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

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

PROVIDER: PRJNA488256 | ENA |

REPOSITORIES: ENA

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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 [RNA-seq]

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.

2019-08-02 | GSE135222 | GEO

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

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

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

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DNA methylation loss promotes immune evasion of tumours with high mutation and copy number load.

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BRD4 marks chromatin on cell cycle genes activates their transcription and orchestrates mitotic cell division

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CRL3-GMCL1 mediates 53BP1 degradation, promoting evasion from mitotic surveillance upon paclitaxel treatment

Project description:The Mitotic Surveillance Pathway (MSP) is a critical quality control mechanism that monitors mitosis duration. Prolonged mitosis - caused by genomic defects, spindle errors, or anti-mitotic drugs such as paclitaxel - induces formation of the ternary -mitotic stopwatch- complex composed of 53BP1, USP28, and p53. This complex protects p53 from MDM2-mediated degradation, and its accumulation transmits a memory of the delayed mitosis to the daughter cells, where p53 signaling triggers cell cycle arrest and apoptosis. In Paclitaxel-resistant cancers, cells bypass the MSP, enabling unchecked proliferation and survival, though the underlying mechanisms remain unknown. Here, we identify CRL3GMCL1 as the ubiquitin ligase that targets 53BP1 for degradation during prolonged M phase. In cancers with high GMCL1 levels, the CRL3GMCL1-mediated degradation of 53BP1 prevents the formation of the mitotic stopwatch complex, leading to p53 degradation and sustained proliferation. Loss of GMCL1 stabilizes mitotic 53BP1 levels and restores paclitaxel sensitivity. Our results indicate that combining GMCL1 inhibition with taxane treatment represent a novel strategy to restore taxane sensitivity in cancers. The mass spectrometric data files for the protein complex analysis of FLAG-tagged: (i) wild-type GMCL1 (GMCL1 WT), (ii) a GMCL1 E142K mutant (GMCL1 EK for short), which disrupts its ability to bind with CUL3, and (iii) a GMCL1 BTB/BACK-only mutant, which misses GMCL1's putative C-terminal substrate-binding domain are included in this entry.

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