Review
Biological significance of the CpG island methylator phenotype

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Highlights

  • CIMP represents a subtype of cancers with multiple CpG island hypermethylation.

  • CIMP-positive tumors are found in a wide variety of human malignancies.

  • CIMP tumors show characteristic molecular and clinicopathological features.

  • CIMP is associated with clinical outcome and it could be a predictive biomarker.

Abstract

Cancers exhibiting the CpG island methylator phenotype (CIMP) are found among a wide variety of human malignancies and represent a subclass of tumors showing concurrent hypermethylation of multiple CpG islands. These CIMP-positive tumors often exhibit characteristic molecular and clinicopathological features, suggesting CIMP represents a distinct carcinogenic pathway. However, marker genes to define CIMP have been largely inconsistent among studies, which has caused results to vary. Nonetheless, recent advances in genome-wide methylation analysis have enabled the existence of CIMP to be confirmed, and large-scale cancer genome analyses have begun to unravel the previously unknown molecular basis of CIMP tumors. CIMP is strongly associated with clinical outcome, suggesting it may be a predictive biomarker.

Introduction

Fifteen years have passed since the first report of the CpG island methylator phenotype (CIMP) was published [1]. It is now known that hypermethylation of CpG islands (CGIs) at gene promoters plays a key role in the silencing of numerous cancer-related genes affecting a variety of vital cellular processes, and that CIMP-tumors represents a subtype of cancers that exhibit concurrent hypermethylation of multiple CGIs. CIMP was first documented in colorectal cancer (CRC), and because of its characteristic molecular and clinicopathological features, CIMP was thought to represent a distinct pathway of colorectal carcinogenesis [1], [2]. Subsequently, methylation of multiple CGIs was also reported in other cancers, including gastric [3], [4], esophageal [5], hepatic [6], [7], pancreatic [8], lung [9], ovarian [10], renal [11], duodenal [12] and oral cancers [13], as well as malignant melanoma [14], neuroblastoma [15], [16] and hematological malignancies [17], [18], [19]. CIMP-positive groups thus exist in a wide variety of human malignancies (Table 1).

Despite its apparently wide distribution of CIMP, it has been difficult to define the methylator phenotype due to the ambiguous borderline between CIMP-positive and CIMP-negative groups. This ambiguity stems mainly from an absence of consistent criteria by which to define CIMP; in particular, there is substantial inconsistency among studies with respect the marker genes and analytical methods used to define CIMP. To address these issues, numerous investigators have put much effort into identifying marker genes that accurately characterize CIMP positive-tumors in CRC. Moreover, in recent years technological advances have enabled genome-wide DNA methylation analysis, and unsupervised clustering of the methylome data has clearly delineated CIMP-positive groups in breast [20], lung [21], colorectal [22], endometrial [23], bladder [24] oral [25] and renal cancer [26], as well as in glioma [27], paraganglioma [28] and ependymoma [29] (Table 1).

The identification of CIMP could potentially lead to better understanding of the molecular basis of tumorigenesis as well as improved treatment of cancer patients. For instance, the recent discovery of IDH1/2 and TET2 gene mutations in CIMP-positive tumors suggested their causal relationship [27], [30]. In addition, several studies have reported an association between CIMP and clinical outcome, suggesting that CIMP could be a predictive marker for patient survival or chemosensitivity (Table 1). In this review, we will summarize our understanding of CIMP in various malignancies and highlight its biological and clinical significance.

Section snippets

Discovery of CIMP in CRC

CIMP was first identified through a genome-wide screen of methylated CGIs in CRC cells. Using methylated CpG island amplification (MCA) coupled with representational difference analysis (RDA), Toyota et al. compared the CGI methylation statuses of the CaCO2 CRC cell line and normal colonic mucosa samples. They identified 30 CGIs hypermethylated in CRC, which they termed MINT (methylated in tumors) clones [1], [31]. The majority of the CGIs (19/30) were methylated in both tumors and normal

Subclasses of CIMP in CRC

Although the tight association between CIMP and MSI has been repeatedly documented, studies have also revealed that there are distinct subclasses of CIMP-positive CRCs (Table 2). Ogino et al. analyzed a panel of 5 CIMP-specific genes (CACNA1G, CDKN2A, CRABP1, MLH1 and NEUROG1) in 840 population-based CRC patients [43]. They found that CRCs with intermediate methylation, termed CIMP-low (defined as 1/5 to 3/5 methylated genes), are strongly associated with male sex and KRAS mutation, which is

Possible mechanisms to induce CIMP in CRC

The mechanism by which aberrant DNA methylation is induced in CRC remains largely unknown, though several factors that may be causally involved have been reported. For instance, one recent study reported overexpression of DNA methyltransferase-3B (DNMT3B) in CIMP-high tumors [55]. DNMT3B expression is also reportedly increased during colorectal neoplastic progression, and its expression correlates positively with the levels of methylation of the CIMP-associated genes (NEUROG1, CACNA1G and CDKN2A

Clinical significance of CIMP in CRC

DNA methylation could be a useful biomarker for cancer risk assessment, detection and outcome prediction. The impact of CIMP on the clinical outcome of CRC patients has been analyzed fairly extensively, but the results have been inconsistent. Multiple lines of evidence suggest that CIMP-high with MSI is a marker of a favorable prognosis in CRC patients, while CIMP in MSS tumors is an indicator of poor survival. Using the classic CIMP markers (MINT1, MINT2, MINT12, MINT31, CDKN2A and MLH1), Ward

CIMP in colorectal premalignant lesions

It is well documented that aberrant DNA methylation occurs early during tumorigenesis, and multiple studies have shown the presence of CIMP in colorectal adenomas and hyperplastic polyps (HPs) [1], [83], [84], [85]. For a long time, HPs were considered to be colorectal lesions with little neoplastic potential, and therefore of little pathogenic consequence. However, the recent proposal of the “serrated pathway,” which can progress to CIMP-positive CRCs, has challenged this view [86]. Serrated

CIMP in gastric cancer

Aberrant DNA methylation is reportedly involved in the development of gastric cancer (GC). Helicobacter pylori (H. pylori) infection is associated with an increased risk of GC, and CGI hypermethylation has been found in H. pylori-induced gastritis, suggesting methylation is an early event during gastric tumorigenesis [93]. CIMP-positive tumors have also been reported in GC. The earliest study used classic CIMP markers and found that approximately 40% of primary GCs are CIMP-positive [3]. A link

Concluding remarks

Until today, studies have shown a strong association between CIMP and clinical outcome or chemosensitivity, which suggests CIMP may be a useful biomarker for some cancer patients. However, the criteria used to define CIMP remains inconsistent for most tumor types. Even among CRCs, where CIMP has been most extensively analyzed, accurate definition of CIMP-low tumors is not easy, and the relationship between CIMP and clinical outcome remains to be clarified. Additional large-scale studies with

Acknowledgments

We thank Dr. William Goldman for editing the manuscript. This study was supported in part by Grants-in-Aid for Scientific Research (C) from the Japan Society for Promotion of Science (H. Suzuki), a Grant-in-Aid for the Third-term Comprehensive 10-year Strategy for Cancer Control (H. Suzuki), Grants-in-Aid for Young Researchers (B) from the Japan Society for Promotion of Science (E. Yamamoto).

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