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Aberrant DNA methylation is a hallmark of human cancer and can be summarized as global hypomethylation and regional hypermethylation. Regional hypermethylation refers to the aberrant methylation of normally unmethylated sequences, most of which are clusters of CpG sites, denoted CpG island. Specifically, regional hypermethylation of promoter-associated CpG islands of tumor-suppressor and repair genes is involved in the initiation and progression of cancer by transcription silencing.1, 2 A subgroup of human cancers is known to have frequent aberrant DNA methylation of the CpG island, referred to as the CpG island methylator phenotype (CIMP). CIMP was first identified in colorectal cancers (CRCs).3 For the determination of CIMP in CRCs, three panels of CIMP marker genes were available: a classic five-marker panel (MINT1, MINT2, MINT31, CDKN2A (p16), and hMLH1),3, 4 the Weisenberger five-marker panel (CACNA1G, IGF2, NEUROG1, RUNX3, and SOCS1),5 and a mixture panel of both. Both classic and Weisenberger CIMP-positive CRCs have been reported to be associated with proximal tumor location, microsatellite instability (MSI), and BRAF mutations.5, 6 Whereas the classic panel outperformed in predicting clinical outcomes, the Weisenberger panel was superior in detecting known clinicopathological features of CIMP but was inferior in prognostication power.7 Recently, genome-wide DNA methylation analysis was performed using the Infinium bead array to identify the CIMP subtype in human cancers, including CRCs. CRCs now can be categorized into CIMP-positive and -negative subtypes or CIMP-high, -low, and -negative subtypes. It has been found that CIMP-positive or CIMP-high CRCs have a close association with molecular and clinicopathological features.8, 9, 10 Identifying the correlation of CIMP with molecular aberrations such as mutation of BRAF in CRCs may improve our understanding of carcinogenesis, identify strategies for subdividing patients into relevant subgroups, and highlight novel molecular target agents. Although the molecular mechanisms of CRC carcinogenesis remain unclear, both genetic and epigenetic alterations are considered to be important. Genetic alterations are responsible for the activation of oncogenes and the inactivation of tumor-suppressor genes, whereas epigenetic alterations through DNA methylation are known to play an important role in inhibiting the expression of tumor-related genes. The presence of CIMP in CRCs has been reported to be associated with worse prognosis,8, 9 but controversial data regarding the correlation of CIMP with molecular and clinicopathological features makes it difficult to understand the internal mechanism. This is possibly because of limited sample size or confounding variables. Therefore, we initiated an international collaborative effort to evaluate the molecular features such as BRAF, KRAS mutations, MSI, and clinicopathological features and prognosis between CIMP-positive and -negative CRCs. The overall OR for BRAF mutations in CIMP-positive vs. -negative CRCs was 34.87 (95% CI, 22.49–54.06; P<0.00001; Figure 3). Subgroup analyses of Weisenberger panel, classic panel, mixture panel, and genome-wide DNA methylation profile showed consistent results. Notably, we found that only the genome-wide methylation profile-defined CIMP subset of CRCs encompassed all BRAF-mutated CRCs. In this study, we aimed to review the data from the published studies in order to estimate the association between CIMP and other molecular incidents or clinicopathological features in CRCs. We found a trend toward more BRAF mutations and MSI and less KRAS mutations in CIMP-positive CRCs than CIMP-negative CRCs. We also clearly demonstrated that CIMP-positive CRCs had female preference and age dependence. Moreover, this subtype of tumors showed a significant correlation with proximal location, mucinous histology, and poor differentiation. Surprisingly, CIMP did not show a correlation with tumor stage, but was significantly associated with shorter overall survival, suggesting CIMP could be used as an independent prognostic marker. One of the major confounding factors in the systematic review on topics relating to CIMP was the lack of a standardized definition of CIMP. Gene-specific methylation markers and genome-wide DNA methylation profile were the two major methods used to define the CIMP in CRCs. Depending on the number and set of genes used for the determination of the CIMP status, a relatively higher heterogeneity can be caused mainly by different panels of CIMP markers compared with genome-wide DNA methylation profile. Till now, two different panels of CIMP markers as well as a mixture of both were widely used in a variety of studies for CRCs. To limit most of the heterogeneity among studies, we screened and only included the studies either using the two panels of CIMP markers or a mixture of these two panels or genome-wide DNA methylation profile. In addition, subgroup analyses of different methodologies and different panels were performed. After the concept of CIMP was initially described in CRCs, other human tumors like glioma, paraganglioma, and gastric cancer were also characterized with similar phenotype. In gliomas, Xu et al.40 revealed that IDH1 and IDH2 gene mutations led to CIMP by reducing the α-ketoglutarate and accumulating 2-hydroxyglutarate that could inhibit histone demethylases and the TET family of 5-methylcytosine hydroxylases. In paragangliomas, Letouze et al.41 reported that SDH mutation was a key factor in causing CIMP by interplaying between the Krebs cycle and 2-oxoglutarate-dependent (2-OG) histone and DNA demethylases. For gastric cancers, Kim et al.42 demonstrated an association between CIMP and oncogene mutations. In this analysis, we clearly showed that BRAF mutation was associated with CIMP in CRCs. In addition, in a recent study, Fang et al.43 provided the first demonstration that a BRAF/MEK/ERK signaling pathway, which mediates silencing of MLH1, is more generally responsible for CIMP. In a subgroup analysis, we found that genome-wide methylation profile-defined CIMP subset of CRCs encompassed all of the BRAF-mutated CRCs, whereas other 3 panels of makers only showed 61.7–83.3% BRAF mutations in CIMP-positive CRCs. BRAF/MEK/ERK signaling pathway could explain the internal mechanism of CIMP. However, in our study, ~49.8% of CIMP-positive CRCs lacked BRAF mutations. We speculated that the subtype of CIMP-positive CRCs without BRAF mutations might be caused by the effect of the microbiome. A recent study by Tahara et al.44 introduced the notion that fusobacterium enrichment was associated with CIMP-positive CRCs. However, they did not find an association between fusobacterium enrichment and BRAF mutations, suggesting microbiome might induce CIMP through different mechanisms. Our results demonstrated CIMP-positive CRCs were associated with proximal location, arguing for a potentially distinct molecular pathway between proximal and distal CRCs. At least two distinct pathways, the serrated pathway and the conventional pathway, underlie most CRCs.45 The CRCs in the serrated pathway have a predilection for frequent BRAF mutations, MSI, and proximal location. On the contrary, the conventional pathway mostly occurs in the distal location with KRAS mutations and microsatellite stability. Combined with our findings, we speculated that CIMP might be a signature of the serrated CRCs. Consistent results among different methodologies or different panels were achieved in most of the subgroup analyses, suggesting that the heterogeneity of the present four different definitions of CIMP was limited. However, there were still some exceptions in the subgroup analyses of KRAS mutations, gender, and age. For analysis of KRAS mutation rates, the overall effects of the classic panel that included three studies and the genome-wide DNA methylation profile that included four studies did not show any differences between CIMP-positive and -negative CRCs. We believe this discrepancy between the Weisenberger panel/mixture panel and the classical panel/genome-wide DNA methylation profile was caused by a relatively limited sample size in these two subgroups, because the total weights of the two were 17.2 and 16.8%. Similarly, the overall effects of the classic panel, including three studies in analysis of gender, and the mixture panel, including three studies in analysis of age, showed heterogeneous results, and their total weights were 6.0 and 21.1%. Regardless of the different definition of CIMP, still many confounding factors such as methods of tissue preservation, sources of patients, smoking history, publication bias, and ethnicity might prevent us from reaching a more precise conclusion.46 We do find that whether the KRAS gene mutation rate is linked to negative CIMP depends on the tissue preservation methods and the sources of patients. However, tissue preservation and sources of patients did not affect the detection accuracy of the associations of BRAF mutations and MSI with positive CIMP. We speculate that the discrepancy might be caused by the limited sample size and the internal heterogeneity among studies, because when the negative data on the association of CIMP-negative CRCs with KRAS gene mutations were observed in formalin-fixed paraffin-embedded or population-based subgroups, a significant heterogeneity existed. In summary, the meta-analysis highlights that CIMP-positive CRCs take their own molecular (especially overlapping with BRAF mutations) and clinicopathological features and worse prognosis from CIMP-negative CRCs, suggesting CIMP could be used as an independent prognostic marker for CRCs.  Guarantor of the article: Duonan Yu, MD, PhD. Specific author contributions: Liang Zong, Duonan Yu, and Wei-Guo Zhu designed the study; Liang Zong and Masanobu Abe collected and analyzed the data; Liang Zong and Jiafu Ji interpreted the data; Liang Zong drafted the manuscript; Duonan Yu, Wei-Guo Zhu, and Jiafu Ji revised the manuscript. Financial support: This work is supported by the National Natural Science Foundation of China (grant 81470277 to Duonan Yu), the Jiangsu Province Specially-appointed Professorship Start-up Fund (to Duonan Yu), a grant from the Ministry of Finance of China for the “Biology & Medical Science Innovation Team” program (to Duonan Yu) and the Priority Academic Program Development of Jiangsu Higher Education Institution (Veterinary Medicine, to Duonan Yu). Potential competing interests: None. We thank Yuan-Jun Yu (University of Pennsylvania) for language editing. Supplementary Information accompanies this paper on the Clinical and Translational Gastroenterology website

clinical and translational gastroenterology

Tracking the Correlation Between CpG Island Methylator Phenotype and Other Molecular Features and Clinicopathological Features in Human Colorectal Cancers: A Systematic Review and Meta-Analysis