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Integrative Genomic Analysis Identifies the Core Transcriptional Hallmarks of Human Hepatocellular Carcinoma.

ABSTRACT: Integrative genomics helped characterize molecular heterogeneity in hepatocellular carcinoma (HCC), leading to targeted drug candidates for specific HCC subtypes. However, no consensus was achieved for genes and pathways commonly altered in HCC. Here, we performed a meta-analysis of 15 independent datasets (n = 784 human HCC) and identified a comprehensive signature consisting of 935 genes commonly deregulated in HCC as compared with the surrounding nontumor tissue. In the HCC signature, upregulated genes were linked to early genomic alterations in hepatocarcinogenesis, particularly gains of 1q and 8q. The HCC signature covered well-established cancer hallmarks, such as proliferation, metabolic reprogramming, and microenvironment remodeling, together with specific hallmarks associated with protein turnover and epigenetics. Subsequently, the HCC signature enabled us to assess the efficacy of signature-relevant drug candidates, including histone deacetylase inhibitors that specifically reduced the viability of six human HCC cell lines. Overall, this integrative genomics approach identified cancer hallmarks recurrently altered in human HCC that may be targeted by specific drugs. Combined therapies targeting common and subtype-specific cancer networks may represent a relevant therapeutic strategy in liver cancer. Cancer Res; 76(21); 6374-81. ©2016 AACR.

SUBMITTER: Allain C

PROVIDER: S-EPMC5660733 | biostudies-literature |

REPOSITORIES: biostudies-literature

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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:BACKGROUND:Hepatocellular carcinoma (HCC) is the major type of primary liver cancer. Intrahepatic metastasis, such as portal vein tumor thrombosis (PVTT), strongly indicates poor prognosis of HCC. But now, there are limited understandings of the molecular features and mechanisms of those metastatic HCCs. METHODS:To characterize the molecular alterations of the metastatic HCCs, we implemented an integrative analysis of the copy number variations (CNVs), DNA methylations and transcriptomes of matched adjacent normal, primary tumor and PVTT samples from 19 HCC patients. RESULTS:CNV analysis identified a frequently amplified focal region chr11q13.3 and a novel deletion peak chr19q13.41 containing three miRNAs. The integrative analysis with RNA-seq data suggests that CNVs and differential promoter methylations regulate distinct oncogenic processes. Then, we used individualized differential analysis to identify the differentially expressed genes between matched primary tumor and PVTT of each patient. Results show that 5 out of 19 studied patients acquire evidential progressive alterations of gene expressions (more than 1000 differentially expressed genes were identified in each patient). While, another subset of eight patients have nearly identical gene expressions between the corresponding matched primary tumor and PVTT. Twenty genes were found to be recurrently and progressively differentially expressed in multiple patients. These genes are mainly associated with focal adhesion, xenobiotics metabolism by cytochrome P450 and amino acid metabolism. For several differentially expressed genes in metabolic pathways, their expressions are significantly associated with overall survivals and vascular invasions of HCC patients. The following transwell assay experiments validate that they can regulate invasive phenotypes of HCC cells. CONCLUSIONS:The metastatic HCCs with PVTTs have significant molecular alterations comparing with adjacent normal tissues. The recurrent alteration patterns are similar to several previously published general HCC cohorts, but usually with higher severity. By an individualized differential analysis strategy, the progressively differentially expressed genes between the primary tumor and PVTT were identified for each patient. A few patients aquire evidential progressive alterations of gene expressions. And, experiments show that several recurrently differentially expressed genes can strongly regulate HCC cell invasions.

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Integrative Genomic Analysis Identifies the Core Transcriptional Hallmarks of Human Hepatocellular Carcinoma.

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