Methylome-wide Sequencing Detects DNA Hypermethylation Distinguishing Indolent from Aggressive Prostate Cancer

Bhasin, Jeffrey M.; Lee, Byron; Matkin, Lars; Taylor, Margaret; Hu, Bo; Xu, Yaomin; Magi‐Galluzzi, Cristina; Klein, Eric A.; Ting, Angela H.

doi:10.1016/j.celrep.2015.10.078

Cited by 41 publications

(46 citation statements)

References 41 publications

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“…A few smaller investigations have reported DNA methylation alterations that associate with more aggressive PCa. Bahsin et al profiled the methylome of 15 prostate tumors (six low grade, nine high grade) obtained at radical prostatectomy and seven benign prostate samples. They identified 41 significantly (FDR P ≤ 9.98 × 10 −5 ) differentially methylated regions (DMRs) that were unique to the high‐grade tumors.…”

Section: Discussionmentioning

confidence: 99%

A five‐CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer

et al. 2018

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BackgroundPrognostic biomarkers for localized prostate cancer (PCa) could improve personalized medicine. Our group previously identified a panel of differentially methylated CpGs in primary tumor tissue that predict disease aggressiveness, and here we further validate these biomarkers.MethodsPyrosequencing was used to assess CpG methylation of eight biomarkers previously identified using the HumanMethylation450 array; CpGs with strongly correlated (r >0.70) results were considered technically validated. Logistic regression incorporating the validated CpGs and Gleason sum was used to define and lock a final model to stratify men with metastatic‐lethal versus non‐recurrent PCa in a training dataset. Coefficients from the final model were then used to construct a DNA methylation score, which was evaluated by logistic regression and Receiver Operating Characteristic (ROC) curve analyses in an independent testing dataset.ResultsFive CpGs were technically validated and all were retained (P < 0.05) in the final model. The 5‐CpG and Gleason sum coefficients were used to calculate a methylation score, which was higher in men with metastatic‐lethal progression (P = 6.8 × 10−6) in the testing dataset. For each unit increase in the score there was a four‐fold increase in risk of metastatic‐lethal events (odds ratio, OR = 4.0, 95%CI = 1.8–14.3). At 95% specificity, sensitivity was 74% for the score compared to 53% for Gleason sum alone. The score demonstrated better prediction performance (AUC = 0.91; pAUC = 0.037) compared to Gleason sum alone (AUC = 0.87; pAUC = 0.025).ConclusionsThe DNA methylation score improved upon Gleason sum for predicting metastatic‐lethal progression and holds promise for risk stratification of men with aggressive tumors. This prognostic score warrants further evaluation as a tool for improving patient outcomes.

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Section: Discussionmentioning

confidence: 99%

A five‐CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer

et al. 2018

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“…Importantly, activity changes in a subset of enhancers correlate with the DNA methylation status over the enhancers (Taberlay et al 2014), and work from our group detected cancer and high grade-specific DMRs at putative enhancers in prostate and prostate cancer (Bhasin et al 2015). Additionally, TSS and CGI DNA methylation are relatively static throughout a prostate cancer, but enhancer DNA methylation is highly variable among different foci within the same cancer (Brocks et al 2014).…”

Section: Enhancersmentioning

confidence: 95%

“…As prostate cancer and high grade-specific DMRs occur near 3′ ends of genes (Bhasin et al 2015), determining if DNA methylation regulates alternative polyadenylation could provide novel disease insights.…”

Section: Alternative Polyadenylation (Apa)mentioning

confidence: 99%

“…One limitation of the TCGA work described previously is that it used DNA methylation data from the Infinium Human Methylation 450 Bead Chip array that only assays a small portion of all possible DNA methylation sites in the human genome. Using methyl-CpG-binding domain (MBD)-isolated genome sequencing, a technique which provides more comprehensive coverage of the mappable genome (Serre et al 2010), we more fully explored the relationship between prostate cancer aggressiveness and genome-wide DNA methylation patterns in a cohort consisting of benign prostates, low-grade cancers (exclusively Gleason grade 3) and high-grade cancers (exclusively Gleason grade 4/5) (Bhasin et al 2015). We identified both cancer-specific and high Gleason grade-specific DNA methylation.…”

Section: Prostate Cancer Genomicsmentioning

confidence: 99%

“…This alternative splicing event renders prostate tumors insensitive to drugs that target the AR ligand-binding domain (Guo et al 2009). Since prostate cancer and high grade-specific DMRs occur throughout gene bodies (Bhasin et al 2015), an interesting future direction will be to test if DNA methylation regulates splicing.…”

Section: :11mentioning

confidence: 99%

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WOMEN IN CANCER THEMATIC REVIEW: Diverse functions of DNA methylation: implications for prostate cancer and beyond

Sweet¹,

Ting²

2016

Endocrine-Related Cancer

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Prostate cancer is one of the most common malignancies in men worldwide. Current clinical screening ensures that most prostate cancers are diagnosed while still organ confined, but disease outcome is highly variable. Thus, a better understanding of the molecular features contributing to prostate cancer aggressiveness is being sought. For many cancers, aberrant genome-wide patterns of cytosine DNA methylation in CpG dinucleotides distinguish tumor from normal tissue and contribute to disease progression by altering the transcriptome. In prostate cancer, recent genomic studies identified cancer and high grade-specific differential DNA methylation in gene promoters, gene bodies, gene 3′ ends and at distal regulatory elements. Using examples from developmental and disease systems, we will discuss how DNA methylation in each of these genomic contexts can contribute to transcriptome diversity by modulating transcription initiation, alternative transcription start site selection, alternative pre-mRNA splicing and alternative polyadenylation. Alternative transcripts from the same gene often exhibit altered protein-coding potential, translatability, stability and/or localization. All of these can have functional consequences in cells. In future work, it will be important to determine if DNA methylation abnormalities in prostate cancer modify the transcriptome through some or all of these mechanisms and if these DNA methylation-mediated transcriptome alterations impact prostate tumorigenesis and aggressiveness.

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Persistent epigenetic alterations in transcription factors after a sustained virological response in hepatocellular carcinoma

et al. 2022

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Background and Aim The risk of hepatocellular carcinoma (HCC) persists in a condition of sustained virologic response (SVR) after hepatitis C virus (HCV) eradication. Comprehensive molecular analyses were performed to test the hypothesis that epigenetic abnormalities present after an SVR play a role in hepatocarcinogenesis. Methods Whole‐genome methylome and RNA sequencing were performed on HCV, SVR, and healthy liver tissue. Integrated analysis of the sequencing data focused on expression changes in transcription factors and their target genes, commonly found in HCV and SVR. Identified expression changes were validated in demethylated cultured HCC cell lines and an independent validation cohort. Results The coincidence rates of the differentially methylated regions between the HCV and SVR groups were 91% in the hypomethylated and 71% in the hypermethylated regions in tumorous tissues, and 37% in the hypomethylated and 36% in the hypermethylated regions in non‐tumorous tissues. These results indicate that many epigenomic abnormalities persist even after an SVR was achieved. Integrated analysis identified 61 transcription factors and 379 other genes that had methylation abnormalities and gene expression changes in both groups. Validation cohort specified gene expression changes for 14 genes, and gene ontology pathway analysis revealed apoptotic signaling and inflammatory response were associated with these genes. Conclusion This study demonstrates that DNA methylation abnormalities, retained after HCV eradication, affect the expression of transcription factors and their target genes. These findings suggest that DNA methylation in SVR patients may be functionally important in carcinogenesis, and could serve as biomarkers to predict HCC occurrence.

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Methylome-wide Sequencing Detects DNA Hypermethylation Distinguishing Indolent from Aggressive Prostate Cancer

Cited by 41 publications

References 41 publications

A five‐CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer

A five‐CpG DNA methylation score to predict metastatic‐lethal outcomes in men treated with radical prostatectomy for localized prostate cancer

WOMEN IN CANCER THEMATIC REVIEW: Diverse functions of DNA methylation: implications for prostate cancer and beyond

Persistent epigenetic alterations in transcription factors after a sustained virological response in hepatocellular carcinoma

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