Scan_Tcga Tools for Integrated Epigenomic and Transcriptomic Analysis of Tumor Subgroups

Chatterjee, Aniruddha; Stockwell, Peter A.; Rodger, Euan J.; Parry, Matthew; Eccles, Michael R.

doi:10.2217/epi-2016-0063

Cited by 14 publications

(8 citation statements)

References 43 publications

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“…These RRBS methylation patterns were remarkably similar within a group (inducible or constitutive), which we hypothesize is the result of a unified mechanism leading to hypomethylation of particular genomic regions across all the PD-L1 constitutively expressing cell lines. Consistent with previously reported data, we found the CD274 promoter was unmethylated ( Chatterjee et al., 2016 ), with no evidence of differential methylation occurring in the core promoter itself, which argues against methylation of the CD274 promoter being involved in constitutive PD-L1 expression. In addition, blocking IFN-γ or interferon type I or type II with antibodies did not inhibit constitutive PD-L1 expression but (surprisingly) consistently enhanced constitutive PD-L1 expression.…”

Section: Discussionsupporting

confidence: 92%

Marked Global DNA Hypomethylation Is Associated with Constitutive PD-L1 Expression in Melanoma

et al. 2018

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SummaryConstitutive expression of the immune checkpoint, PD-L1, inhibits anti-tumor immune responses in cancer, although the factors involved in PD-L1 regulation are poorly understood. Here we show that loss of global DNA methylation, particularly in intergenic regions and repeat elements, is associated with constitutive (PD-L1CON), versus inducible (PD-L1IND), PD-L1 expression in melanoma cell lines. We further show this is accompanied by transcriptomic up-regulation. De novo epigenetic regulators (e.g., DNMT3A) are strongly correlated with PD-L1 expression and methylome status. Accordingly, decitabine-mediated inhibition of global methylation in melanoma cells leads to increased PD-L1 expression. Moreover, viral mimicry and immune response genes are highly expressed in lymphocyte-negative plus PD-L1-positive melanomas, versus PD-L1-negative melanomas in The Cancer Genome Atlas (TCGA). In summary, using integrated genomic analysis we identified that global DNA methylation influences PD-L1 expression in melanoma, and hence melanoma's ability to evade anti-tumor immune responses. These results have implications for combining epigenetic therapy with immunotherapy.

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Section: Discussionsupporting

confidence: 92%

Marked Global DNA Hypomethylation Is Associated with Constitutive PD-L1 Expression in Melanoma

et al. 2018

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“…For the majority of sites the data were not distributed normally, and therefore a Mann-Whitney U test was also performed. These analyses were performed using the scan_tcga set of tools [49]. …”

Section: Methodsmentioning

confidence: 99%

Genome-wide methylation sequencing of paired primary and metastatic cell lines identifies common DNA methylation changes and a role for EBF3 as a candidate epigenetic driver of melanoma metastasis

et al. 2016

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Epigenetic alterations are increasingly implicated in metastasis, whereas very few genetic mutations have been identified as authentic drivers of cancer metastasis. Yet, to date, few studies have identified metastasis-related epigenetic drivers, in part because a framework for identifying driver epigenetic changes in metastasis has not been established. Using reduced representation bisulfite sequencing (RRBS), we mapped genome-wide DNA methylation patterns in three cutaneous primary and metastatic melanoma cell line pairs to identify metastasis-related epigenetic drivers. Globally, metastatic melanoma cell lines were hypomethylated compared to the matched primary melanoma cell lines. Using whole genome RRBS we identified 75 shared (10 hyper- and 65 hypomethylated) differentially methylated fragments (DMFs), which were associated with 68 genes showing significant methylation differences. One gene, Early B Cell Factor 3 (EBF3), exhibited promoter hypermethylation in metastatic cell lines, and was validated with bisulfite sequencing and in two publicly available independent melanoma cohorts (n = 40 and 458 melanomas, respectively). We found that hypermethylation of the EBF3 promoter was associated with increased EBF3 mRNA levels in metastatic melanomas and subsequent inhibition of DNA methylation reduced EBF3 expression. RNAi-mediated knockdown of EBF3 mRNA levels decreased proliferation, migration and invasion in primary and metastatic melanoma cell lines. Overall, we have identified numerous epigenetic changes characterising metastatic melanoma cell lines, including EBF3-induced aggressive phenotypic behaviour with elevated EBF3 expression in metastatic melanoma, suggesting that EBF3 promoter hypermethylation may be a candidate epigenetic driver of metastasis.

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“…It was questioned whether low PD-L1 expression could be attributed to methylation of the promoter region encoding PD-L1, as prior studies in lung carcinoma have linked resistance to anti-PD1 antibody treatment with DNA methylation at the promoter region [22]. Previous analysis of the Skin Cutaneous Melanoma (SKCM) TCGA data revealed two CpG sites in the proximal promoter region encoding PD-L1, which were not methylated [23,24]. These observations suggested that a distal enhancer similar to an enhancer previously described might be involved in the epigenetic regulation of PD-L1 [25].…”

Section: Dna Methylation Status In Melanoma Tumorsmentioning

confidence: 99%

Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy

Emran

Chatterjee

Rodger

et al. 2019

Trends in Immunology

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Methylation of DNA at CpG sites is the most common and stable of epigenetic changes in cancer. Hypermethylation acts to limit immune checkpoint blockade immunotherapy by inhibiting endogenous interferon responses needed for recognition of cancer cells. By contrast, global hypomethylation results in the expression of programmed death ligand 1 (PD-L1) and inhibitory cytokines, accompanied by epithelial-mesenchymal changes that can contribute to immunosuppression. The drivers of these contrasting methylation states are not well understood. DNA methylation also plays a key role in cytotoxic T cell 'exhaustion' associated with tumor progression. We present an updated exploratory analysis of how DNA methylation may define patient subgroups and can be targeted to develop tailored treatment combinations to help improve patient outcomes. DNA Methylation, ICB, and Cancer DNA methylation can have major effects on gene expression and is the most commonly studied type of epigenetic modification (see Glossary). It comprises the covalent modification of the nucleotide cytosine at the 5ʹ position at sites preceding guanine (CpG) [1]. During mammalian cell division, it is replicated by the maintenance enzyme DNA methyltransferase 1 (DNMT1) on the daughter strand cytosine at the complementary CpG, usually resulting in gene silencing. New sites of DNA methylation, known as de novo methylation, can be introduced by DNMT3a or DNMT3b (Box 1). Conversely, methyl groups can be erased by ten-eleven translocation (TET) family proteins followed by glycosylation and replacement with an unmethylated cytosine. DNMT1 recruitment to replicating chromatin is facilitated by the 'ubiquitin-like with PHD and ring-finger domains' (UHRF) E3 ubiquitin ligase UHRF1 [2,3]. Methylation at CpG sites can also be recognized by methyl CpG binding 'reader' proteins such as methyl-CpG binding domain protein 1 (MBD1) and methyl-CpG binding protein 2 (MeCP2) harboring transcriptionally repressive activity. The latter may bind histone deacetylases (HDACs), which can contribute to the repression of certain genes [4]. Highlights Genome-wide DNA methylation is a relatively stable epigenetic characteristic of cells, which can be dysregulated in cancer cells by oncogenic signals.

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Scan_Tcga Tools for Integrated Epigenomic and Transcriptomic Analysis of Tumor Subgroups

Cited by 14 publications

References 43 publications

Marked Global DNA Hypomethylation Is Associated with Constitutive PD-L1 Expression in Melanoma

Marked Global DNA Hypomethylation Is Associated with Constitutive PD-L1 Expression in Melanoma

Genome-wide methylation sequencing of paired primary and metastatic cell lines identifies common DNA methylation changes and a role for EBF3 as a candidate epigenetic driver of melanoma metastasis

Targeting DNA Methylation and EZH2 Activity to Overcome Melanoma Resistance to Immunotherapy

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