Pan-cancer stratification of solid human epithelial tumors and cancer cell lines reveals commonalities and tissue-specific features of the CpG island methylator phenotype

Francisco Sánchez-Vega,Laura Elnitski,Gennady Margolin,Valer Gotea

doi:10.1186/s13072-015-0007-7

Francisco Sánchez-Vega, Laura Elnitski + Show 2 more

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https://doi.org/10.1186/s13072-015-0007-7

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Abstract

BackgroundThe term CpG island methylator phenotype (CIMP) has been used to describe widespread DNA hypermethylation at CpG-rich genomic regions affecting clinically distinct subsets of cancer patients. Even though there have been numerous studies of CIMP in individual cancer types, a uniform analysis across tissues is still lacking.ResultsWe analyze genome-wide patterns of CpG island hypermethylation in 5,253 solid epithelial tumors from 15 cancer types from TCGA and 23 cancer cell lines from ENCODE. We identify differentially methylated loci that define CIMP+ and CIMP− samples, and we use unsupervised clustering to provide a robust molecular stratification of tumor methylomes for 12 cancer types and all cancer cell lines. With a minimal set of 89 discriminative loci, we demonstrate accurate pan-cancer separation of the 12 CIMP+/− subpopulations, based on their average levels of methylation. Tumor samples in different CIMP subclasses show distinctive correlations with gene expression profiles and recurrence of somatic mutations, copy number variations, and epigenetic silencing. Enrichment analyses indicate shared canonical pathways and upstream regulators for CIMP-targeted regions across cancer types. Furthermore, genomic alterations showing consistent associations with CIMP+/− status include genes involved in DNA repair, chromatin remodeling genes, and several histone methyltransferases. Associations of CIMP status with specific clinical features, including overall survival in several cancer types, highlight the importance of the CIMP+/− designation for individual tumor evaluation and personalized medicine.ConclusionsWe present a comprehensive computational study of CIMP that reveals pan-cancer commonalities and tissue-specific differences underlying concurrent hypermethylation of CpG islands across tumors. Our stratification of solid tumors and cancer cell lines based on CIMP status is data-driven and agnostic to tumor type by design, which protects against known biases that have hindered classic methods previously used to define CIMP. The results that we provide can be used to refine existing molecular subtypes of cancer into more homogeneously behaving subgroups, potentially leading to more uniform responses in clinical trials.Electronic supplementary materialThe online version of this article (doi:10.1186/s13072-015-0007-7) contains supplementary material, which is available to authorized users.

Highlights

The term CpG island methylator phenotype (CIMP) has been used to describe widespread DNA hypermethylation at CpG-rich genomic regions affecting clinically distinct subsets of cancer patients
We analyzed DNA methylation data from the Illumina HumanMethylation450K platform for 5,253 solid tumors from 15 different cancer types made available by The Cancer Genome Atlas (TCGA) and for 51 cultured cell lines with known cancer (n = 23) or non-cancer (n = 28) origins made available by The Encyclopedia of Coding Elements (ENCODE)
Based on reports of heterogeneous DNA methylation levels across a majority of tumor subtypes in recent studies [24,25,26,27,28], we hypothesize that the CIMP designation extends to subpopulations within the majority of cancer types and, that large cohorts of cancer patients may reveal a mixture of CpG island methylator phenotype positive (CIMP+) and CpG island methylator phenotype negative (CIMP−) tumor genomes

Summary

Introduction

The term CpG island methylator phenotype (CIMP) has been used to describe widespread DNA hypermethylation at CpG-rich genomic regions affecting clinically distinct subsets of cancer patients. Even though there have been numerous studies of CIMP in individual cancer types, a uniform analysis across tissues is still lacking. Since methylation of specific genomic loci is a potentially actionable event, the analysis of these patterns may influence therapeutic approaches aimed at individual subtypes of tumors [8,9,10]. Concurrent and widespread hypermethylation of CpG islands in clinically distinct cancer subtypes is known as CpG island methylator phenotype (CIMP) [11,12]. Evidence for a pan-cancer overlap of individual gene targets is virtually absent in these previous reports, suggesting a tissuespecific CIMP program for each type of cancer [18]

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