Clinical, Pathological, and Molecular Characteristics of CpG Island Methylator Phenotype in Colorectal Cancer: A Systematic Review and Meta-analysis

Abstract

BACKGROUND: CpG island methylator phenotype (CIMP) tumors, comprising 20% of colorectal cancers, are associated with female sex, age, right-sided location, and BRAF mutations. However, other factors potentially associated with CIMP have not been robustly examined. This meta-analysis provides a comprehensive assessment of the clinical, pathologic, and molecular characteristics that define CIMP tumors. METHODS: We conducted a comprehensive search of the literature from January 1999 through April 2018 and identified 122 articles, on which comprehensive data abstraction was performed on the clinical, pathologic, molecular, and mutational characteristics of CIMP subgroups, classified based on the extent of DNA methylation of tumor suppressor genes assessed using a variety of laboratory methods. Associations of CIMP with outcome parameters were estimated using pooled odds ratio or standardized mean differences using random-effects model. RESULTS: We confirmed prior associations including female sex, older age, right-sided tumor location, poor differentiation, and microsatellite instability. In addition to the recognized association with BRAF mutations, CIMP was also associated with PIK3CA mutations and lack of mutations in KRAS and TP53. Evidence of an activated immune response was seen with high rates of tumor-infiltrating lymphocytes (but not peritumoral lymphocytes), Crohn-like infiltrates, and infiltration with Fusobacterium nucleatum bacteria. Additionally, CIMP tumors were associated with advance T-stage and presence of perineural and lymphovascular invasion. CONCLUSION: The meta-analysis highlights key features distinguishing CIMP in colorectal cancer, including molecular characteristics of an active immune response. Improved understanding of this unique molecular subtype of colorectal cancer may provide insights into prevention and treatment.

Stage-differentiated modelling of methylation patterns uncovers salient biomarkers and prognostic signatures in colorectal cancer progression

“…Still it is clear from Table 6 that the stage-salient hypermethylated biomarkers identified in our study could constitute an aggregate novel CIMP. The CIMP has been associated with advanced T staging (T3/T4) [68], which accords with our finding of five hypermethylated stage IV-salient DMGs. Epigenetic intervention for CIMP-positive cancers has been suggested as a possible treatment strategy [69].…”

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

“…Interestingly, 15-20% of human CRCs are characterized by the CpG-island methylator phenotype (CIMP), subdivided in CIMP-high (CIMP-H) and CIMP-low (CIMP-L) and this correlates with the MSI phenotype (19). Thus, the relationship between our 12-genes hypermethylated signature and CIMP status was evaluated in TCGA COAD dataset and in our in-house cohort according to Hinoue et al (20).…”

Potential Use of Biotherapeutic Bacteria to Target Colorectal Cancer-Associated Taxa

“…The Fusobacterium-CRC link was further strengthened, when Rezasoltani et al [30] found an enrichment of F. nucleatum in adenomatous polyps compared with healthy matched controls. Ultimately, in 2018, a meta-analysis which included 122 studies associated high F. nucleatum numbers with the tumorigenesis pathway and the CpG island methylator phenotype [49]. Over time, evidence has continued to accumulate about the relationship between F. nucleatum and CRC going beyond a correlation, with the species now being viewed as a causative agent.…”