Abstract
Epigenetic dysregulation is recognized as a hallmark of cancer. In the last 16 years, a CpG island methylator phenotype (CIMP) has been documented in tumors originating from different tissues. However, a looming question in the field is whether or not CIMP is a pan-cancer phenomenon or a tissue-specific event. Here, we give a synopsis of the history of CIMP and describe the pattern of DNA methylation that defines the CIMP phenotype in different cancer types. We highlight new conceptual approaches of classifying tumors based on CIMP in a cancer type-agnostic way that reveal the presence of distinct CIMP tumors in a multitude of The Cancer Genome Atlas (TCGA) datasets, suggesting that this phenotype may transcend tissue-type specificity. Lastly, we show evidence supporting the clinical relevance of CIMP-positive tumors and suggest that a common CIMP etiology may define new mechanistic targets in cancer treatment.
Highlights
Through the auspices of large-scale consortium projects, such as The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium, Cancer Epigenome, and the InternationalHuman Epigenome Consortium, our understanding of cancer processes and epigenetic landscapes has vastly accelerated in the past five years
We focus on the CpG island methylator phenotype (CIMP): a pattern of extensive
It was demonstrated that the overactive Kirsten rat sarcoma viral oncogene homolog (KRAS) protein transcriptionally upregulates protein kinase D1 (PRKD1) and the deubiquitinase ubiquitin specific peptidase 28 (USP28), which prevents degradation of zinc finger protein 304 (ZNF304) [25]
Summary
Through the auspices of large-scale consortium projects, such as The Cancer Genome Atlas (TCGA), the International Cancer Genome Consortium, Cancer Epigenome, and the International. Because epigenetic dysregulation can affect gene transcription, identifying affected loci gives clues to tumorigenic processes. This information may inform the use of drugs that target epigenetic pathways, which are increasingly being viewed as powerful adjuncts to combination drug therapies [12,13]. A better understanding of cancer epigenetic dysregulation can be leveraged to identify tumor subtypes, improve precision medicine regimens, and lay the groundwork for diagnostic and screening purposes. Can we clearly demarcate CIMP subtypes in multiple cancer types, but we can begin to explore the molecular underpinnings that drive the phenotype. We present evidence that establishes CIMP as a pan-cancer phenomenon rather than a tissue-specific mechanism and explore the relevance of driver mutations to this phenotype. Our goal is to summarize the state of the field and highlight future directions in this rapidly evolving area of study
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