Abstract
Cancer is a complex disease, driven by aberrant activity in numerous signaling pathways in even individual malignant cells. Epigenetic changes are critical mediators of these functional changes that drive and maintain the malignant phenotype. Changes in DNA methylation, histone acetylation and methylation, noncoding RNAs, posttranslational modifications are all epigenetic drivers in cancer, independent of changes in the DNA sequence. These epigenetic alterations were once thought to be crucial only for the malignant phenotype maintenance. Now, epigenetic alterations are also recognized as critical for disrupting essential pathways that protect the cells from uncontrolled growth, longer survival and establishment in distant sites from the original tissue. In this review, we focus on DNA methylation and chromatin structure in cancer. The precise functional role of these alterations is an area of active research using emerging high-throughput approaches and bioinformatics analysis tools. Therefore, this review also describes these high-throughput measurement technologies, public domain databases for high-throughput epigenetic data in tumors and model systems and bioinformatics algorithms for their analysis. Advances in bioinformatics data that combine these epigenetic data with genomics data are essential to infer the function of specific epigenetic alterations in cancer. These integrative algorithms are also a focus of this review. Future studies using these emerging technologies will elucidate how alterations in the cancer epigenome cooperate with genetic aberrations during tumor initiation and progression. This deeper understanding is essential to future studies with epigenetics biomarkers and precision medicine using emerging epigenetic therapies.
Highlights
This review focuses on describing current resources to discover reversible epigenetic events in cancer that may be targeted therapeutically in cancer: DNA methylation and chromatin organization (Figure 1)
In this review, we will briefly describe high-throughput approaches for epigenetic mapping from DNA methylation, chromatin modification markers and chromatin structure commonly used in cancer genomics, with details about each measurement technology in Supplemental File 1
Elucidating the relationships between different epigenetic mechanisms and their regulation of gene expression is essential to finding hidden sources of variation in cancer and therapeutic selection
Summary
Genetic alterations to genes encoding for histone modifying proteins can cause widespread epigenetic changes These changes can dysregulate cell homeostasis pathways independent of mutations to critical oncogenes or tumor suppressor genes in these pathways [55]. In the current era of high-throughput data, new technologies to measure the genome-wide state of DNA methylation and chromatin structure are actively emerging (Figure 2). In this review, we will briefly describe high-throughput approaches for epigenetic mapping from DNA methylation, chromatin modification markers and chromatin structure commonly used in cancer genomics, with details about each measurement technology in Supplemental File 1. New bioinformatics techniques for preprocessing bisulfitebased data remain a critical challenge preceding the analysis of DNA methylation data in cancer In both cases, measurements of epigenetic variation within tumors are only possible with bisulfite sequencing techniques.
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