Genome-wide impact of hydrogen peroxide on maintenance DNA methylation in replicating cells

Seddon, Annika R.; Liau, Yusmiati; Pace, Paul E.; Miller, Allison L.; Das, Andrew B.; Kennedy, Martin A.; Hampton, Mark B.; Stevens, Aaron J.

doi:10.1186/s13072-021-00388-6

Cited by 17 publications

(15 citation statements)

References 95 publications

(100 reference statements)

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“…An interesting conjecture emerges that these non-MAGE-driven, high MAGEC3 expressing tumors may retain their MAGE-related putative DNA repair functions. In addition, differentially expressed genes associated with MAGEC3 were clustered in specific genome locations indicating that MAGEC3 may affect chromatin accessibility due to a stress-related program [48] that can be related to cell cycle and DNA repair.…”

Section: Discussionmentioning

confidence: 99%

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers

Ellegate

Mastri

Isenhart

et al. 2022

Cancers

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Rare variants in MAGEC3 are associated with BRCA negative, early-onset ovarian cancers. Given this association, we evaluated the impact of MAGEC3 protein expression on prognosis and transcription. We quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in n = 394 advanced ovarian cancers, assessed the correlation of these values with clinicopathologic and immunological features and modeled survival using univariate and multivariate models. To extend these results, we quantified MAGEC3 protein expression in n = 180 cancers and used matching RNA sequencing data to determine MAGEC3-associated differentially expressed genes and to build an RNA-based model of MAGEC3 protein levels. This model was tested in a third independent cohort of patients from TCGA’s OV dataset (n = 282). MAGEC3 protein was sporadically lost in ovarian cancers, with half of the cases falling below the 9.5th percentile of normal tissue expression. Cases with MAGEC3 loss demonstrated better progression-free survival [HR = 0.71, p = 0.004], and analyses performed on predicted protein scores were consistent [HR = 0.57 p = 0.002]. MAGEC3 protein was correlated with CD8 protein expression [Pearson’s r = 0.176, p = 0.011], NY-ESO-1 seropositivity, and mRNA expression of tumor antigens at Xq28. Results of gene set enrichment analysis showed that genes associated with MAGEC3 protein expression cluster around G2/M checkpoint (NES = 3.20, FDR < 0.001) and DNA repair (NES = 2.28, FDR < 0.001) hallmark pathways. These results show that MAGEC3 is a prognostic biomarker in ovarian cancer.

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Section: Discussionmentioning

confidence: 99%

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers

Ellegate

Mastri

Isenhart

et al. 2022

Cancers

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“…Firstly, H 2 O 2 is a well described activator of signalling cascades leading to transcription factor activation (2,6,55). Secondly a low dose of H 2 O 2 decreases DNA methylation 4 h after treatment (56), possibly due to inhibition of DNA methyltransferases during DNA replication (57).…”

Section: Discussionmentioning

confidence: 99%

Insights into H₂O₂-induced signaling in Jurkat cells from analysis of gene expression

Taylor

Black

Hampton

et al. 2022

Preprint

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Hydrogen peroxide (H2O2) is a ubiquitous oxidant produced in a regulated manner by various enzymes in mammalian cells. H2O2reversibly oxidises thiol groups of cysteine residues to mediate intracellular signalling. Whilst examples of H2O2dependent signalling have been reported, the exact molecular mechanism(s) of signalling and the pathways affected are not well understood. Here, the transcriptomic response of Jurkat T cells to H2O2was investigated to determine global effects on gene expression. With a low H2O2concentration (10 μM) that did not induced an oxidative stress response or cell death, extensive changes in gene expression occurred after 4 hours (6803 differentially expressed genes). Of the genes with greater then 2-fold change in expression, 85% were upregulated suggesting that in a physiological setting H2O2predominantly activates gene expression. Pathway analysis identified gene expression signatures associated with FOXO and NTRK signalling. These signatures were associated with an overlapping set of transcriptional regulators. Overall, our results provide a snapshot of gene expression changes in response to H2O2, which, along with further studies, will lead to new insights into the specific pathways that are activated in response to endogenous production of H2O2, and the molecular mechanisms of H2O2signalling.

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“…An interesting conjecture emerges that these non-MAGE driven, high MAGEC3 expressing tumors may retain their MAGE-related putative DNA repair functions. In addition, differentially expressed genes associated with MAGEC3 were clustered in specific genome locations indicating that MAGEC3 may affect chromatin accessibility due to a stress related program [42] that can be related to cell cycle and DNA repair.…”

Section: Discussionmentioning

confidence: 99%

MAGEC3 is a prognostic biomarker in ovarian and kidney cancers

Ellegate

Mastri

Isenhart

et al. 2021

Preprint

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Rare variants in MAGEC3, members of the melanoma antigen gene family, are associated with BRCA-independent early onset ovarian cancers, while somatic mutations of this gene have been associated with kidney cancers. In this report, we quantified normal and tumor protein expression of MAGEC3 via immunohistochemistry in N=394 ovarian cancers and N=220 renal cell carcinomas. MAGEC3 protein levels fell into two categories – normal MAGEC3 and MAGEC3 loss – characterized by expression equivalent to normal tissue or significantly lower than normal tissue, respectively. Interestingly, cases with MAGEC3 loss demonstrated better overall survival in both ovarian cancers and renal cell carcinomas, which resembles patient outcomes with BRCA2 loss. MAGEC3 protein expression was associated with upregulation of pathways regulating G2/M checkpoint (NES: 4.13, FDR<0.001) and mitotic spindle formation (NES: 2.84, FDR<0.001). Increased CD8+ cell infiltration, coordinate expression of other cancer testis antigens, and tumor mutational burden were also associated with MAGEC3 expression. To emphasize the impact of these results, we built a prognostic RNA-based model using N=180 cancers of an independent cohort with matching transcriptomic data and tested its performance in two large public cohorts (N=282 ovary and N=606 kidney). Results based on predicted protein scores within these patients validated those discovered in patients with directly measured MAGEC3 protein. The RNA model was reproduced in independent cohorts implying a broader potential for MAGEC3-driven disease etiology and relevance to potential treatment selection.STATEMENT OF TRANSLATIONAL RELEVANCEMAGEC3 protein is expressed in multiple tissues and is dysregulated in cancer. In this work, we show that ovarian and kidney cancer patients with loss of MAGEC3 protein have favorable prognosis, indicating that MAGEC3 protein level may be used as a prognostic biomarker. Integrative genomic analysis of patients spanning more than nine cancer types showed an association between MAGEC3 protein and genes affecting stress response, including those involved in cell cycle and DNA damage repair. Additionally, it is correlated with tumor mutational burden in patients with mutated oncogenes. These associations suggest that MAGEC3 protein levels may be used to identify patients with deficient DNA damage repair mechanisms that can be targeted by PARP inhibitors. To operationalize this idea, we use machine learning to predict MAGEC3 protein levels from RNA sequencing data which can facilitate the identification of patients for treatment stratification according to their MAGEC3 status.

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Genome-wide impact of hydrogen peroxide on maintenance DNA methylation in replicating cells

Cited by 17 publications

References 95 publications

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers

Insights into H₂O₂-induced signaling in Jurkat cells from analysis of gene expression

MAGEC3 is a prognostic biomarker in ovarian and kidney cancers

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Genome-wide impact of hydrogen peroxide on maintenance DNA methylation in replicating cells

Cited by 17 publications

References 95 publications

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers

Loss of MAGEC3 Expression Is Associated with Prognosis in Advanced Ovarian Cancers

Insights into H2O2-induced signaling in Jurkat cells from analysis of gene expression

MAGEC3 is a prognostic biomarker in ovarian and kidney cancers

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Insights into H₂O₂-induced signaling in Jurkat cells from analysis of gene expression