Dataset Information

NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma.

ABSTRACT: The MYC oncogene is dysregulated in approximately 30% of liver cancer. In an effort to exploit MYC as a therapeutic target, including in hepatocellular carcinoma (HCC), strategies have been developed on the basis of MYC amplification or gene translocation. Due to the failure of these strategies to provide accurate diagnostics and prognostic value, we have developed a Negative Elongation Factor E (NELFE)-Dependent MYC Target (NDMT) gene signature. This signature, which consists of genes regulated by MYC and NELFE, an RNA binding protein that enhances MYC-induced hepatocarcinogenesis, is predictive of NELFE/MYC-driven tumors that would otherwise not be identified by gene amplification or translocation alone. We demonstrate the utility of the NDMT gene signature to predict a unique subtype of HCC, which is associated with a poor prognosis in three independent cohorts encompassing diverse etiologies, demographics, and viral status. The application of gene signatures, such as the NDMT signature, offers patients access to personalized risk assessments, which may be utilized to direct future care.

SUBMITTER: Dang H

PROVIDER: S-EPMC6399236 | biostudies-literature | 2019 Mar

REPOSITORIES: biostudies-literature

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NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma.

Dang Hien H Pomyen Yotsawat Y Martin Sean P SP Dominguez Dana A DA Yim Sun Young SY Lee Ju-Seog JS Budhu Anuradha A Shah Ashesh P AP Bodzin Adam S AS Wang Xin Wei XW

Scientific reports 20190304 1

The MYC oncogene is dysregulated in approximately 30% of liver cancer. In an effort to exploit MYC as a therapeutic target, including in hepatocellular carcinoma (HCC), strategies have been developed on the basis of MYC amplification or gene translocation. Due to the failure of these strategies to provide accurate diagnostics and prognostic value, we have developed a Negative Elongation Factor E (NELFE)-Dependent MYC Target (NDMT) gene signature. This signature, which consists of genes regulated ...[more]

PMID: 30833661

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Project description:Background & aimsThe hepatocyte Notch pathway is a pathogenic factor in non-alcoholic steatohepatitis (NASH)-associated fibrosis, but its role in hepatocellular carcinoma (HCC) is less well defined. Herein, we aimed to characterize the molecular and clinical features of Notch-active human HCC, and to investigate the mechanisms by which Notch affects NASH-driven HCC.MethodsUsing a 14-gene Notch score, we stratified human HCCs from multiple comprehensively profiled datasets. We performed gene set enrichment analyses to compare Notch-active HCCs with published HCC subtype signatures. Next, we sorted Notch-active hepatocytes from Notch reporter mice for RNA sequencing and characterized Notch-active tumors in an HCC model combining a carcinogen and a NASH-inducing diet. We used genetic mouse models to manipulate hepatocyte Notch to investigate the sufficiency and necessity of Notch in NASH-driven tumorigenesis.ResultsNotch-active signatures were found in ~30% of human HCCs that transcriptionally resemble cholangiocarcinoma-like HCC, exhibiting a lack of activating CTNNB1 (β-catenin) mutations and a generally poor prognosis. Endogenous Notch activation in hepatocytes is associated with repressed β-catenin signaling and hepatic metabolic functions, in lieu of increased interactions with the extracellular matrix in NASH. Constitutive hepatocyte Notch activation is sufficient to induce β-catenin-inactive HCC in mice with NASH. Notch and β-catenin show a pattern of mutual exclusivity in carcinogen-induced HCC; in this mouse model, chronic blockade of Notch led to β-catenin-dependent tumor development.ConclusionsNotch activity characterizes a distinct HCC molecular subtype with unique histology and prognosis. Sustained Notch signaling in chronic liver diseases can drive tumor formation without acquiring specific genomic driver mutations.Lay summaryThe Notch signaling pathway is known to be involved in the pathogenesis of liver fibrosis. However, its role in liver cancer has not been well defined. Herein, we show that Notch activity is increased in a subset of liver cancers and is associated with poor outcomes. We also used a mouse model to show that aberrant Notch activity can drive cancer progression in obese mice.

Project description:Globally, hepatocellular carcinoma (HCC) is the sixth most common cancer. In this study, the correlation between mitophagy and HCC prognosis was evaluated using data from The Cancer Genome Atlas (TCGA). Clinical and transcriptomic data of HCC patients were downloaded from TCGA dataset, and mitophagy-related gene (MRG) datasets were obtained from the Molecular Signature Database. Then, a consensus clustering analysis was performed to classify the patients into two clusters. Furthermore, tumor prognosis, clinicopathological features, functional analysis, immune infiltration, immune checkpoint (IC)-related gene expression level, tumor stem cells, ferroptosis status, and N6-methyladenosine analysis were compared between the two clusters. Finally, a mitophagy-related signature was developed. Two clusters (C1 and C2) were identified using the consensus clustering analysis based on the MRG signature. Patients with the C1 subtype exhibited upregulated pathways with better liver function, downregulated cancer-related pathways, lower cancer stem cell scores, lower Tumor Immune Dysfunction and Exclusion scores (TIDE), different ferroptosis status, and better prognosis compared with the patients with the C2 subtype. The C2 subtype was characterized by the increased grade of HCC, as well as the increased number of immune-related pathways and m6A-related genes. Higher immune scores were also observed for the C2 subtype. A signature containing four MRGs (PGAM5, SQSTM1, ATG9A, and GABARAPL1) which can accurately predict the prognosis of HCC patients was then identified. This four-gene signature exhibited a predictive effect in five other cancer types, namely glioma, uveal melanoma, acute myeloid leukemia, adrenocortical carcinoma, and mesothelioma. The mitophagy-associated subtypes of HCC were closely related to the immune microenvironment, immune checkpoint-related gene expression, cancer stem cells, ferroptosis status, m6A, prognosis, and HCC progression. The established MRG signature could predict prognosis in patients with HCC.

Dataset Information

NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma.

Publications

NELFE-Dependent MYC Signature Identifies a Unique Cancer Subtype in Hepatocellular Carcinoma.

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