Transition to naïve human pluripotency mirrors pan-cancer DNA hypermethylation

Patani, Hemalvi; Rushton, Michael D.; Higham, Jonathan; Álvarez-Teijeiro, Saúl; Oxley, David; Cutillas, Pedro R.; Sproul, Duncan; Ficz, Gabriella

doi:10.1038/s41467-020-17269-3

Cited by 17 publications

(15 citation statements)

References 69 publications

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“…These efforts typically identified many promoters that display aberrant methylation in a given tumour type, though the biological relevance of most of their associated genes to cancer is unclear and many are altered in a manner largely predictable from their epigenetic features in normal cells. Indeed, the changes at many promoters seem to reflect the activation of certain pre-programmed transcriptional and developmental processes in cancer development ( 65 ) rather than the individual role of their associated genes in tumorigenesis.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events

Heery

Schaefer

2021

Nucleic Acids Research

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While large-scale studies applying various statistical approaches have identified hundreds of mutated driver genes across various cancer types, the contribution of epigenetic changes to cancer remains more enigmatic. This is partly due to the fact that certain regions of the cancer genome, due to their genomic and epigenomic properties, are more prone to dysregulated DNA methylation than others. Thus, it has been difficult to distinguish which promoter methylation changes are really driving carcinogenesis from those that are mostly just a reflection of their genomic location. By developing a novel method that corrects for epigenetic covariates, we reveal a small, concise set of potential epigenetic driver events. Interestingly, those changes suggest different modes of epigenetic carcinogenesis: first, we observe recurrent inactivation of known cancer genes across tumour types suggesting a higher convergence on common tumour suppressor pathways than previously anticipated. Second, in prostate cancer, a cancer type with few recurrently mutated genes, we demonstrate how the epigenome primes tumours towards higher tolerance of other aberrations.

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Section: Discussionmentioning

confidence: 99%

DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events

Heery

Schaefer

2021

Nucleic Acids Research

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“…In addition, they have been used for characterization of subgroups within a tumor entity, for example in central nervous system tumors 56 , breast cancer 53 , ovarian cancer 57 as well as tissue origin of cell-free DNA (cfDNA) in disease 48 . Furthermore, methylation analysis has shown the significance of hypermethylation during the transition of committed cells to a naive stem cell state 44 . The cell type from which a cancer originates is highly informative to its identification, classification, treatment and prognosis 58 .…”

Section: Discussionmentioning

confidence: 99%

“…1f). Recent work evaluating the transition of primed human Embryonic Stem Cells (hESC) to naive state demonstrated a gradual and stable acquisition of CpG hypermethylation in genes associated with development which was mirrored in multiple cancer entities 44 . We found that the naive hESC-associated and hypermethylated CpGs were significantly more hypermethylated in Group B compared to Group A tumors (Fig.…”

Section: Dna Methylation Classification Identifies a Distinct Pannec Subgroup Within Pannen Samplesmentioning

confidence: 99%

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

Simon

Riemer

Detjen

et al. 2020

Preprint

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Pancreatic Neuroendocrine Neoplasms (PanNENs) comprise a rare and heterogeneous group of tumors derived from neuroendocrine cells of the pancreas. Despite recent genetic and epigenetic characterization, biomarkers for improved patient stratification and personalized therapy are sparse and targeted therapies, including the mTOR inhibitor Everolimus, have shown limited success. To better define PanNENs tumors we performed multi-omic analyses on 59 tumors with varying grades (NET G1, NET G2, NET G3 and NEC), combining mutational profiling with epigenetic analysis and targeted proteomics. An unsupervised approach using DNA methylation profiles uncovered two major subgroups in PanNENs resembling α-like and β-like cells. DNA copy number analysis further divided the α-like subgroup into two distinct groups, indicating differential mechanisms of tumorigenesis from α-cells. β-like tumors however showed two distinct groups at the epigenetic level and suggest NET G3/NEC samples are of β-cell origin.DNA mutation profiling clearly separated α and β-cell derived PanNENs, whereby only αlike tumors had mutations within MEN1/DAXX/ATRX tumor suppressor genes. Targeted proteomic analysis further indicated overexpression of distinct components of the mTOR pathway. Our data provide further insights into the potential mechanisms behind PanNEN heterogeneity and form a basis for future diagnostic and therapy relevant patient stratification.

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“…Methylation of tumor suppressor genes plays critical roles in the pathogenesis of various cancers. It is generally considered that methylation of tumor suppressor gene is equivalent to gene loss or functional mutation (13)(14)(15). Therefore, reversing methylation of tumor suppressor genes may be a promising strategy for cancer prevention and treatment (16,17).…”

Section: Introductionmentioning

confidence: 99%

3,3’-Diindolylmethane Enhances Paclitaxel Sensitivity by Suppressing DNMT1-Mediated KLF4 Methylation in Breast Cancer

et al. 2021

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Paclitaxel (PTX) is a first-line chemotherapeutic drug for the treatment of breast cancer, but drug resistance seriously limits its clinical use. The aim of the present work was to explore the effect of 3,3’-diindolylmethane (DIM) on PTX sensitivity and its possible mechanism in breast cancer. The expression of Krüppel-like factor 4 (KLF4) and DNA-methyltransferase 1 (DNMT1) in breast cancer tissues were assessed by immunohistochemistry and Western blotting. The methylation of KLF4 was evaluated by the MassARRAY platform. The lentivirus carrying KLF4 and DNMT1 gene or shRNA targeting DNMT1 were used to overexpress KLF4 or knockdown DNMT1 in MCF-7 and T47D breast cancer cells and the role of KLF4 and DNMT1 in regulation of PTX sensitivity was investigated. The effect of PTX on inhibiting the proliferation of MCF-7 and T47D cells was measured by CCK-8 assay. Flow cytometry was used to examine cell apoptosis. The expression of mRNA and protein was evaluated by qRT-PCR and Western blotting analysis, respectively. Our data showed that the expression of DNMT1 was increased, and the methylation level of CpG sites (−148 bp) in the KLF4 promoter was increased while the KLF4 expression was significantly decreased in breast cancer tissues. Overexpression of KLF4 increased the sensitivity of MCF-7 and T47D cells to PTX. DNMT1 increased the methylation of the KLF4 promoter and decrease the expression of KLF4. Knockdown of DNMT1 increased the sensitivity of MCF-7 and T47D cells to PTX. DIM enhanced the PTX sensitivity of MCF-7 and T47D cells, decreased the expression of DNMT1 and the methylation level of KLF4 promoter, thus increasing the level of KLF4. Furthermore, overexpression of DNMT1 attenuated the effect of DIM on the regulation of PTX sensitivity. Collectively, our data indicated that DNMT1-mediated hypermethylation of KLF4 promoter leads to downregulation of KLF4 in breast cancer. The level of KLF4 is correlated with the sensitivity of MCF-7 and T47D cells to PTX. DIM could enhance the antitumor efficacy of PTX on MCF-7 and T47D cells by regulating DNMT1 and KLF4.

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Transition to naïve human pluripotency mirrors pan-cancer DNA hypermethylation

Cited by 17 publications

References 69 publications

DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events

DNA methylation variation along the cancer epigenome and the identification of novel epigenetic driver events

DNA methylation reveals distinct cells of origin for pancreatic neuroendocrine carcinomas (PanNECs) and pancreatic neuroendocrine tumors (PanNETs)

3,3’-Diindolylmethane Enhances Paclitaxel Sensitivity by Suppressing DNMT1-Mediated KLF4 Methylation in Breast Cancer

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