The Emergence of Pan-Cancer CIMP and Its Elusive Interpretation

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.

Keywords: CpG island methylator phenotype; DNA methylation; pan-cancer.

Figure 1

Mechanisms establishing CpG island methylator phenotype (CIMP) in colorectal cancer: (A) Model reproduced from [24] with permission from Elsevier; protein kinase B-Raf (BRAF) V600E increases MAPK/ERK kinase (MEK)/extracellular signal-regulated kinase (ERK) signaling and causes levels of MAF BZIP transcription factor G (MAFG) to increase via phosphorylation, which protects it from polyubiquitination and subsequent degradation via the proteasome. MAFG directs a transcriptional repression complex that includes the DNA methyl transferase DNMT3B to CIMP-associated genomic loci; (B) Model reproduced from [25] published by eLife Sciences Publications Ltd.; activated V-Ki-ras2 Kirsten rat sarcoma viral oncogene homolog (KRAS) increases levels of zinc finger protein 304 (ZNF304) through transcriptional upregulation of the deubiquitinase ubiquitin specific peptidase 28 (USP28) and the serine/threonine kinase protein kinase D1 (PRKD1). ZNF304 recruits a transcriptional repression complex that includes the DNA methyl transferase DNMT1 to CIMP associated genomic loci. Illustrations reproduced by Darryl Leja. BACH1: BTB domain and CNC homolog 1; CHD8: chromodomain-helicase-DNA-binding protein 8; INK4-ARF: inhibitors of CDK4-ADP ribosylation factors; KAP1: KRAB-associated protein-1; MLH1: MutL homolog 1; SETDB: SET domain bifurcated 1; Ub: ubiquitin.

Figure 2

Number of differentially methylated genomic loci across cancers: (A) Figure generated using data from [62]. The vertical axis represents total count. For each cancer, the differentially methylated CpGs were defined as those with average methylation levels above 25% in tumors and less than 5% in controls; (B) Figure generated using data from [62]. The horizontal axis represents the number of features (either differentially methylated CpGs or genes that contain differentially methylated CpGs) that are shared by a number of cancer types that is greater than or equal to the value shown in the vertical axis. COAD: colon adenocarcinoma; LUAD: lung adenocarcinoma; BRCA: breast invasive carcinoma; PAAD: pancreatic adenocarcinoma; UCEC: uterine corpus endometrial carcinoma; HNSC: head and neck squamous cell carcinoma; READ: rectum adenocarcinoma; LUSC: lung squamous cell carcinoma; STAD: stomach adenocarcinoma; LIHC: liver hepatocellular carcinoma; PRAD: prostate adenocarcinoma; BLCA: bladder urothelial carcinoma; KIRC: kidney renal clear cell carcinoma; KIRP: kidney renal papillary cell carcinoma.

Figure 3

Survival curves in four cancer types based on CIMP: figure reproduced from [62] and published by BioMed Central. Data generated using The Cancer Genome Atlas clinical data for these cancer types. p values were determined using a log-rank test for survival differences. Ratio (n) indicates number of CIMP-/CIMP + samples.