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.

Dataset Information

A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma.

Publications

A Survey of Molecular Heterogeneity in Hepatocellular Carcinoma.

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