Molecular heterogeneity in hepatocellular carcinoma

Zhu, Shijia; Hoshida, Yujin

doi:10.2217/hep-2018-0005

Cited by 24 publications

(19 citation statements)

References 28 publications

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“…Approved chemotherapeutic strategies against HCC include multi-kinase inhibitors and immune-checkpoint inhibitors. However, patient response to these drugs and improvement in survival are marginal (Zhu and Hoshida, 2018). Genome-wide analyses of clinical HCC samples reveal a range of functional molecular aberrations that can be grouped into distinct molecular subclasses (Chiang et al, 2008).…”

Section: Introductionmentioning

confidence: 99%

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Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish

et al. 2019

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Up to 41% of hepatocellular carcinomas (HCCs) result from activating mutations in the CTNNB1 gene encoding β-catenin. HCC-associated CTNNB1 mutations stabilize the β-catenin protein, leading to nuclear and/or cytoplasmic localization of β-catenin and downstream activation of Wnt target genes. In patient HCC samples, β-catenin nuclear and cytoplasmic localization are typically patchy, even among HCC with highly active CTNNB1 mutations. The functional and clinical relevance of this heterogeneity in β-catenin activation are not well understood. To define mechanisms of β-catenin-driven HCC initiation, we generated a Cre-lox system that enabled switching on activated β-catenin in (1) a small number of hepatocytes in early development; or (2) the majority of hepatocytes in later development or adulthood. We discovered that switching on activated β-catenin in a subset of larval hepatocytes was sufficient to drive HCC initiation. To determine the role of Wnt/β-catenin signaling heterogeneity later in hepatocarcinogenesis, we performed RNA-seq analysis of zebrafish β-catenin-driven HCC. At the single-cell level, 2.9% to 15.2% of hepatocytes from zebrafish β-catenin-driven HCC expressed two or more of the Wnt target genes axin2, mtor, glula, myca and wif1, indicating focal activation of Wnt signaling in established tumors. Thus, heterogeneous β-catenin activation drives HCC initiation and persists throughout hepatocarcinogenesis.

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Section: Introductionmentioning

confidence: 99%

“…Researchers are beginning to understand the importance of intratumor heterogeneity in the pathogenesis and treatment of cancer, including HCC (Zhu and Hoshida, 2018). Eighty-seven percent of HCC show intratumor heterogeneity with respect to morphology, immunohistochemistry and/or mutational status of CTNNB1 or TP53 (Friemel et al, 2015).…”

Section: Introductionmentioning

confidence: 99%

Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish

et al. 2019

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“…Moreover, as HCCs exhibit significant intertumoral or intratumoral heterogeneity from genetic aberrations, transcriptional and epigenetic dysregulation, a single biopsy specimen containing a small amount of tumor tissue may not be representative of the whole HCC tumor. ( 17 )…”

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confidence: 99%

Detection of Circulating Tumor Cells and Their Implications as a Biomarker for Diagnosis, Prognostication, and Therapeutic Monitoring in Hepatocellular Carcinoma

et al. 2021

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Hepatocellular carcinoma (HCC) is among the leading causes of worldwide cancer‐related morbidity and mortality. Poor prognosis of HCC is attributed primarily to tumor presentation at an advanced stage when there is no effective treatment to achieve the long term survival of patients. Currently available tests such as alpha‐fetoprotein have limited accuracy as a diagnostic or prognostic biomarker for HCC. Liver biopsy provides tissue that can reveal tumor biology but it is not used routinely due to its invasiveness and risk of tumor seeding, especially in early‐stage patients. Liver biopsy is also limited in revealing comprehensive tumor biology due to intratumoral heterogeneity. There is a clear need for new biomarkers to improve HCC detection, prognostication, prediction of treatment response, and disease monitoring with treatment. Liquid biopsy could be an effective method of early detection and management of HCC. Circulating tumor cells (CTCs) are cancer cells in circulation derived from the original tumor or metastatic foci, and their measurement by liquid biopsy represents a great potential in facilitating the implementation of precision medicine in patients with HCC. CTCs can be detected by a simple peripheral blood draw and potentially show global features of tumor characteristics. Various CTC detection platforms using immunoaffinity and biophysical properties have been developed to identify and capture CTCs with high efficiency. Quantitative abundance of CTCs, as well as biological characteristics and genomic heterogeneity among the CTCs, can predict disease prognosis and response to therapy in patients with HCC. This review article will discuss the currently available technologies for CTC detection and isolation, their utility in the clinical management of HCC patients, their limitations, and future directions of research.

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“…However, detection sensitivity and specificity need to be substantially improved to reliably monitor them in cirrhosis patients with no clinically recognizable tumor. 99–101 For example, sensitivity of circulating cfDNA-based detection of somatic DNA mutations found in tissue is less than 50% even with deep sequencing of targeted genes. 102 Detection of CTC and ctDNA may be biased toward specific tumor cell population prone to die, closely located to vascular system, or with other properties.…”

Section: Circulating Factorsmentioning

confidence: 99%

Hepatocellular Carcinoma Risk Stratification by Genetic Profiling in Patients with Cirrhosis

Fujiwara

Hoshida

2019

Semin Liver Dis

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Prediction of future hepatocellular carcinoma (HCC) risk in the sizable chronic liver disease population is an urgent unmet need to enable regular HCC screening for early detection. Germline DNA polymorphisms likely represent etiology-specific host factors that determine HCC susceptibility, including single nucleotide polymorphisms in EGF, IFNL3, MICA, and TLL1 in hepatitis C with or without active viral infection, and PNPLA3, TM6SF2, and MBOAT7 in metabolic liver diseases. Transcriptome-based prognostic liver signature in diseased liver tissue has been associated with long-term HCC risk in viral and metabolic etiologies. Transcriptomic signatures of hepatic injury and specific cell type such as aggregated lymphocytes also predict HCC development. Circulating factors such as proteins and their chemical modification, nucleotides, and metabolites may serve for less-invasive assessment of short- or long-term HCC risk. These biomarkers will enable individual HCC risk-based personalized clinical management for cost-effective early HCC detection and improvement of patient survival.

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Molecular heterogeneity in hepatocellular carcinoma

Cited by 24 publications

References 28 publications

Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish

Heterogeneous beta-catenin activation is sufficient to cause hepatocellular carcinoma in zebrafish

Detection of Circulating Tumor Cells and Their Implications as a Biomarker for Diagnosis, Prognostication, and Therapeutic Monitoring in Hepatocellular Carcinoma

Hepatocellular Carcinoma Risk Stratification by Genetic Profiling in Patients with Cirrhosis

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