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  • 1
    Abstract: Despite much evidence on epigenetic abnormalities in cancer, it is currently unclear to what extent epigenetic alterations can be associated with tumors' clonal genetic origins. Here, we show that the prostate intratumor heterogeneity in DNA methylation and copy-number patterns can be explained by a unified evolutionary process. By assaying multiple topographically distinct tumor sites, premalignant lesions, and lymph node metastases within five cases of prostate cancer, we demonstrate that both DNA methylation and copy-number heterogeneity consistently reflect the life history of the tumors. Furthermore, we show cases of genetic or epigenetic convergent evolution and highlight the diversity in the evolutionary origins and aberration spectrum between tumor and metastatic subclones. Importantly, DNA methylation can complement genetic data by serving as a proxy for activity at regulatory domains, as we show through identification of high epigenetic heterogeneity at androgen-receptor-bound enhancers. Epigenome variation thereby expands on the current genome-centric view on tumor heterogeneity.
    Type of Publication: Journal article published
    PubMed ID: 25066126
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  • 2
    Publication Date: 2012-04-14
    Description: Cancer is characterized by gene expression aberrations. Studies have largely focused on coding sequences and promoters, even though distal regulatory elements play a central role in controlling transcription patterns. We used the histone mark H3K4me1 to analyze gain and loss of enhancer activity genome-wide in primary colon cancer lines relative to normal colon crypts. We identified thousands of variant enhancer loci (VELs) that comprise a signature that is robustly predictive of the in vivo colon cancer transcriptome. Furthermore, VELs are enriched in haplotype blocks containing colon cancer genetic risk variants, implicating these genomic regions in colon cancer pathogenesis. We propose that reproducible changes in the epigenome at enhancer elements drive a specific transcriptional program to promote colon carcinogenesis.〈br /〉〈br /〉〈a href="" target="_blank"〉〈img src="" border="0"〉〈/a〉   〈a href="" target="_blank"〉This paper as free author manuscript - peer-reviewed and accepted for publication〈/a〉〈br /〉〈br /〉〈span class="detail_caption"〉Notes: 〈/span〉Akhtar-Zaidi, Batool -- Cowper-Sal-lari, Richard -- Corradin, Olivia -- Saiakhova, Alina -- Bartels, Cynthia F -- Balasubramanian, Dheepa -- Myeroff, Lois -- Lutterbaugh, James -- Jarrar, Awad -- Kalady, Matthew F -- Willis, Joseph -- Moore, Jason H -- Tesar, Paul J -- Laframboise, Thomas -- Markowitz, Sanford -- Lupien, Mathieu -- Scacheri, Peter C -- 1P50CA150964/CA/NCI NIH HHS/ -- 5T32GM008056-29/GM/NIGMS NIH HHS/ -- P20 GM103534/GM/NIGMS NIH HHS/ -- P50 CA150964/CA/NCI NIH HHS/ -- R01 CA155004/CA/NCI NIH HHS/ -- R01 CA160356/CA/NCI NIH HHS/ -- R01 LM009012/LM/NLM NIH HHS/ -- R01 LM010098/LM/NLM NIH HHS/ -- R01-LM009012/LM/NLM NIH HHS/ -- R01-LM010098/LM/NLM NIH HHS/ -- R01CA1555004/CA/NCI NIH HHS/ -- R01CA160356/CA/NCI NIH HHS/ -- R01HD056369/HD/NICHD NIH HHS/ -- U01 CA152756/CA/NCI NIH HHS/ -- UL1 RR024989/RR/NCRR NIH HHS/ -- Howard Hughes Medical Institute/ -- New York, N.Y. -- Science. 2012 May 11;336(6082):736-9. doi: 10.1126/science.1217277. Epub 2012 Apr 12.〈br /〉〈span class="detail_caption"〉Author address: 〈/span〉Department of Genetics and Genome Sciences, Case Western Reserve University, Cleveland, OH 44106, USA.〈br /〉〈span class="detail_caption"〉Record origin:〈/span〉 〈a href="" target="_blank"〉PubMed〈/a〉
    Keywords: Cell Line, Tumor ; Chromatin Immunoprecipitation ; Colon/metabolism ; Colonic Neoplasms/*genetics/metabolism ; *Enhancer Elements, Genetic ; *Epigenesis, Genetic ; Gene Expression Profiling ; Gene Expression Regulation, Neoplastic ; Genes, Neoplasm ; Genetic Loci ; Histones/*metabolism ; Humans ; Intestinal Mucosa/metabolism ; Methylation ; Polymorphism, Single Nucleotide ; Promoter Regions, Genetic ; *Transcriptome
    Print ISSN: 0036-8075
    Electronic ISSN: 1095-9203
    Topics: Biology , Chemistry and Pharmacology , Computer Science , Medicine , Natural Sciences in General , Physics
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