Evidence for Converging DNA Methylation Pathways in Placenta and Cancer

Lorincz, Matthew C.; Schübeler, Dirk

doi:10.1016/j.devcel.2017.10.009

Cited by 27 publications

(29 citation statements)

References 11 publications

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“…Increasing evidence has shown that epigenetic regulation, such as abnormal hypermethylation of CpG islands in promoters, is key to tumorigenesis [48]. In our study, the genes, corresponding to 437 specific methylation sites in the promoter region were considered for TF enrichment analysis.…”

Section: Discussionmentioning

confidence: 99%

DNA methylation-based classification and identification of renal cell carcinoma prognosis-subgroups

et al. 2019

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Background Renal cell carcinoma (RCC) is the most common kidney cancer and includes several molecular and histological subtypes with different clinical characteristics. The combination of DNA methylation and gene expression data can improve the classification of tumor heterogeneity, by incorporating differences at the epigenetic level and clinical features. Methods In this study, we identified the prognostic methylation and constructed specific prognosis-subgroups based on the DNA methylation spectrum of RCC from the TCGA database. Results Significant differences in DNA methylation profiles among the seven subgroups were revealed by consistent clustering using 3389 CpGs that indicated that were significant differences in prognosis. The specific DNA methylation patterns reflected differentially in the clinical index, including TNM classification, pathological grade, clinical stage, and age. In addition, 437 CpGs corresponding to 477 genes of 151 samples were identified as specific hyper/hypomethylation sites for each specific subgroup. A total of 277 and 212 genes corresponding to DNA methylation at promoter sites were enriched in transcription factor of GKLF and RREB-1, respectively. Finally, Bayesian network classifier with specific methylation sites was constructed and was used to verify the test set of prognoses into DNA methylation subgroups, which was found to be consistent with the classification results of the train set. DNA methylation-based classification can be used to identify the distinct subtypes of renal cell carcinoma. Conclusions This study shows that DNA methylation-based classification is highly relevant for future diagnosis and treatment of renal cell carcinoma as it identifies the prognostic value of each epigenetic subtype. Electronic supplementary material The online version of this article (10.1186/s12935-019-0900-4) contains supplementary material, which is available to authorized users.

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Section: Discussionmentioning

confidence: 99%

DNA methylation-based classification and identification of renal cell carcinoma prognosis-subgroups

et al. 2019

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“…In addition, using a similar approach, a decision-tree model incorporating also -hCG levels was built; this is shown in Suppl. Human placentation is an intricate process of fetal-maternal interaction that shares some similarities with cancer migration and metastasis (35). In this context, kisspeptins, initially identified as potential metastasis-suppressing factors abundantly expressed in the placenta, were suspected as important players for the fine control of trophoblast invasion and placentation (17,18).…”

Section: Circulating Kisspeptin/mir-324-3p As New Early Biomarker Of Epmentioning

confidence: 99%

Deregulation of miR-324/KISS1/kisspeptin in early ectopic pregnancy: mechanistic findings with clinical and diagnostic implications

Romero-Ruíz

Avendaño

Domı́nguez

et al. 2019

American Journal of Obstetrics and Gynecology

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Background: Ectopic pregnancy (EP) is a life-threatening condition, for which novel screening tools enabling early accurate diagnosis would improve clinical outcomes. Kisspeptins, encoded by KISS1, play an essential role in human reproduction, at least partially by regulating placental function and possibly embryo implantation. Kisspeptin levels are massively elevated in normal pregnancy and reportedly altered in various gestational pathologies. Yet, the pathophysiological role of KISS1/kisspeptin in EP has not been investigated previously. Methods: Measurements of plasma kisspeptins and KISS1 expression analyses in human embryonic/placental tissue were conducted in EP and their controls (women undergoing voluntary termination of pregnancy, VTOP) during early gestational window (<12-wks). Putative miRNA regulators of KISS1 were predicted in silico, followed by expression analyses of selected miRNAs and validation of repressive interactions in vitro. Circulating levels of these miRNAs were also assayed in EP vs. VTOP. Results: Circulating kisspeptins gradually increased during the first trimester of normal pregnancy, but were massively reduced in EP. This profile correlated with expression levels of KISS1 in human embryonic/placental tissue, which increased in VTOP but remained suppressed in EP. Bioinformatic predictions and expression analyses identified miR-27b-3p and miR-324-3p as putative repressors of KISS1 in human embryonic/placental tissue at <12-wks gestation, when expression of both miRNAs was low in VTOP controls, but significantly increased in EP. Yet, a significant repressive interaction was documented only for miR-324-3p, occurring at the predicted 3'-UTR of KISS1. Interestingly, circulating levels of miR-324-3p, but not of miR-27b-3p, were dramatically suppressed in EP, despite elevated tissue expression of the pre-miRNA, suggesting defective export in EP. A decision-tree model using kisspeptin and miR-324-3p levels was successful in discriminating EP vs. VTOP, with a receiver-operating characteristic (ROC) AUC of 0.95 ± 0.02 (95% CI). Conclusions: Our results document a massive down-regulation of KISS1/kisspeptins in early stages of EP, likely via a repressive interaction with miR-324-3p. Our data identify circulating kisspeptins and miR-324-3p as novel biomarkers for accurate for screening of EP at early gestational ages.

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“…Approximately half of bivalent promoters with a high PDR in MM are associated with PC-PMDs. Therefore, the DNA methylation landscape of MM resembles that of the placenta, with stochastic methylated gain in CGIs embedded in large hypomethylated regions, suggesting that, as in other cancers, myeloma cells coopt placental nuclear programming [48,49]; this finding is of particular interest since placental and cancerous tissues share relevant features such as immune modulation, angiogenesis and tissue invasion [50]. Interestingly, the specific enrichment of genes in immune-related pathways was revealed when we focused our analysis on genes located near PC-PMD boundaries.…”

Section: Discussionmentioning

confidence: 99%

The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability

Derrien

Guérin‐Charbonnel

Gaborit

et al. 2020

Preprint

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Background: Cancer evolution depends on epigenetic and genetic diversity. Historically, in multiple myeloma (MM), subclonal diversity and tumor evolution have been investigated mostly from a genetic perspective. Results: Here, we combined the notions of epipolymorphism and epiallele switching to analyze DNA methylation heterogeneity in MM patients. We show that MM is characterized by the continuous accumulation of stochastic methylation at the promoters of development-related genes. High entropy change is associated with poor outcomes and depends predominantly on partially methylated domains (PMDs). These PMDs, which represent the major source of inter- and intrapatient DNA methylation heterogeneity in MM, are linked to other key epigenetic aberrations, such as CpG island (CGI)/transcription start site (TSS) hypermethylation and H3K27me3 redistribution as well as 3D organization alterations. In addition, transcriptome analysis revealed that intratumor methylation heterogeneity was associated with low-level expression and high variability. Conclusion: We propose that disordered methylation in MM is responsible for high epigenetic and transcriptomic instability allowing tumor cells to adapt to environmental changes by tapping into a pool of evolutionary trajectories.

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Evidence for Converging DNA Methylation Pathways in Placenta and Cancer

Cited by 27 publications

References 11 publications

DNA methylation-based classification and identification of renal cell carcinoma prognosis-subgroups

DNA methylation-based classification and identification of renal cell carcinoma prognosis-subgroups

Deregulation of miR-324/KISS1/kisspeptin in early ectopic pregnancy: mechanistic findings with clinical and diagnostic implications

The DNA methylation landscape of multiple myeloma shows extensive inter- and intrapatient heterogeneity that fuels transcriptomic variability

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