DNA Methylation of Shelf, Shore and Open Sea CpG Positions Distinguish High Microsatellite Instability from Low or Stable Microsatellite Status Colon Cancer Stem Cells

Visone, Rosa; Bacalini, Maria Giulia; Franco, Simone Di; Ferracin, Manuela; Colorito, Maria Luisa; Pagotto, Sara; Laprovitera, Noemi; Licastro, Danilo; Marco, Mirco Di; Scavo, Emanuela; Bassi, Cristian; Saccenti, Elena; Nicotra, Antonietta; Grzes, Maria; Garagnani, Paolo; Laurenzi, Vincenzo De; Valeri, Nicola; Mariani-Costantini, Renato; Negrini, Massimo; Stassi, Giorgio; Veronese, Angelo

doi:10.2217/epi-2018-0153

Cited by 35 publications

(25 citation statements)

References 74 publications

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“…The CpG clusters can be identified as ‘islands’, ‘shores’, ‘seas’ and ‘shelves’. 60 CpG islands are defined as 1 kb regions of high CpG density, usually found near promoters; shores are within the 2 kb sequence neighboring the islands with seas and shelves being flanked further from shores, with occurrence of CpGs decreasing in density the further away from the island it is. 60 …”

Section: Resultsmentioning

confidence: 99%

Epigenetic mechanisms in Tendon Ageing

Riasat

Bardell

Goljanek‐Whysall

et al. 2020

British Medical Bulletin

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Introduction Tendon is a composite material with a well-ordered hierarchical structure exhibiting viscoelastic properties designed to transfer force. It is recognized that the incidence of tendon injury increases with age, suggesting a deterioration in homeostatic mechanisms or reparative processes. This review summarizes epigenetic mechanisms identified in ageing healthy tendon. Sources of data We searched multiple databases to produce a systematic review on the role of epigenetic mechanisms in tendon ageing. Areas of agreement Epigenetic mechanisms are important in predisposing ageing tendon to injury. Areas of controversy The relative importance of epigenetic mechanisms are unknown in terms of promoting healthy ageing. It is also unknown whether these changes represent protective mechanisms to function or predispose to pathology. Growing point Epigenetic markers in ageing tendon, which are under-researched including genome-wide chromatin accessibility, should be investigated. Areas timely for developing research Metanalysis through integration of multiple datasets and platforms will enable a holistic understanding of the epigenome in ageing and its relevance to disease.

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Section: Resultsmentioning

confidence: 99%

Epigenetic mechanisms in Tendon Ageing

Riasat

Bardell

Goljanek‐Whysall

et al. 2020

British Medical Bulletin

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“…On the other hand, unlike MSS CRCs, MSI-high CRCs showed a much better response to immune checkpoint inhibitors (42,43). More recently, several MSI-like gene expression signatures were also proposed with likewise controversial signi cance (18,44,45). Our data suggest that the 12-genes hypermethylated cohort of mCRCs is characterized by a MSI-like phenotype and that the methylation pro le of the 12-genes signature may represent an alternative strategy to better de ne a subgroup of mCRCs with a CIMP-H status and a MSIlike phenotype, characterized by a poor clinical outcome.…”

Section: Discussionmentioning

confidence: 99%

Novel Epigenetic 12-gene Signature Predictive of Poor Prognosis and MSI-like Phenotype in Human Metastatic Colorectal Carcinomas

Condelli

Calice

Cassano

et al. 2020

Preprint

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Background. Epigenetic remodeling is responsible for tumor progression and drug resistance in human colorectal carcinoma (CRC). A subgroup of human CRCs exhibits the CIMP status, with extensive hypermethylation events in promoter regions of several genes, even though the prognostic significance of CIMP is controversial. This study addressed the hypothesis that DNA methylation profiling may identify metastatic CRC (mCRC) subtypes with different clinical behavior. Methods. Global methylation profile was comparatively analyzed between 24 first-line primary-resistant and 12 drug-sensitive mCRCs (in-house cohort), two subgroups of tumors with significantly different outcome. Methylation and gene expression data from 33 mCRCs of the TCGA COAD dataset (TCGA COAD cohort) were used to identify, among differentially methylated genes, a prognostic signature of functionally methylated genes. Clusters of mCRCs with different methylation patterns were further characterized for DNA mutational load, gene copy number and gene expression profiles. Human CRC HT29 and HCT116 cell lines were adapted to growth in presence of oxaliplatin and irinotecan and used as in vitro model to validate gene expression data.Results. Twelve functionally methylated genes yielded a hierarchical clustering of patients in two well-defined clusters with hypermethylated tumors characterized by a significantly worse relapse-free and overall survival compared to hypomethylated cancers and this was reproduced in both the in-house and the TCGA COAD cohorts. Interestingly, the hypermethylated poor prognosis cluster was enriched of CIMP-high and MSI-like cases. Furthermore, methylation events were enriched in genes located on q-arm of chromosomes 13 and 20, two chromosomal regions with gain/loss alterations strongly associated with adenoma-to-carcinoma progression. Finally, the expression of the 12-genes signature and MSI-enriching genes was confirmed in two independent oxaliplatin- and irinotecan-resistant CRC cell lines. Conclusions. These data represent the proof of concept that the hypermethylation of specific sets of genes may provide prognostic information being able to identify a subgroup of mCRCs with poor prognosis.

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“…Several molecular mechanisms, including advanced glycation end product (AGE) [10], aberrant glycosylation [11], abnormal telomerase activity [12], unfolded protein response (UPR) [13], angiogenesis [14], reactive oxygen species (ROS) production [15], epithelial-mesenchymal transition (EMT) [16], cell apoptosis, proliferation, survival, migration, invasion, self-renewal, differentiation and dedifferentiation reprogramming, are altered to survive host defense or therapeutic insults. However, the dysregulation of these molecular mechanisms may not explain CRC origins and development, suggesting that various genetic and epigenetic events occur at the gene level [17,18].…”

Section: Introductionmentioning

confidence: 99%

“…Moreover, the interaction of these pathways is precise and complicated. In addition, a growing body of research shows that genetic perturbation or epigenetic dysregulation can promote the development of CRC or that the cancer itself can provoke genetic perturbation or epigenetic dysregulation [18]. Vdovikova et al found that bacteria can target host cell epigenetics to promote carcinogenesis in HCT8 cells [31].…”

Section: Introductionmentioning

confidence: 99%

Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways

et al. 2020

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Colorectal cancer (CRC) is the third most common malignancy and one of the leading causes of cancer-related death among men worldwide. CRC is a multifactor digestive pathology, which is a huge problem faced not only by clinicians but also by researchers. Importantly, a unique feature of CRC is the dysregulation of molecular signaling pathways. To date, a series of reviews have indicated that different signaling pathways are disordered and have potential as therapeutic targets in CRC. Nevertheless, an overview of the function and interaction of multiple signaling pathways in CRC is needed. Therefore, we summarized the pathways, biological functions and important interactions involved in CRC. First, we investigated the involvement of signaling pathways, including Wnt, PI3K/Akt, Hedgehog, ErbB, RHOA, Notch, BMP, Hippo, AMPK, NF-κB, MAPK and JNK. Subsequently, we discussed the biological function of these pathways in pathophysiological aspects of CRC, such as proliferation, apoptosis and metastasis. Finally, we summarized important interactions among these pathways in CRC. We believe that the interaction of these pathways could provide new strategies for the treatment of CRC.

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DNA Methylation of Shelf, Shore and Open Sea CpG Positions Distinguish High Microsatellite Instability from Low or Stable Microsatellite Status Colon Cancer Stem Cells

Cited by 35 publications

References 74 publications

Epigenetic mechanisms in Tendon Ageing

Epigenetic mechanisms in Tendon Ageing

Novel Epigenetic 12-gene Signature Predictive of Poor Prognosis and MSI-like Phenotype in Human Metastatic Colorectal Carcinomas

Colorectal cancer (CRC) as a multifactorial disease and its causal correlations with multiple signaling pathways

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