Homo sapiens
Ontology highlight
ABSTRACT:
PROVIDER: PRJNA406886 | ENA |
REPOSITORIES: ENA
Dataset's files
| Action | DRS | |||
|---|---|---|---|---|
| SRR6027970.fastq.gz | Fastqsanger.gz | |||
| SRR6027980.fastq.gz | Fastqsanger.gz | |||
| SRR6027971.fastq.gz | Fastqsanger.gz | |||
| SRR6027981.fastq.gz | Fastqsanger.gz | |||
| SRR6027972.fastq.gz | Fastqsanger.gz |
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Project description:Purpose: This study unravel the mechanisms that link viral infection and cancer Methods:Human HCC cell line and HCC liver FFPE samples from HCC patients from three etiology groups- HBV, HCV infection, or neither were taken to explore their genomic DNA in two aspects: The HCC genomic mutations within the exons of 224 candidate genes, frequently mutated in HCC, using SureSelect™ Target Enrichment System kit and the transient response of liver cells to HCV infection, in genome wide histone modifications and gene expression, as demonstrated by ChIP-Seq and RNA-Seq. Results:Mutational signature was explored by high-resolution targeted sequencing that detected low-frequency passenger mutations in 64 HCC samples from three etiology groups – HBV, HCV, or other. We identified novel distinct etiology-dependent regional mutations signatures. To explore the link between genomic signature and genome wide chromatin organization we studied the epigenetic changes occur following HCV infection. We demonstrated that HCV infection induces epigenetic changes that persist as "epigenetic signature" following virus eradication and reprogram host gene expression. High mutation rate associated with HCV etiology correlated with HCV-induced changes in epigenetic markers leading to closed chromatin. Conclusions:We present a new link between cancer causing mutagenesis, and increase in liver cancer predisposition in chronic HCV-infected individuals. The sequential events begin with HCV-specific epigenetic signature that in turn dictates a unique HCV-specific somatic mutational profile in HCC
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Project description:Mitotic cell division increases tumour mutation burden and copy number load, predictive markers of the clinical benefit of immunotherapy. Cell division correlates also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation in precision immunotherapy.
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Project description:Mitotic cell division increases tumour mutation burden and copy number load with a positive and inverse correlation, respectively, with the clinical benefit of immunotherapy. Markers of cell division correlate also with genomic demethylation involving methylation loss in late-replicating partial methylation domains. Here we find that immunomodulatory pathway genes are concentrated in these domains and transcriptionally repressed in demethylated tumours with CpG island promoter hypermethylation. Global methylation loss correlated with immune evasion signatures independently of mutation burden and aneuploidy. Methylome data of our cohort (n = 60) and a published cohort (n = 81) in lung cancer and a melanoma cohort (n = 40) consistently demonstrated that genomic methylation alterations counteract the contribution of high mutation burden and increase immunotherapeutic resistance. Higher predictive power was observed for methylation loss than mutation burden. We also found that genomic hypomethylation correlates with the immune escape signatures of aneuploid tumours. Hence, DNA methylation alterations implicate epigenetic modulation as a combination regimens for precision immunotherapy.
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