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Project 2
Integrating Genomic and Epigenomic Alterations in Cancer and its Microenvironment

Human cancer genetic studies over the last 20 years have clearly demonstrated that genetic defects, including intragenic mutations, deletions and rearrangements, contribute to carcinogenesis. Similarly, it is now clear that epigenetic defects, such as aberrant DNA methylation of promoter sequences, also contribute to human tumorigenesis. It is well documented that DNA methylation events are frequently involved in transcriptional changes in both tumor suppressor genes and oncogenes. Moreover, recent data demonstrate that in addition to DNA methylation, chromatin modifications are also involved in gene regulation. We are now beginning to understand this interesting interplay between chromatin modifications, DNA methylation and gene regulation. The technological knowledge for genome-wide views of gene expression profiles, copy number alterations, DNA modifications and protein localization and levels are all currently possible. However, we are still currently limited to cataloguing activities. Indeed, it will be a tremendous challenge to develop computational approaches that can integrate these different global overviews of the genome in health and disease. Thus, much still needs to be done before we understand how genetic and epigenetic modifications interact to initiate and promote neoplasia, even more so in the context of epithelial-stromal interactions. Using a 381-microsatellite marker loss-of-heterozygosity (LOH) scan in 135 distinct sporadic invasive breast cancers, we have identified 19 key loci on 15 chromosomes with significant LOH in the epithelium and 38 key loci on 19 chromosomes with significant LOH in the stroma (chromosome-wise modeling). We therefore initially hypothesize that these regions which when loss would play a role in breast cancer progression; we also hypothesize that these regions act as signposts for genes which when epigenetically modified which together with structural loss play some role in breast cancer progression as germane to epithelial-stromal interactions. If our data to date are correct, then we may also postulate that the stroma will have a multiplicity of genetic and epigenetic targets. What we do not know is when these genetic and epigenetic alterations occur and interact in epithelium and stroma to result in progression. Unlike gene expression, both genetic and epigenetic modification can stably pass from progenitor cells to progeny cells. In other words, they are "molecular relics" heritable at the cellular level and thus, more amenable for use as a biomarker. In this project bringing together experimental and computational scientists, we take advantage of the heritability hallmark to dissect and integrate the epigenetic and genetic pathways related to progression in the epithelium and surrounding stroma of sporadic breast carcinomas. We are developing a heritable clustering algorithm that features an entropy selection criterion for selecting meaningful progression models that will reflect integration of both genetic and epigenetic alterations as they relate to progression. Subsequently, as a natural extension, we propose developing a network-type model to "3-dimensionally" integrate genetic and epigenetic alterations in neoplastic epithelium and surrounding stroma germane to progression in sporadic breast cancer.


The Ohio State University:

Shili Lin, Principle Investigator
Pearlly Yan, Co-Investigator
Abbas Khalili, Postdoctoral Fellow
Alfred Cheng, Postdoctoral Fellow

Cleveland Clinic:
Charis Eng, Principle Investigator
Frank Weber, Postdoctoral Fellow
Glen Lobo, Rsearch Associate
Christina Gaughan, Senior Research Technologist

Relevant Publications: