Project description:Hepatoblastoma (HB) is the most common pediatric liver malignancy; however, hereditary predisposition and acquired molecular aberrations related to HB clinicopathological diversity are not well understood. We performed an integrative genomic profiling of 163 pediatric liver tumors (154 HB and 9 hepatocellular carcinoma) based on data acquired from a cohort study (JPLT-2). The total number of somatic mutations was found to be extremely low (0.52 /Mb on exonic regions) but correlated with age at diagnosis. TERT promoter mutations are prevalent in the tween HBs, selective in the transitional liver cell tumor (TLCT, > 8 years old). DNA methylation profiling revealed that classical HBs are characterized by the specific hypomethylated enhancers, which are enriched with binding sites for ASCL2, a regulatory transcription factor for definitive endoderm in Wnt-pathway. Prolonged upregulation of ASCL2, as well as fetal-liver-like methylation patterns of IGF2 promoters, suggests their “cell of origin” derived from the premature hepatoblast, similar to intestinal epithelial cells, which are highly proliferative. Systematic molecular profiling of HB is a promising approach to understanding the epigenetic drivers of hepatoblast carcinogenesis and clues for risk stratification.
Project description:BACKGROUND: Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis. METHODS: We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years. RESULTS: Fourteen of 47 livers displayed prominent features of inflammation (N=9) or fibrosis (N=5), with the remainder showing similar levels of both simultaneously. Differential profiling of gene expression of the 14 livers displayed a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival. CONCLUSION: Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes. Clinical and laboratory data and liver biopies were obtained from 47 infants at diagnosis of biliary atresia and every 3-6 month intervals until 2 years of age as part of a prospective, observational study of the Biliary Atresia Research Consortium. Liver biopsies underwent histological scoring and those specimens classified as inflammation or fibrosis were used to generate a group-specific gene expression profile. The profile was used to assign a molecular stages of inflammation or fibrosis to the entire cohort. Molecular groups were tested for biological plausibility using immunostaining to quantify hepatic inflammatory cells, and quantitative PCR to reproduce the expression of gene groups and the expression of collagen genes. They were also tested for clinical relevance by testing of association with indicators of liver function, complications of disease, and clinical outcome. This dataset is part of the TransQST collection.
Project description:BACKGROUND: Young age at portoenterostomy has been linked to improved outcome in biliary atresia, but pre-existing biological factors may influence the rate of disease progression. In this study, we aimed to determine whether molecular profiling of the liver identifies stages of disease at diagnosis. METHODS: We examined liver biopsies from 47 infants with biliary atresia enrolled in a prospective observational study. Biopsies were scored for inflammation and fibrosis, used for gene expression profiles, and tested for association with indicators of disease severity, response to surgery, and survival at 2 years. RESULTS: Fourteen of 47 livers displayed prominent features of inflammation (N=9) or fibrosis (N=5), with the remainder showing similar levels of both simultaneously. Differential profiling of gene expression of the 14 livers displayed a unique molecular signature containing 150 gene probes. Applying prediction analysis models, the probes classified 29 of the remaining 33 livers into inflammation or fibrosis. Molecular classification into the two groups was validated by the findings of increased hepatic population of lymphocyte subsets or tissue accumulation of matrix substrates. The groups had no association with traditional markers of liver injury or function, response to surgery, or complications of cirrhosis. However, infants with an inflammation signature were younger, while those with a fibrosis signature had decreased transplant-free survival. CONCLUSION: Molecular profiling at diagnosis of biliary atresia uncovers a signature of inflammation or fibrosis in most livers. This signature may relate to staging of disease at diagnosis and has implications to clinical outcomes.
Project description:Hepatocellular carcinoma (HCC) is one of the main subtypes of primary liver cancer, which accounts for 75-85% of all cases [1]. Despite increasing availability of treatments for liver cancer, HCC clinical trials are not promising since most HCC patients are in an advanced stage of HCC at the time of diagnosis. Additionally, highly metastatic and recurrent phenotype aggravate poor prognosis of liver cancer [2]. Therefore, there is an urgent need to explore the underlying molecular mechanism in HCC progression.
Project description:The next generation of personalized medical treatment according to the type of personal genetic information are evolving rapidly. The genome analysis needs systematic infra and database based on personal genetic information. Therefore, a big data of genome-clinical information is important.
To determine the feasibility of the use of tumor’s molecular profiling and targeted therapies in the treatment of advanced cancer and to determine the clinical outcome(Response rate,PFS, duration of response and overall survival )of patients with advanced cancer, the investigators are going to take a tumor tissue of patients and process molecular profiling and receive molecular profile directed treatments.
Project description:Liver biopsy samples were obtained from 64 infants with biliary atresia at the time of intraoperative cholangiogram. Liver biopsy samples were obtained from 14 age-matched infants with other causes of intrahepatic cholestasis, and from 7 deceased-donor children. GeneChip® Human Gene 1.0 ST Array (Affymetrix, CA) were used to screen mRNAs whose expression was specifically regulated in the livers from patients with biliary atresia. Gene expression profiling: Liver biopsy samples obtained from infantas with other causes of intrahepatic cholestasis were served as diseased control. Liver tissue obtained from deceased-donor children were served as normal control. A molecular signataure of biliary atresia at the time of diagnosis was identified by comparing hepatic gene expression profile from biliary atresia to those from diseased and normal controls. This dataset is part of the TransQST collection.
Project description:Hepatitis C virus (HCV) infection is an important etiology of chronic liver disease. Multiple possible molecular mechanisms were involved in the progression of liver fibrosis in chronically HCV-infected patients. Therefore, the further revealing novel genes for regulating liver fibrosis might provide evidence for gene diagnosis and molecular-targeted therapy. In this study, we examined the differentially expressed mRNA in plasma samples from the healthy control and patients with HCV-related liver fibrosis, in order to explore the potential predicted and therapeutic target for the development of HCV-related liver fibrosis.
Project description:To compare the characteristics and mechanisms of Myc and xmrk induced zebrafish liver tumor, next generation sequencing-based SAGE analyses were used to examine the transcriptomes of tumor and control samples. The results indicated that relatively small overlaps of significantly deregulated genes and biological pathways among different zebrafish liver tumor models.Nevertheless, they all significantly correlate with advanced or very advanced human hepatocellular carcinoma (HCC). Molecular signature from each oncogene-induced zebrafish liver tumor correlated with only a small subset of human HCC samples, and they share conserved up-regulated pathways. A short list of commonly deregulated genes among different zebrafish liver tumors showed accordant deregulation in the majority of human HCCs, suggesting that they may serve as common diagnosis markers and therapeutic targets.Thus, these transgenic zebrafish models with well-defined oncogene-induced tumors are valuable tools for molecular classification of human HCCs and for understanding of molecular drivers in hepatocarcinogenesis in each human HCC subgroup. Transcriptome profiling of Myc tumor sample (X-M+D+) and control samples (X-M-D-, X-M+D-, X-M-D+), xmrk tumor sample (X+M-D+) and control samples (X-M-D-, X+M-D-, X-M-D+), were generated by deep sequencing, using 3' RNA-SAGE on SOLiD system