors associated with hospital mortality and major operative morbidity. RESULTS The overall major morbidity and hospital mortality rates were 14.0% and 8.1%, respectively. On multivariate analysis, small tumor size, conventional-approach hepatectomy, Child-Pugh grade B cirrhosis, and preexisting tumor rupture were the independent factors significantly associated with an increased risk of operative mortality. Discriminant analysis showed that a tumor size smaller than 10 cm significantly increased the risk of operative mortality compared with larger tumors (17.2% vs 3.5%; P = .046). CONCLUSIONS Anterior approach is the preferred technique for extended right-sided hepatic resection for HCC. Increased risk of operative mortality was identified in patients who had a small tumor, which was associated with the resection of a large volume of functioning liver parenchyma. Preoperative portal vein embolization should be considered in this group of patients to enhance atrophy of the right lobe and hypertrophy of the future liver remnant to minimize the operative risk.Arch Surg. 2007;142:63-69-->
A phase I dose-escalating study of pazopanib was conducted to determine the maximum tolerated dose (MTD), pharmacokinetic/pharmacodynamic relationships, and clinical activity in patients with ...advanced hepatocellular carcinoma (HCC).
Asian patients (N = 28) were dose escalated on pazopanib (200-800 mg) once daily (QD) on 21-day cycles, with MTD as the primary endpoint using a modified 3 + 3 design. Changes in tumor vasculature were evaluated by dynamic contrast-enhanced MRI (DCE-MRI).
Two of five patients at the 800-mg dose level experienced dose-limiting toxicities grade 3 aspartate aminotransferase (AST)/alanine aminotransferase (ALT) elevations and grade 3 malaise. The MTD in patients with HCC (Child-Pugh class A) was 600 mg QD. Diarrhea, skin hypopigmentation, and AST elevation were the most commonly reported adverse events at the MTD. Mean C(max) and area under the concentration-time curve (AUC(0-6)) of pazopanib and its metabolites did not increase dose proportionally across the 200 to 800 mg range. Reductions in IAUGC and K(trans) were shown at all pazopanib doses evaluated, with the greatest reductions at 600 and 800 mg. Although larger DCE-MRI parameter decreases were associated with larger C(24) and C(max) values, there was no constant relationship between tumor perfusion decreases measured by DCE-MRI and plasma pazopanib pharmacokinetic parameters. Overall, 19 patients (73%) had either partial response or stable disease.
Pazopanib has a manageable safety profile in patients with advanced HCC, and 600 mg was chosen for further development of pazopanib in advanced HCCs. Moreover, pazopanib reduced tumor vessel leakage, as shown by DCE-MRI, indicating a direct effect on HCC vasculature that might be associated with its antitumor activity.
The peptidyl-proplyl-isomerase, PIN1, upregulates beta-catenin by inhibiting its interaction with APC. beta-catenin accumulation occurs in about 70% of hepatocellular carcinoma (HCC), of which only ...20% are due to beta-catenin mutations. The role of PIN1 in beta-catenin upregulation in HCC was investigated. PIN1 was shown to be overexpressed in more than 50% of HCC. All cases with PIN1 overexpression also showed beta-catenin accumulation, with 68% of cases showing concomitant beta-catenin and cyclin D1 accumulation. PIN1 was shown to contribute to beta-catenin and cyclin D1 overexpression directly by in vitro cell-line transfection experiments. Finally, we showed that PIN1 overexpression and beta-catenin gene mutations appeared to be mutually exclusive events, leading to beta-catenin accumulation in HCC. These results showed that PIN1 overexpression leading to beta-catenin accumulation might be a critical event in hepatocarcinogenesis, and that PIN1 is a potential target for therapeutic intervention in HCC.
Purpose: Thrombospondin 1 (THBS 1) is a matricellular protein capable of modulating angiogenesis. However, the actual role of THBS
1 in angiogenesis and tumor progression remains controversial. ...Hepatocellular carcinoma (HCC) is a hypervascular tumor characterized
by neovascularization. The significance of THBS 1 in HCC remains unknown. In this study, the significance of THBS 1 in HCC
was evaluated by correlating its expression with clinicopathological data. The possible role of THBS 1 in the angiogenesis
of HCC was also studied by correlating its expression with vascular endothelial growth factor (VEGF) expression.
Experimental Design: Sixty HCC patients were recruited in this study. THBS 1 and VEGF protein expression in tumorous livers were localized by
immunohistochemical staining and quantified by ELISA. THBS 1 mRNA was quantified by quantitative reverse transcription-PCR.
Results: Immunohistochemical staining of THBS 1 was positive in HCC cells in 51.7% of patients and in stromal cells in 65% of patients.
Tumor THBS 1 protein level was significantly correlated with its mRNA expression ( P = 0.001) and was significantly correlated with tumor VEGF protein levels ( P = 0.001). Its expression was significantly associated with the presence of venous invasion ( P = 0.008) and advanced tumor stage ( P = 0.049). High THBS 1 expression was also a prognostic marker of poor survival in HCC patients.
Conclusions: This study shows that high expression of THBS 1 is associated with tumor invasiveness and progression in HCC. THBS 1 appears
to be a proangiogenic factor that stimulates angiogenesis in HCC in view of its positive correlation with VEGF expression.
AIM: Recent studies suggested that cyclooxygenase-2 (COX-2) enhances tumor angiogenesis via upregulation of vascular endothelial growth factor (VEGF). Although COX-2 expression has been demonstrated ...in hepatocellular carcinoma (HCC), the significance of COX-2 in progression of HCC remains unclear. This study evaluated the clinicopathological correlation of COX-2 level and its relationship with VEGF level in HCC. METHODS: Fresh tumor tissues were obtained from 100p atients who underwent resection of HCC. COX-2 protein expression was examined by immunohistochemistry, and quantitatively by an enzyme immunometric assay (EIA) of tumor cytosolic COX-2 levels. Tumor cytosolic VEGF levels were measured by an ELISA. RESULTS: Immunostaining showed expression of COX-2 in tumor cells. Tumor cytosolic COX-2 levels correlated with VEGF levels (r = 0.469, P<0.001). Correlation with clinicopathological features showed significantly higher tumor cytosolic COX-2 levels in the presence of multiple tumors (P = 0.027), venous invasion (P = 0.030), microsatellite lesions (P = 0.037) and advanced tumor stage (P = 0.008). Higher tumor cytosolic COX-2 levels were associated with worse patient survival. CONCLUSION: This study shows that elevated tumor COX-2 levels correlate with elevated VEGF levels and invasiveness in HCC, suggesting that COX-2 plays a significant role in the progression of HCC.
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