WITHDRAWN: Genomic and Epigenomic Features of Primary and Recurrent Hepatocellular Carcinomas

Ding, Xueliang; He, Mian; Chan, Anthony Wing–Hung; Song, Qian; Sze, Siu Ching; Chen, Hui; Man, Matthew; Man, Kwan; Chan, Stephen L.; Lai, Paul B.S.; Wang, Xin; Wong, Nathalie

doi:10.1053/j.gastro.2019.09.056

Cited by 69 publications

(85 citation statements)

References 65 publications

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“… [70] , [71] , [72] Importantly, the methylation changes observed in non-tumoural liver tissues from patients with chronic hepatitis and cirrhosis may have prognostic value for HCC development or recurrence. 69 , 71 , 75 These findings already indicate a causal relationship between epigenetic alterations and liver carcinogenesis. Early studies did not observe significant differences in overall changes to DNA methylation in HCCs from patients with different liver disease aetiologies.…”

Section: Epigenetic Alterations In Hepatocarcinogenesismentioning

confidence: 62%

“… 94 , 118 Interestingly, a recent study identified the HMTs MLL1/KMT2A and MLL2/KMT2B as transcriptional targets of mutated TP53 (p53 R249S ), and their pharmacological inhibition abrogated p53 R249S -driven HCC cell growth. 75 There are also numerous examples of the dysregulation of KDM enzymes in HCC tissues and their association with enhanced tumour progression. For instance, increased KDM3A expression was associated with tumour recurrence after resection, 119 while the upregulation of LSD1/KDM1, KDM5B, KDM6B, KDM4B and KDM2A has been related to tumour aggressiveness and poor prognosis.…”

Section: Epigenetic Alterations In Hepatocarcinogenesismentioning

confidence: 99%

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Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

et al. 2020

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Summary Hepatocellular carcinoma (HCC) is a deadly tumour whose causative agents are generally well known, but whose pathogenesis remains poorly understood. Nevertheless, key genetic alterations are emerging from a heterogeneous molecular landscape, providing information on the tumorigenic process from initiation to progression. Among these molecular alterations, those that affect epigenetic processes are increasingly recognised as contributing to carcinogenesis from preneoplastic stages. The epigenetic machinery regulates gene expression through intertwined and partially characterised circuits involving chromatin remodelers, covalent DNA and histone modifications, and dedicated proteins reading these modifications. In this review, we summarise recent findings on HCC epigenetics, focusing mainly on changes in DNA and histone modifications and their carcinogenic implications. We also discuss the potential drugs that target epigenetic mechanisms for HCC treatment, either alone or in combination with current therapies, including immunotherapies.

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Section: Epigenetic Alterations In Hepatocarcinogenesismentioning

confidence: 62%

Section: Epigenetic Alterations In Hepatocarcinogenesismentioning

confidence: 99%

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

et al. 2020

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“…Although surgery, transcatheter arterial chemoembolization (TACE), radiofrequency ablation, radiotherapy and other therapeutic approaches can control the progress of HCC, generally speaking, HCC is still under exploration in the areas of molecular typing, molecular diagnosis and gene target selection. Although CDH 21 , LDH 22 , NCOR1 23 and other mutant genes are new biomarkers in HCC subtype classification 24,25 , identification of gene mutations that affect recurrence is complex but will have clinical significance. Meanwhile, various probability theories and linear algebra algorithms can be used for comprehensive analysis.…”

Section: Discussionmentioning

confidence: 99%

Identification of a novel gene signature for the prediction of recurrence in HCC patients by machine learning of genome-wide databases

Shen

Liang

Zou

et al. 2020

Sci Rep

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Hepatocellular carcinoma (HCC) is a common malignant tumor in China. In the present study, we aimed to construct and verify a prediction model of recurrence in HCC patients using databases (TCGA, AMC and Inserm) and machine learning methods and obtain the gene signature that could predict early relapse of HCC. Statistical methods, such as feature selection, survival analysis and Chi-Square test in R software, were used to analyze and select mutant genes related to disease free survival (DFS), race and vascular invasion. In addition, whole-exome sequencing was performed on 10 HCC patients recruited from our center, and the sequencing results were compared with the databases. Using the databases and machine learning methods, the prediction model of recurrence was constructed and optimized, and the selected mutant genes were verified in the test group. The accuracy of prediction was 74.19%. Moreover, these 10 patients from our center were used to verify these mutant genes and the prediction model, and a success rate of 80% was achieved. Collectively, we discovered recurrence-related genes and established recurrence prediction model of recurrence for HCC patients, which could provide significant guidance for clinical prediction of recurrence. Hepatocellular carcinoma (HCC) is a common malignant tumor in China, which ranks the third in morbidity and the second in mortality. Its morbidity is usually associated with specific risk factors, including infections with HBV and HCV, high alcohol intake, obesity and consumption of aflatoxin-containing food 1. With the development of the second-generation sequencing techniques increasing research on HCC has been conducted on the molecular level. In 2014, Totoki et al. 2 have reported the whole-genome sequencing of 608 HCC patients from Asia and Europe. In 2015, Schulze et al. 3 have reported the whole-genome sequencing of 243 HCC patients from Europe and America. In 2016, Fujimoto et al. 4 have reported the whole-genome sequencing of 300 HCC patients from Japan. The molecular blueprint of HCC including somatic mutation, mRNA expression, methylation and miRNA regulation has been gradually outlined, which could be used for the diagnosis, treatment, and prediction of recurrence and survival of liver cancer patients. In 2017, TCGA working group 5 has systematically analyzed the sequencing results of the whole exome of more than 360 HCC patients in TCGA database and compared these data with other published HCC sequencing samples. Various statistical methods, related classification and clustering algorithms of machine learning have been used. TERT, TP53, CTNNB1, AXIN1, ARID1A, ARID2, RB1, ALB, APOB, PTEN, CDKN2A, DOCK2 6-15 and other somatic cells with significantly mutant genes (SMGs) and driver mutation have been identified. These findings have been rapidly applied as potential therapeutic targets and prognostic indicators in clinical practice. However, the high cost of whole-exome sequencing and whole-genome sequencing limits its use in clinical practice. Actually, patients often ...

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“…We used three different definitions of genetic distance. First, Nei’s genetic distance [ 62 , 63 ] was calculated as follows:…”

Section: Methodsmentioning

confidence: 99%

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

Lee

Reuben

et al. 2020

Genome Biol

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Background Metastasis is the primary cause of cancer mortality accounting for 90% of cancer deaths. Our understanding of the molecular mechanisms driving metastasis is rudimentary. Results We perform whole exome sequencing (WES), RNA sequencing, methylation microarray, and immunohistochemistry (IHC) on 8 pairs of non-small cell lung cancer (NSCLC) primary tumors and matched distant metastases. Furthermore, we analyze published WES data from 35 primary NSCLC and metastasis pairs, and transcriptomic data from 4 autopsy cases with metastatic NSCLC and one metastatic lung cancer mouse model. The majority of somatic mutations are shared between primary tumors and paired distant metastases although mutational signatures suggest different mutagenesis processes in play before and after metastatic spread. Subclonal analysis reveals evidence of monoclonal seeding in 41 of 42 patients. Pathway analysis of transcriptomic data reveals that downregulated pathways in metastases are mainly immune-related. Further deconvolution analysis reveals significantly lower infiltration of various immune cell types in metastases with the exception of CD4+ T cells and M2 macrophages. These results are in line with lower densities of immune cells and higher CD4/CD8 ratios in metastases shown by IHC. Analysis of transcriptomic data from autopsy cases and animal models confirms that immunosuppression is also present in extracranial metastases. Significantly higher somatic copy number aberration and allelic imbalance burdens are identified in metastases. Conclusions Metastasis is a molecularly late event, and immunosuppression driven by different molecular events, including somatic copy number aberration, may be a common characteristic of tumors with metastatic plasticity.

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WITHDRAWN: Genomic and Epigenomic Features of Primary and Recurrent Hepatocellular Carcinomas

Cited by 69 publications

References 65 publications

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

Epigenetics in hepatocellular carcinoma development and therapy: The tip of the iceberg

Identification of a novel gene signature for the prediction of recurrence in HCC patients by machine learning of genome-wide databases

Multiomics profiling of primary lung cancers and distant metastases reveals immunosuppression as a common characteristic of tumor cells with metastatic plasticity

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