Dataset Information

A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma.

ABSTRACT: Understanding the heterogeneity of dysregulated pathways associated with the development of hepatocellular carcinoma (HCC) may provide prognostic and therapeutic avenues for disease management. As HCC involves a complex process of genetic and epigenetic modifications, we evaluated expression of both polyadenylated transcripts and microRNAs from HCC and liver samples derived from two cohorts of patients undergoing either partial hepatic resection or liver transplantation. Copy number variants were inferred from whole genome low-pass sequencing data, and a set of 56 cancer-related genes were screened using an oncology panel assay. HCC was associated with marked transcriptional deregulation of hundreds of protein-coding genes. In the partially resected livers, diminished transcriptional activity was observed in genes associated with drug catabolism and increased expression in genes related to inflammatory responses and cell proliferation. Moreover, several long noncoding RNAs and microRNAs not previously linked with HCC were found to be deregulated. In liver transplant recipients, down-regulation of genes involved in energy production and up-regulation of genes associated with glycolysis were detected. Numerous copy number variants events were observed, with hotspots on chromosomes 1 and 17. Amplifications were more common than deletions and spanned regions containing genes potentially involved in tumorigenesis. Colony stimulating factor 1 receptor (CSF1R), fibroblast growth factor receptor 3 (FGFR3), fms-like tyrosine kinase 3 (FLT3), nucleolar phosphoprotein B23 (NPM1), platelet-derived growth factor receptor alpha polypeptide (PDGFRA), phosphatase and tensin homolog (PTEN), G-protein-coupled receptors-like receptor Smoothened (SMO), and tumor protein P53 (TP53) were mutated in all tumors; another 26 cancer-related genes were mutated with variable penetrance. Conclusion: Our results underscore the marked molecular heterogeneity between HCC tumors and reinforce the notion that precision medicine approaches are needed for management of individual HCC. These data will serve as a resource to generate hypotheses for further research to improve our understanding of HCC biology. (Hepatology Communications 2018; 00:000-000).

SUBMITTER: Jovel J

PROVIDER: S-EPMC6078210 | biostudies-literature | 2018 Aug

REPOSITORIES: biostudies-literature

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A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma.

Jovel Juan J Lin Zhen Z O'keefe Sandra S Willows Steven S Wang Weiwei W Zhang Guangzhi G Patterson Jordan J Moctezuma-Velázquez Carlos C Kelvin David J DJ Ka-Shu Wong Gane G Mason Andrew L AL

Hepatology communications 20180712 8

Understanding the heterogeneity of dysregulated pathways associated with the development of hepatocellular carcinoma (HCC) may provide prognostic and therapeutic avenues for disease management. As HCC involves a complex process of genetic and epigenetic modifications, we evaluated expression of both polyadenylated transcripts and microRNAs from HCC and liver samples derived from two cohorts of patients undergoing either partial hepatic resection or liver transplantation. Copy number variants wer ...[more]

PMID: 30094405

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Project description:Genome-wide gene expression profiles of multiple hepatocellular carcinoma tumors and non-tumor liver tissues from the same patients. Introduction: Hepatocellular Carcinoma (HCC) is the second cause of cancer-related death worldwide. Understanding tumor heterogeneity is relevant for the pathogenesis and treatment of this neoplasm. Particularly, whether multinodular tumors result from intrahepatic metastasis (IM or clonal tumors) or de novo cancers (synchronic tumors) have direct implications in treatment decisionmaking for resection and transplantation. We aimed to assess the genomic heterogeneity of multifocal HCC using single-nucleotide polymorphism (SNP) and gene expression analyses. Methods: Among 544 HCC patients consecutively transplanted at Mount Sinai Hospital between 1990- 2007, we selected 18 patients with a total of 42 multinodular tumors (2-3 non-satellite foci HCCs) for this molecular study. Formalin-fixed blocks were collected for each tumor along with corresponding clinico-pathological data. SNP array and gene expression profiling was generated. Clonality was defined by measuring the similarity of genome-wide copy number variation (CNV) profiles between two nodules. Unsupervised hierarchical clustering based on gene expression data was performed to measure genetic proximity between each tumor. Prediction of previously published signatures was performed using Nearest Template Prediction (NTP). Association of clonality with clinic-pathological parameters was assessed. Results: A total of 42 tumors have been analyzed (10 patients- 2 tumors; 8- 3 tumors). Most patients were male (17/18, 95%) with median age of 53-yr-old (range 39–67), HCV (10/18, 56%) or HBV infection (6/18, 33%). Median tumor size was 3 cm (range 1.5-6.5), satellites were present in 3 (17%) and vascular invasion in 11 patients (61%), respectively. CNV profiles predicted clonal tumors in 38% (6/16) and non-clonality in 62% of cases (10/16). CNV profiles of the remaining 2 cases were not informative. Clonal tumors were significantly associated with HCV infected patients (5/6 vs 3/10, p=0.007), whereas all HBV-induced HCC were synchronic tumors (0/6 vs 6/10, p=0.03). Furthermore, clonal tumors were significantly associated with presence of satellites and shorter time-torecurrence. Assessment of genetic proximity based on gene expression revealed that each clonal tumor showed proximity to its paired tumor and clustered around the same node (6/6,100%) as opposed to non-clonal (2/9,22%). When exploring molecular subclasses within clonal tumors (intrahepatic metastases), while half of them retained the molecular fingerprint, the other half switch to more aggressive subclasses. Conversely, all non-clonal tumors within the same patient belonged to distinct molecular subclasses. Conclusion: Multinodular HCCs undergoing transplantation are molecularly heterogeneous. Using CNV profiling we identified clonal multinodular tumors (true intrahepatic metastasis) in 40% of cases and de novo tumors in 60%. Clonal tumors were significantly associated with HCV infection, satellites and recurrence. Genetic proximity was observed in clonal tumors, but molecular subclasses prediction revealed that intrahepatic metastases share more aggressive subclasses in half of cases.

Project description:Genome-wide DNA copy number profiles of multiple hepatocellular carcinoma tumors and non-tumor liver tissues from the same patients. Introduction: Hepatocellular Carcinoma (HCC) is the second cause of cancer-related death worldwide. Understanding tumor heterogeneity is relevant for the pathogenesis and treatment of this neoplasm. Particularly, whether multinodular tumors result from intrahepatic metastasis (IM or clonal tumors) or de novo cancers (synchronic tumors) have direct implications in treatment decisionmaking for resection and transplantation. We aimed to assess the genomic heterogeneity of multifocal HCC using single-nucleotide polymorphism (SNP) and gene expression analyses. Methods: Among 544 HCC patients consecutively transplanted at Mount Sinai Hospital between 1990- 2007, we selected 18 patients with a total of 42 multinodular tumors (2-3 non-satellite foci HCCs) for this molecular study. Formalin-fixed blocks were collected for each tumor along with corresponding clinico-pathological data. SNP array and gene expression profiling was generated. Clonality was defined by measuring the similarity of genome-wide copy number variation (CNV) profiles between two nodules. Unsupervised hierarchical clustering based on gene expression data was performed to measure genetic proximity between each tumor. Prediction of previously published signatures was performed using Nearest Template Prediction (NTP). Association of clonality with clinic-pathological parameters was assessed. Results: A total of 42 tumors have been analyzed (10 patients- 2 tumors; 8- 3 tumors). Most patients were male (17/18, 95%) with median age of 53-yr-old (range 39–67), HCV (10/18, 56%) or HBV infection (6/18, 33%). Median tumor size was 3 cm (range 1.5-6.5), satellites were present in 3 (17%) and vascular invasion in 11 patients (61%), respectively. CNV profiles predicted clonal tumors in 38% (6/16) and non-clonality in 62% of cases (10/16). CNV profiles of the remaining 2 cases were not informative. Clonal tumors were significantly associated with HCV infected patients (5/6 vs 3/10, p=0.007), whereas all HBV-induced HCC were synchronic tumors (0/6 vs 6/10, p=0.03). Furthermore, clonal tumors were significantly associated with presence of satellites and shorter time-torecurrence. Assessment of genetic proximity based on gene expression revealed that each clonal tumor showed proximity to its paired tumor and clustered around the same node (6/6,100%) as opposed to non-clonal (2/9,22%). When exploring molecular subclasses within clonal tumors (intrahepatic metastases), while half of them retained the molecular fingerprint, the other half switch to more aggressive subclasses. Conversely, all non-clonal tumors within the same patient belonged to distinct molecular subclasses. Conclusion: Multinodular HCCs undergoing transplantation are molecularly heterogeneous. Using CNV profiling we identified clonal multinodular tumors (true intrahepatic metastasis) in 40% of cases and de novo tumors in 60%. Clonal tumors were significantly associated with HCV infection, satellites and recurrence. Genetic proximity was observed in clonal tumors, but molecular subclasses prediction revealed that intrahepatic metastases share more aggressive subclasses in half of cases.

Project description:BackgroundHepatocellular carcinoma (HCC) often presents with multiple nodules within the liver, with limited effective interventions. The high genetic heterogeneity of HCC might be the major cause of treatment failure. We aimed to characterize genomic heterogeneity, infer clonal evolution, investigate RNA expression pattern and explore tumour immune microenvironment profile of multifocal HCC.Patients and methodsWhole-exome sequencing and RNA sequencing were carried out in 34 tumours and 6 adjacent normal liver tissue samples from 6 multifocal HCC patients. Protein expression of Ki67, AFP, P53, Survivin and CD8 was detected by immunohistochemistry. Fluorescence in situ hybridization was carried out to validate the amplification status of sorafenib-targeted genes.ResultsWe deciphered genomic and transcriptional heterogeneity among tumours in each multifocal HCC patient including mutational profiles, copy number alterations, tumour evolutionary trajectory and tumour immune microenvironment profiles. Of note, sorafenib-targeted alterations were identified in the trunk of phylogenetic tree in only one out of the six patients, which may explain the relative low treatment response rate to sorafenib in clinical practice. Moreover, we demonstrated RNA expression patterns and tumour immune microenvironment profiles of all nodules. We found that RNA expression pattern was associated with Edmondson-Steiner grading. Based on the differential expression of 66 reported immune markers, unsupervised hierarchical clustering analysis of 34 nodules identified immune subsets: one low expression cluster with seven nodules and one high expression cluster with 11 nodules. CD8+ T cells were more enriched in nodules of the high expression cluster.ConclusionsOur study provided a detailed view of genomic and transcriptional heterogeneity, clonal evolution and immune infiltration of multifocal HCC. The heterogeneity of druggable targets and immune landscape might help interpret the clinical responsiveness to targeted drugs and immunotherapy for multifocal HCC patients.

Project description:BackgroundHepatocellular carcinoma (HCC) is leading cause of cancer-related mortality and is categorized among the most common malignancies around the world. It is a heterogeneous tumor, which shows significant degree of histopathological heterogeneity. Despite the apparent histopathological diversity there has been very little distinct correlation between histopathological features and molecular aberrations particularly when it comes to the expression level of Wnt and Hh pathway molecules. The role of Wnt and Hh pathways in relation to HCC behavior viz. histopathological heterogeneity and aggressiveness is not known. Determining the sequential molecular changes and associated histopathological characteristic during HCC initiation, promotion, and progression would probably lead to a better treatment and prognosis.MethodsN-Nitrosodiethylamine (DEN) induced HCC model in male Wistar rats were established to study the expression level of Wnt and Hh pathway molecules during different stages of hepatocarcinogenesis. Their expression levels were checked at mRNA and protein levels at initiation, promotion, and progression stages of HCC. The expression levels of Wnt and Hh pathway molecules were correlated with biospecimens of HCC patients of different stages.ResultsIn the present study we identified the comprehensive change in the expression pattern of Wnt and Hh pathway molecules in DEN induced rodent hepatocarcinogenesis model. Our results demonstrate that ?-catenin /CTNNB1 plays important role in tumor initiation and promotion by stimulating tumor cell proliferation. The activated Wnt signaling in early stage of HCC is associated with well-differentiated histological pattern. The Hh activity although activated during the initiation stage but is significantly increased during the early promotion stage of hepatocarcinogenesis. The increased activity of both Wnt & Hh pathways during promotion stage is associated with moderately-differentiated histological pattern and was simultaneously linked with an increased expression of MMP9. Furthermore, our data demonstrated that during the progression stage Wnt pathway is modestly down-regulated but the Hh pathway activity sustained which in turn is associated with aggressive and invasive phenotype and poorly-differentiated histopathology.ConclusionOur data uncovers the grade related expression of Wnt and Hh pathway molecules and the potential utility of these molecular signatures in daily clinical practice is to decide best therapy according to patients characteristic. Additionally, our data offer insight into the interaction between Wnt and Hh pathways which triggers HCC development and progression.

Project description:BACKGROUND & AIMS: In approximately 70% of patients with hepatocellular carcinoma (HCC) treated by resection or ablation, disease recurs within 5 years. Although gene expression signatures have been associated with outcome, there is no method to predict recurrence based on combined clinical, pathology, and genomic data (from tumor and cirrhotic tissue). We evaluated gene expression signatures associated with outcome in a large cohort of patients with early stage (Barcelona-Clinic Liver Cancer 0/A), single-nodule HCC and heterogeneity of signatures within tumor tissues. METHODS: We assessed 287 HCC patients undergoing resection and tested genome-wide expression platforms using tumor (n = 287) and adjacent nontumor, cirrhotic tissue (n = 226). We evaluated gene expression signatures with reported prognostic ability generated from tumor or cirrhotic tissue in 18 and 4 reports, respectively. In 15 additional patients, we profiled samples from the center and periphery of the tumor, to determine stability of signatures. Data analysis included Cox modeling and random survival forests to identify independent predictors of tumor recurrence. RESULTS: Gene expression signatures that were associated with aggressive HCC were clustered, as well as those associated with tumors of progenitor cell origin and those from nontumor, adjacent, cirrhotic tissues. On multivariate analysis, the tumor-associated signature G3-proliferation (hazard ratio [HR], 1.75; P = .003) and an adjacent poor-survival signature (HR, 1.74; P = .004) were independent predictors of HCC recurrence, along with satellites (HR, 1.66; P = .04). Samples from different sites in the same tumor nodule were reproducibly classified. CONCLUSIONS: We developed a composite prognostic model for HCC recurrence, based on gene expression patterns in tumor and adjacent tissues. These signatures predict early and overall recurrence in patients with HCC, and complement findings from clinical and pathology analyses. Center and peripheral portions of hepatocellular carcinoma tumors as well as surrounding non-tumor cirrhotic liver tissues were obtained from fresh frozen surgically resected tissues, and isolated total RNA samples were analyzed for genome-wide expression profiles.

Dataset Information

A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma.

Publications

A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma.

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