Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype

Xu, Tong; Li, Hongtao; Wei, Jianqin; Li, Meng; Hsieh, Tien‐Chan; Lu, Yi‐Tsung; Lakshminarasimhan, Ranjani; Xu, Rong; Hodara, Emmanuelle; Morrison, Gareth; Gujar, Hemant; Rhie, Suhn Kyong; Siegmund, Kimberly D.; Liang, Gangning; Goldkorn, Amir

doi:10.1002/ijc.32904

Cited by 12 publications

(18 citation statements)

References 59 publications

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“…Understanding the relationship between DNA methylation alterations and gene expression changes will provide not only a functional DNA methylation marker for gene expression status, but also a potential therapeutic biomarker, especially for DNA methylation inhibitors [ 88 ]. We recently demonstrated that epigenetic alterations are more frequent than genetic alterations in regulating gene expression, and this may be identified by correlating gene expression with DNA methylation and/or nucleosome accessibility of gene promoters or gene bodies [ 68 , 69 , 83 , 87 , 89 ].…”

Section: Resultsmentioning

confidence: 99%

Characterizing DNA methylation signatures and their potential functional roles in Merkel cell carcinoma

Gujar

Mehta

et al. 2021

Genome Med

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Background Merkel cell carcinoma (MCC) is a rare but aggressive skin cancer with limited treatment possibilities. Merkel cell tumors display with neuroendocrine features and Merkel cell polyomavirus (MCPyV) infection in the majority (80%) of patients. Although loss of histone H3 lysine 27 trimethylation (H3K27me3) has been shown during MCC tumorigenesis, epigenetic dysregulation has largely been overlooked. Methods We conducted global DNA methylation profiling of clinically annotated MCC primary tumors, metastatic skin tumors, metastatic lymph node tumors, paired normal tissues, and two human MCC cell lines using the Illumina Infinium EPIC DNA methylation BeadArray platform. Results Significant differential DNA methylation patterns across the genome are revealed between the four tissue types, as well as based on MCPyV status. Furthermore, 964 genes directly regulated by promoter or gene body DNA methylation were identified with high enrichment in neuro-related pathways. Finally, our findings suggest that loss of H3K27me3 occupancy in MCC is attributed to KDM6B and EZHIP overexpression as a consequence of promoter DNA hypomethylation. Conclusions We have demonstrated specific DNA methylation patterns for primary MCC tumors, metastatic MCCs, and adjacent-normal tissues. We have also identified DNA methylation markers that not only show potential diagnostic or prognostic utility in MCC management, but also correlate with MCC tumorigenesis, MCPyV expression, neuroendocrine features, and H3K27me3 status. The identification of DNA methylation alterations in MCC supports the need for further studies to understand the clinical implications of epigenetic dysregulation and potential therapeutic targets in MCC.

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Section: Resultsmentioning

confidence: 99%

Characterizing DNA methylation signatures and their potential functional roles in Merkel cell carcinoma

Gujar

Mehta

et al. 2021

Genome Med

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“…Thus, in order to better define the prognostic relevance of promoter hypermethylation events in human CRC, this study was designed to characterize epigenetic signatures helpful to identify mCRCs molecular subgroups with defined clinical behavior. In such a context, primary-resistant colorectal carcinomas were selected as cases representative of poor outcome [ 33 ] based on the evidence that methylation modifications are key events used by cancer cells to rapidly adapt to unfavorable environments and acquire drug resistance [ 34 , 35 ]. Our data suggest that the methylation profile of eight functionally methylated genes is predictive of clinical outcome being able to clusterize two independent mCRC cohorts (i.e., the TCGA COAD and the in-house datasets) in two well-defined clusters with hypermethylated tumors characterized by worse prognosis and an MSI-like phenotype compared to hypomethylated tumors.…”

Section: Discussionmentioning

confidence: 99%

Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas

Condelli

Calice

Cassano

et al. 2021

Cancers

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Epigenetics is involved in tumor progression and drug resistance in human colorectal carcinoma (CRC). This study addressed the hypothesis that the DNA methylation profiling may predict the clinical behavior of metastatic CRCs (mCRCs). The global methylation profile of two human mCRC subgroups with significantly different outcome was analyzed and compared with gene expression and methylation data from The Cancer Genome Atlas COlon ADenocarcinoma (TCGA COAD) and the NCBI GENE expression Omnibus repository (GEO) GSE48684 mCRCs datasets to identify a prognostic signature of functionally methylated genes. A novel epigenetic signature of eight hypermethylated genes was characterized that was able to identify mCRCs with poor prognosis, which had a CpG-island methylator phenotype (CIMP)-high and microsatellite instability (MSI)-like phenotype. Interestingly, methylation events were enriched in genes located on the q-arm of chromosomes 13 and 20, two chromosomal regions with gain/loss alterations associated with adenoma-to-carcinoma progression. Finally, the expression of the eight-genes signature and MSI-enriching genes was confirmed in oxaliplatin- and irinotecan-resistant CRC cell lines. These data reveal that the hypermethylation of specific genes may provide prognostic information that is able to identify a subgroup of mCRCs with poor prognosis.

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“…Thus, in order to better de ne the prognostic relevance of promoter hypermethylation events in human CRC, this study was designed to characterize epigenetic signatures helpful to identify mCRCs molecular subgroups with de ned clinical behavior. In such a context, primary-resistant colorectal carcinomas were selected as cases representative of poor outcome (33), based on the evidence that methylation modi cations are key events used by cancer cells to rapidly adapt to unfavorable environments and acquire drug resistance (34,35). Our data suggest that the methylation pro le of 12 functionally methylated genes is predictive of clinical outcome being able to clusterize two independent mCRC cohorts (i.e., the TCGA COAD and the inhouse datasets) in two well-de ned clusters with hypermethylated tumors characterized by worse prognosis and a MSI-like phenotype compared to hypomethylated tumors.…”

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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Epigenetic plasticity potentiates a rapid cyclical shift to and from an aggressive cancer phenotype

Cited by 12 publications

References 59 publications

Characterizing DNA methylation signatures and their potential functional roles in Merkel cell carcinoma

Characterizing DNA methylation signatures and their potential functional roles in Merkel cell carcinoma

Novel Epigenetic Eight-Gene Signature Predictive of Poor Prognosis and MSI-Like Phenotype in Human Metastatic Colorectal Carcinomas

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

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