Deciphering the etiology and role in oncogenic transformation of the CpG island methylator phenotype: a pan-cancer analysis

Abstract

Numerous cancer types have shown to present hypermethylation of CpG islands, also known as a CpG island methylator phenotype (CIMP), often associated with survival variation. Despite extensive research on CIMP, the etiology of this variability remains elusive, possibly due to lack of consistency in defining CIMP. In this work, we utilize a pan-cancer approach to further explore CIMP, focusing on 26 cancer types profiled in the Cancer Genome Atlas (TCGA). We defined CIMP systematically and agnostically, discarding any effects associated with age, gender or tumor purity. We then clustered samples based on their most variable DNA methylation values and analyzed resulting patient groups. Our results confirmed the existence of CIMP in 19 cancers, including gliomas and colorectal cancer. We further showed that CIMP was associated with survival differences in eight cancer types and, in five, represented a prognostic biomarker independent of clinical factors. By analyzing genetic and transcriptomic data, we further uncovered potential drivers of CIMP and classified them in four categories: mutations in genes directly involved in DNA demethylation; mutations in histone methyltransferases; mutations in genes not involved in methylation turnover, such as KRAS and BRAF; and microsatellite instability. Among the 19 CIMP-positive cancers, very few shared potential driver events, and those drivers were only IDH1 and SETD2 mutations. Finally, we found that CIMP was strongly correlated with tumor microenvironment characteristics, such as lymphocyte infiltration. Overall, our results indicate that CIMP does not exhibit a pan-cancer manifestation; rather, general dysregulation of CpG DNA methylation is caused by heterogeneous mechanisms.

Cell-free Tumor Methylome Analysis of Small Cell Lung Cancer Patients Identifies Subgroups with Prognostic Associations

“…Our study demonstrated the utility of the cfMeDIP-seq assay in studying the methylome of SCLC and demonstrated that plasma methylation is representative of tissue (Figure 1C) and is enriched in regions that are cancer specific (Figure 1D, Figure 1E) 13 . To our knowledge, this is the largest study to comprehensively examine the DNA methylation of SCLC patients by whole genome analysis.…”

A role for SETD2 loss in tumorigenesis through DNA methylation dysregulation

“…Similarly, studies on the CpG Island methylator phenotype (CIMP+) have highlighted the association of SETD2 and DNA methylation in cancer, with gene body hypomethylation and promoter hypermethylation which is in line with our results [ 45 – 47 ]. While SETD2 mutations can drive CIMP + phenotypes, not all CIMP + phenotypes occur due to SETD2 mutations and Yates et al found that SETD2 was a driver of CIMP + in only 3 cancer types [ 46 ]. Further, several mutations may drive CIMP + in the same cancer type.…”

Cell-free DNA methylation-defined prognostic subgroups in small-cell lung cancer identified by leukocyte methylation subtraction

“…Our study demonstrated the utility of the cfMeDIP-seq assay in studying the methylome of SCLC and demonstrated that plasma methylation is representative of tissue ( Figure 1 C) and is enriched in regions that are cancer specific ( Figures 1 D and 1E). 23 We report one of the largest studies to comprehensively examine the DNA methylation of patients with SCLC by whole-genome analysis alongside a contemporaneously published study that demonstrates the value of liquid biopsy assays. 21 In contrast to prior tissue-based studies, 8 , 9 our genome-wide approach profiled methylated DNA loci beyond 450K/EPIC array probes and identified hypermethylated noncoding and repeat elements (e.g.…”