Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas

Tian, Ying; Arai, Eri; Makiuchi, Satomi; Tsuda, Noboru; Kuramoto, Junko; Ohara, Kentaro; Takahashi, Yoshinori; Ito, Norihisa; Ojima, Hidenori; Hiraoka, Nobuyoshi; Gotoh, Masahiro; Yoshida, Teruhiko; Kanai, Yae

doi:10.1007/s00432-020-03298-4

Cited by 40 publications

(28 citation statements)

References 50 publications

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“…A2M was identified as a key gene associated with various tumors, including non–small cell lung cancer, bladder cancer, osteosarcoma, and HCC (Ma et al, 2019 ; Huang et al, 2020 ). TUBA1B was related to breast cancer, HCC, and Wilms tumor (Lou et al, 2020 ; Tian et al, 2020 ). These nine PRGs are involved in the pathogenesis and development of many tumors, supporting their potential as a powerful biomarker to predict ICC prognosis.…”

Section: Discussionmentioning

confidence: 99%

Development of a Prognostic Signature Based on Single-Cell RNA Sequencing Data of Immune Cells in Intrahepatic Cholangiocarcinoma

Qiao

Xie

et al. 2021

Front. Genet.

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Analysis of single-cell RNA sequencing (scRNA-seq) data of immune cells from the tumor microenvironment (TME) may identify tumor progression biomarkers. This study was designed to investigate the prognostic value of differentially expressed genes (DEGs) in intrahepatic cholangiocarcinoma (ICC) using scRNA-seq. We downloaded the scRNA-seq data of 33,991 cell samples, including 17,090 ICC cell samples and 16,901 ICC adjacent tissue cell samples regarded as normal cells. scRNA-seq data were processed and classified into 20 clusters. The immune cell clusters were extracted and processed again in the same way, and each type of immune cells was divided into several subclusters. In total, 337 marker genes of macrophages and 427 marker genes of B cells were identified by comparing ICC subclusters with normal subclusters. Finally, 659 DEGs were obtained by merging B cell and macrophage marker genes. ICC sample clinical information and gene expression data were downloaded. A nine-prognosis-related-gene (PRG) signature was established by analyzing the correlation between DEGs and overall survival in ICC. The robustness and validity of the signature were verified. Functional enrichment analysis revealed that the nine PRGs were mainly involved in tumor immune mechanisms. In conclusion, we established a PRG signature based on scRNA-seq data from immune cells of patients with ICC. This PRG signature not only reflects the TME immune status but also provides new biomarkers for ICC prognosis.

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Section: Discussionmentioning

confidence: 99%

Development of a Prognostic Signature Based on Single-Cell RNA Sequencing Data of Immune Cells in Intrahepatic Cholangiocarcinoma

Qiao

Xie

et al. 2021

Front. Genet.

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“…Lastly, to reduce potential analytical artefacts in the DMR biomarker discovery we processed the training dataset (859 samples from 6 different studies [31,45,46,[56][57][58]) from raw data with the same pipeline and applied stringent filters to remove problematic measurements and account for potential confounders, such as sex, age, tumour purity and global methylation, often not considered by other studies. Additionally, we validated our approach using not only hold-out samples and cross-validated procedures, but also an assembled validation dataset (692 samples from 7 independent datasets [1,[49][50][51][52][53][54][55]), which was never used for training and comprises differently and independently processed datasets, thus testing the robustness of our DMRs to diverse processing pipelines.…”

Section: Discussionmentioning

confidence: 99%

“…A total of 452,567 methylation sites (CpG sites) are measured and methylation levels represented using beta methylation values, ranging between 0, hypomethylated, and 1, hypermethylated. Additionally, we compiled a Validation dataset containing 692 tissue samples from 7 independent datasets [1,[49][50][51][52][53][54][55] for which original data or publication was not accessible but processed beta methylation values was available (Figure 1a, Supplementary Figure 1c). This validation dataset comprises multiple studies with distinct experimental and analytical pipelines and is intended to be used as independent validation of the approaches adopted in this study.…”

Section: Dna Methylation Dataset For the Discovery Of Hcc Biomarkersmentioning

confidence: 99%

“…Here, we perform a systematic discovery of a HCC methylation signature by compiling 1,551 genome-wide DNA methylation arrays from 13 studies [1,31,45,46,[49][50][51][52][53][54][55][56][57][58], including both tissue and liquid biopsy samples from HCC, cirrhosis and healthy controls. We developed a machine learning pipeline to harness this resource to identify differentially methylated regions (DMRs) predictive of HCC in both tissue and liquid biopsies, from a background of cirrhotic samples.…”

Section: Introductionmentioning

confidence: 99%

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DNA methylation fingerprint for the diagnosis and monitoring of hepatocellular carcinoma from tissue and liquid biopsies

Gonçalvès¹,

Reis²,

Pereira-Leal³

et al. 2021

Preprint

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Hepatocellular carcinoma (HCC) is amongst the cancers with highest mortality rates and is the most common malignancy of the liver. Early detection is vital to provide the best treatment possible and liquid biopsies combined with analysis of circulating tumour DNA methylation show great promise as a non-invasive approach for early cancer diagnosis and monitoring with low false negative rates. To identify reliable diagnostic biomarkers of early HCC, we performed a systematic analysis of multiple hepatocellular studies and datasets comprising >1,500 genome-wide DNA methylation arrays, to define a methylation signature predictive of HCC in both tissue and cell-free DNA liquid biopsy samples. Our machine learning pipeline identified differentially methylated regions in HCC, some associated with transcriptional repression of genes related with cancer progression, that benchmarked positively against independent methylation signatures. Combining our signature of 38 DNA methylation regions, we derived a HCC detection score which confirmed the utility of our approach by identifying in an independent dataset 96% of HCC tissue samples with a precision of 98%, and most importantly successfully separated cfDNA of tumour samples from healthy controls. Notably, our risk score could identify cell-free DNA samples from patients with other tumours, including colorectal cancer. Taken together, we propose a comprehensive HCC DNA methylation fingerprint and an associated risk score for the early diagnosis and early relapse detection of HCC from liquid biopsies.

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“…In addition, NASH patients with PNPLA3 GG alleles had a higher level of aspartate aminotransferase (AST) and advanced liver fibrosis compared to patients with PNPLA3 CC alleles [ 10 ]. As the most evaluated epigenetic factor, DNA methylation in the CpG islands can be applied to test the progression of NAFLD to liver fibrosis and HCC [ 11 , 12 ]. These factors have been well described in other review papers [ 13 , 14 ], which will not be discussed here.…”

Section: Introductionmentioning

confidence: 99%

Current Options and Future Directions for NAFLD and NASH Treatment

Zhang

Yang

2021

IJMS

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Nonalcoholic fatty liver disease (NAFLD) is the most common chronic liver disease worldwide, with a broad spectrum ranging from simple steatosis to advanced stage of nonalcoholic steatohepatitis (NASH). Although there are many undergoing clinical trials for NAFLD treatment, there is no currently approved treatment. NAFLD accounts as a major causing factor for the development of hepatocellular carcinoma (HCC), and its incidence rises accompanying the prevalence of obesity and diabetes. Reprogramming of antidiabetic and anti-obesity medicine is a major treatment option for NAFLD and NASH. Liver inflammation and cellular death, with or without fibrosis account for the progression of NAFLD to NASH. Therefore, molecules and signaling pathways involved in hepatic inflammation, fibrosis, and cell death are critically important targets for the therapy of NAFLD and NASH. In addition, the avoidance of aberrant infiltration of inflammatory cytokines by treating with CCR antagonists also provides a therapeutic option. Currently, there is an increasing number of pre-clinical and clinical trials undergoing to evaluate the effects of antidiabetic and anti-obesity drugs, antibiotics, pan-caspase inhibitors, CCR2/5 antagonists, and others on NAFLD, NASH, and liver fibrosis. Non-invasive serum diagnostic markers are developed for fulfilling the need of diagnostic testing in a large amount of NAFLD cases. Overall, a better understanding of the underlying mechanism of the pathogenesis of NAFLD is helpful to choose an optimized treatment.

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Aberrant DNA methylation results in altered gene expression in non-alcoholic steatohepatitis-related hepatocellular carcinomas

Cited by 40 publications

References 50 publications

Development of a Prognostic Signature Based on Single-Cell RNA Sequencing Data of Immune Cells in Intrahepatic Cholangiocarcinoma

Development of a Prognostic Signature Based on Single-Cell RNA Sequencing Data of Immune Cells in Intrahepatic Cholangiocarcinoma

DNA methylation fingerprint for the diagnosis and monitoring of hepatocellular carcinoma from tissue and liquid biopsies

Current Options and Future Directions for NAFLD and NASH Treatment

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