Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors

Timp, Winston; Bravo, Héctor Corrada; McDonald, Oliver G.; Goggins, Michael; Umbricht, Chris; Zeiger, Martha A.; Feinberg, Andrew P.; Irizarry, Rafael A.

doi:10.1186/preaccept-1714377612132518

Cited by 19 publications

(23 citation statements)

References 16 publications

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“…This is somewhat different from the distribution of all probes on the 450 K array, where the corresponding proportions on CpG islands, Shelf, Shore, and Open Sea are 31, 10, 23, and 36%, respectively. More differentially methylated probes are located in the Open Sea regions, which is consistent with previous observations (Timp et al, ). For the annotation with respect to functional genomic elements, no difference is observed between GFlars and Bumphunter, nor between any of those and the probe design.…”

Section: Detecting Differentially Methylated Regionssupporting

confidence: 92%

Estimating DNA Methylation Levels by Joint Modeling of Multiple Methylation Profiles From Microarray Data

2015

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Summary DNA methylation studies have been revolutionized by the recent development of high throughput array-based platforms. Most of the existing methods analyze microarray methylation data on a probe-by-probe basis, ignoring probe-specific effects and correlations among methylation levels at neighboring genomic locations. These methods can potentially miss functionally relevant findings associated with genomic regions. In this paper, we propose a statistical model that allows us to pool information on the same probe across multiple samples to estimate the probe affinity effect, and to borrow strength from the neighboring probe sites to better estimate the methylation values. Using a simulation study we demonstrate that our method can provide accurate model-based estimates. We further use the proposed method to develop a new procedure for detecting differentially methylated regions, and compare it with a state-of-the-art approach via a data application.

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Section: Detecting Differentially Methylated Regionssupporting

confidence: 92%

Estimating DNA Methylation Levels by Joint Modeling of Multiple Methylation Profiles From Microarray Data

2015

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“…Interestingly, the UHC of our CpG islands panel in a fourth data set (GSE53051), assigned colon cancer metastases on the same branches of CRC, with the exception of two cases (Fig. d ).…”

Section: Resultsmentioning

confidence: 84%

Colorectal cancer early methylation alterations affect the crosstalk between cell and surrounding environment, tracing a biomarker signature specific for this tumor

Fadda

Gentilini

Moi

et al. 2018

Intl Journal of Cancer

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Colorectal cancer (CRC) develops through the accumulation of both genetic and epigenetic alterations. However, while the former are already used as prognostic and predictive biomarkers, the latter are less well characterized. Here, performing global methylation analysis on both CRCs and adenomas by Illumina Infinium HumanMethylation450 Bead Chips, we identified a panel of 74 altered CpG islands, demonstrating that the earliest methylation alterations affect genes coding for proteins involved in the crosstalk between cell and surrounding environment. The panel discriminates CRCs and adenomas from peritumoral and normal mucosa with very high specificity (100%) and sensitivity (99.9%). Interestingly, over 70% of the hypermethylated islands resulted in downregulation of gene expression. To establish the possible usefulness of these non-invasive markers for detection of colon cancer, we selected three biomarkers and identified the presence of altered methylation in stool DNA and plasma cell-free circulating DNA from CRC patients.

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“…Such demethylation takes place in regions known as 'partially methylated domains' (PMDs), rather than 'highly methylated domains (HMDs). PMDs are characterized by late replication, and their demethylation is a passive event, as a result of inefficient DNA remethylation during DNA replication [22][23][24][25][26][27] . Recent reanalysis of the B cell lineage DNA methylation profiles published by the BLUEPRINT consortium 17 has shown the occurrence of demethylation of PMDs in the transition towards memory cell and antibody-secreting plasma cells 28 .…”

Section: A High Proportion Of Dna Demethylation Events Identified In mentioning

confidence: 99%

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

Català-Moll

Weichenhan

Lutsik

et al. 2019

Preprint

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Mutations in activation induced deaminase (AID) lead to hyper-IgM syndrome type 2 (HIGM2), a rare human primary antibody deficiency. AID-mediated cytosine deamination has been proposed as mediating active demethylation, although evidences both support and cast doubt on such a role. We here made use of HIGM2 B cells to investigate direct AID involvement in active DNA demethylation.HIGM2 naïve and memory B cells both display widespread DNA methylation defects, of which approximately 25% of these defects correspond to active events. For genes that undergo active demethylation that is impaired in HIGM2 individuals, we did not observe AID involvement but a participation of TET enzymes. DNA methylation alterations in HIGM2 naïve B cells are related to premature overstimulation of the B-cell receptor prior to the germinal center reaction. Our data supports a role for AID in B cell central tolerance in preventing the expansion of autoreactive cell clones, affecting the correct establishment of DNA methylation patterns.

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Large hypomethylated blocks as a universal defining epigenetic alteration in human solid tumors

Cited by 19 publications

References 16 publications

Estimating DNA Methylation Levels by Joint Modeling of Multiple Methylation Profiles From Microarray Data

Estimating DNA Methylation Levels by Joint Modeling of Multiple Methylation Profiles From Microarray Data

Colorectal cancer early methylation alterations affect the crosstalk between cell and surrounding environment, tracing a biomarker signature specific for this tumor

Activation-induced deaminase is critical for the establishment of DNA methylation patterns prior to the germinal center reaction

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