The past three decades have witnessed an accumulating body of evidence that epigenetic mechanisms play an instrumental role in human cancer. Epigenetic alterations can serve as driver events in cancer by inactivating tumor-suppressor genes. The finding that these silencing events are mutually exclusive with structural or mutational inactivation of the same gene reinforces the functional significance of epigenetic silencing. The majority of cases of microsatellite instability in sporadic human tumors can be attributed to epigenetic silencing of the MLH1 mismatch repair gene. One of the most striking discoveries to emerge from cancer genome projects has been the previously unappreciated preponderance of somatic mutations in epigenetic regulators in most types of human cancer. Clearly, epigenetic mechanisms play a key role in human cancer, and a comprehensive molecular characterization of cancer should include epigenomic profiling. We propose to create an Integrative Cancer Epigenomic Data Analysis Center (ICE-DAC) to provide specialized analysis pipelines and expertise as part of the Genome Data Analysis Network (GDAN). We anticipate that epigenomic data will be provided as bisulfite-based sequence data or as DNA methylation BeadArray data, and we provide an analysis workflow that can accommodate either. We propose to apply specialized epigenetic analyses we have developed for both data types in our extensive experience in cancer genome consortia.
In Specific Aim 1, we will develop, improve and implement analytic bioinformatic tools for epigenomic data analysis, including improvements to analysis tools for processing bisulfite sequence data. We will continue the development of analysis tools that use DNA methylation data to analyze tumor heterogeneity and subclonal structure, including the deconstruction of non-malignant cellular composition of the tumor.
In Specific Aim 2, we will provide advanced specialized analysis of cancer epigenomic data generated by the Genome Characterization Center and/or provided through the Data Processing GDAC. Our automated workflow will provide timely primary data analysis for AWGs, and can accommodate both sequence-based or array-based DNA methylation data. This workflow will call differentially methylated regions (DMRs), identify cancer subtypes through stratified cluster analysis, analyze CpH methylation, and analyze tumor purity and subclonal heterogeneity. Performing variant analysis from bisulfite sequence data allows us to determine the impact of non-coding mutations on epigenetic state.
In Specific Aim 3, we will integrate epigenomic data with other genomic, transcriptomic, proteomic, and clinical data to derive biologically and clinically relevant novel insights. Integration of DNA methylation and RNA-Seq data will be used for epigenetic silencing calls and for our custom enhancer identification ELMER pipeline, both of which will feed into pathway and network analyses.
Cancer arises from the loss of control of growth in cells. Although attention has focused mostly on genetic mutations as the origin of these defects, it has become clear that changes in the epigenetic control of gene activity also contribute to this loss of growth control. This project aims to provide specialized and integrated analyses of clinical trial epigenomic data to advance our understanding of how epigenetic defects impact cancer biology and clinical outcome.
| Zhou, Wanding; Dinh, Huy Q; Ramjan, Zachary et al. (2018) DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat Genet 50:591-602 |
| Corces, M Ryan; Granja, Jeffrey M; Shams, Shadi et al. (2018) The chromatin accessibility landscape of primary human cancers. Science 362: |
| Huang, Kuan-Lin; Mashl, R Jay; Wu, Yige et al. (2018) Pathogenic Germline Variants in 10,389 Adult Cancers. Cell 173:355-370.e14 |
| Liu, Yang; Sethi, Nilay S; Hinoue, Toshinori et al. (2018) Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas. Cancer Cell 33:721-735.e8 |
| Zhou, Wanding; Laird, Peter W; Shen, Hui (2017) Comprehensive characterization, annotation and innovative use of Infinium DNA methylation BeadChip probes. Nucleic Acids Res 45:e22 |
