title: Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer.
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.
authors: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: David
authors: D
authors: Brocks
authors: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: Yassen
authors: Y
authors: Assenov
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors: Sarah
authors: S
authors: Minner
authors: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: Olga
authors: O
authors: Bogatyrova
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors: Ronald
authors: R
authors: Simon
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors: Christina
authors: C
authors: Koop
authors: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: Christopher
authors: C
authors: Oakes
authors: Division of Biostatistics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: Manuela
authors: M
authors: Zucknick
authors: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; Department of Hematology and Oncology, University Medical Center, Otto-von-Guericke University, Leipziger Strasse 44, 39120 Magdeburg, Germany.
authors: Daniel Bernhard
authors: DB
authors: Lipka
authors: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany.
authors: Joachim
authors: J
authors: Weischenfeldt
authors: Division of Theoretical Bioinformatics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: Lars
authors: L
authors: Feuerbach
authors: The Princess Margaret Cancer Centre,University Health Network, 610 University Avenue, Toronto, ON M5G 1L7, Canada.
authors: Richard
authors: R
authors: Cowper-Sal Lari
authors: The Princess Margaret Cancer Centre,University Health Network, 610 University Avenue, Toronto, ON M5G 1L7, Canada; Ontario Institute for Cancer Research, 661 University Avenue, Toronto, ON M5G 0A3, Canada; Department of Medical Biophysics, University of Toronto, TMDT, 101 College Street, Toronto, ON M5G 1L7, Canada.
authors: Mathieu
authors: M
authors: Lupien
authors: Division of Theoretical Bioinformatics, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: Benedikt
authors: B
authors: Brors
authors: Genome Biology Unit, European Molecular Biology Laboratory (EMBL), Meyerhofstrasse 1, 69117 Heidelberg, Germany; European Bioinformatics Institute, Wellcome Trust Genome Campus, Hinxton, Cambridge CB10 1SD, UK.
authors: Jan
authors: J
authors: Korbel
authors: Martini-Clinic, Prostate Cancer Center, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany; Department of Urology, Section for Translational Prostate Cancer Research, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors: Thorsten
authors: T
authors: Schlomm
authors: Department of Computer Science and Applied Mathematics and Department of Biological Regulation, Weizmann Institute of Science, Rehovot 76100, Israel.
authors: Amos
authors: A
authors: Tanay
authors: Institute of Pathology, University Medical Center Hamburg-Eppendorf, Martinistrasse 52, 20246 Hamburg, Germany.
authors: Guido
authors: G
authors: Sauter
authors: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany.
authors: Clarissa
authors: C
authors: Gerhäuser
authors: Division of Epigenomics and Cancer Risk Factors, German Cancer Research Center, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany; The German Cancer Consortium, Im Neuenheimer Feld 280, 69120 Heidelberg, Germany. Electronic address: c.plass@dkfz.de.
authors: Christoph
authors: C
authors: Plass
mesh_terms: D000230:Adenocarcinoma / Q000235:genetics* / Q000473:pathology; D060965:Clonal Evolution; D056915:DNA Copy Number Variations; D019175:DNA Methylation; D044127:Epigenesis, Genetic; D018740:Genetic Heterogeneity; D006801:Humans; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology