Browse
Submit Data
Databases
API
Help

Dataset Information

0 Views

0 Connections

0 Citations

0 Reanalyses

0 Downloads

Omics score: 0

DNA methylation loss coupled with mitotic cell division promotes immune evasion of tumours with high mutation load [RNA-seq]

ABSTRACT: 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.

ORGANISM(S): Homo sapiens

PROVIDER: GSE135222 | GEO | 2019/08/02

REPOSITORIES: GEO

ACCESS DATA

Json Xml

Similar Datasets

DNA methylation loss coupled with mitotic cell division promotes immune evasion of tumours with high mutation load

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.

2019-07-31 | GSE119144 | GEO

DNA Methylation loss coupled with mitotic cell division promotes immune evasion of tumours with high mutation load

| EGAS00001003731 | EGA

Molecular Diagnostic Program for Early Screening of Colorectal Cancer in China

Project description:Interventions: Gold Standard:Pathological diagnosis;Index test:Early screening model of colorectal cancer Primary outcome(s): Sensibility;Specificity;Positive Predictive Value;Negative Predictive Value;Tissue Biomarker Methylation;Tissue Biomarker Mutation;Blood Biomarker Methylation;Stool Mutation;Stool Methylation;Stool Bacteria Study Design: Sequential

| 2688309 | ecrin-mdr-crc

Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

Project description:Mutations and expression changes of epigenetic modifiers are pervasive in human tumours, making epigenetic factors attractive as antitumour targets. However, the mutational landscape of tumours correlates with the chromatin state of their cell-of-origin, raising the concern that targeting epigenetic factors might alter the mutational burden and possibly aggravate disease progression. Nonetheless, a causal link between changes in chromatin in tissues and the mutational landscape of their cognate tumours has not yet been established. Here we show that increasing chromatin accessibility through a conditional deletion of the histone H3K9 methyltransferase G9a severely delays and reduces carcinogen-induced squamous tumour initiation and burden. Strikingly, after a prolonged latency, G9a-mutant mice develop highly aggressive tumours with an expanded cancer stem cell (SC) pool. Loss of G9a leads to extensive chromatin opening in the cells of origin of these tumours (i.e. epidermal and hair follicle SCs) . Although this does not alter the number of single-nucleotide variants, the type of substitutions, or the overall mutational topography, it significantly changes the mutational signatures (i.e. microcontext) in the tumor cells. G9a-depleted tumours also display pronounced genomic instability and a frequent accumulation of loss-of-function p53 mutations, compared to their wild-type counterparts. Our results therefore provide evidence for a causal link between chromatin modifications and mutational load in tumours and call for caution when assessing the long-term therapeutic benefits of inhibiting epigenetic factors.

2018-11-13 | GSE99945 | GEO

Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

2018-11-13 | GSE99932 | GEO

Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

2018-11-13 | GSE99931 | GEO

Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

2018-11-13 | GSE99930 | GEO

Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

2018-11-13 | GSE99885 | GEO

Loss of G9a preserves mutation patterns but increases chromatin accessibility, genomic instability and aggressiveness in skin tumours

2018-11-13 | GSE99934 | GEO

Project description:DNA methylation loss coupled with mitotic cell division promotes immune evasion of tumours with high mutation load