Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer

David Brocks; Yassen Assenov; Sarah Minner; Olga Bogatyrova; Ronald Simon; Christina Koop; Christopher Oakes; Manuela Zucknick; Daniel Bernhard Lipka; Joachim Weischenfeldt; Lars Feuerbach; Richard Cowper-Sal Lari; Mathieu Lupien; Benedikt Brors; Jan Korbel; Thorsten Schlomm; Amos Tanay; Guido Sauter; Clarissa Gerhäuser; Christoph Plass; ICGC Early Onset Prostate Cancer Project

doi:10.1016/j.celrep.2014.06.053

Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer

David Brocks, Yassen Assenov, Sarah Minner, Olga Bogatyrova, Ronald Simon, Christina Koop, Christopher Oakes, Manuela Zucknick, Daniel Bernhard Lipka, Joachim Weischenfeldt, Lars Feuerbach, Richard Cowper-Sal Lari, Mathieu Lupien, Benedikt Brors, Jan Korbel, Thorsten Schlomm, Amos Tanay, Guido Sauter, Clarissa Gerhäuser, Christoph PlassICGC Early Onset Prostate Cancer Project

153 Citations (Scopus)

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.

Original language	English
Journal	Cell Reports
Volume	8
Issue number	3
Pages (from-to)	798-806
Number of pages	9
ISSN	2211-1247
DOIs	https://doi.org/10.1016/j.celrep.2014.06.053
Publication status	Published - 7 Aug 2014
Externally published	Yes

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Brocks, D., Assenov, Y., Minner, S., Bogatyrova, O., Simon, R., Koop, C., Oakes, C., Zucknick, M., Lipka, D. B., Weischenfeldt, J., Feuerbach, L., Cowper-Sal Lari, R., Lupien, M., Brors, B., Korbel, J., Schlomm, T., Tanay, A., Sauter, G., Gerhäuser, C., ... ICGC Early Onset Prostate Cancer Project (2014). Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Reports, 8(3), 798-806. https://doi.org/10.1016/j.celrep.2014.06.053

Brocks, D, Assenov, Y, Minner, S, Bogatyrova, O, Simon, R, Koop, C, Oakes, C, Zucknick, M, Lipka, DB, Weischenfeldt, J, Feuerbach, L, Cowper-Sal Lari, R, Lupien, M, Brors, B, Korbel, J, Schlomm, T, Tanay, A, Sauter, G, Gerhäuser, C, Plass, C & ICGC Early Onset Prostate Cancer Project 2014, 'Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer', Cell Reports, vol. 8, no. 3, pp. 798-806. https://doi.org/10.1016/j.celrep.2014.06.053

@article{e39f999ca3c44334bf428b46bf28daf9,

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.",

keywords = "Adenocarcinoma, Clonal Evolution, DNA Copy Number Variations, DNA Methylation, Epigenesis, Genetic, Genetic Heterogeneity, Humans, Lymphatic Metastasis, Male, Middle Aged, Prostatic Neoplasms",

author = "David Brocks and Yassen Assenov and Sarah Minner and Olga Bogatyrova and Ronald Simon and Christina Koop and Christopher Oakes and Manuela Zucknick and Lipka, {Daniel Bernhard} and Joachim Weischenfeldt and Lars Feuerbach and {Cowper-Sal Lari}, Richard and Mathieu Lupien and Benedikt Brors and Jan Korbel and Thorsten Schlomm and Amos Tanay and Guido Sauter and Clarissa Gerh{\"a}user and Christoph Plass and {ICGC Early Onset Prostate Cancer Project}",

year = "2014",

month = aug,

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doi = "10.1016/j.celrep.2014.06.053",

language = "English",

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pages = "798--806",

journal = "Cell Reports",

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T1 - Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer

AU - Brocks, David

AU - Assenov, Yassen

AU - Minner, Sarah

AU - Bogatyrova, Olga

AU - Simon, Ronald

AU - Koop, Christina

AU - Oakes, Christopher

AU - Zucknick, Manuela

AU - Lipka, Daniel Bernhard

AU - Weischenfeldt, Joachim

AU - Feuerbach, Lars

AU - Cowper-Sal Lari, Richard

AU - Lupien, Mathieu

AU - Brors, Benedikt

AU - Korbel, Jan

AU - Schlomm, Thorsten

AU - Tanay, Amos

AU - Sauter, Guido

AU - Gerhäuser, Clarissa

AU - Plass, Christoph

AU - ICGC Early Onset Prostate Cancer Project

PY - 2014/8/7

Y1 - 2014/8/7

N2 - 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.

AB - 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.

KW - Adenocarcinoma

KW - Clonal Evolution

KW - DNA Copy Number Variations

KW - DNA Methylation

KW - Epigenesis, Genetic

KW - Genetic Heterogeneity

KW - Humans

KW - Lymphatic Metastasis

KW - Male

KW - Middle Aged

KW - Prostatic Neoplasms

U2 - 10.1016/j.celrep.2014.06.053

DO - 10.1016/j.celrep.2014.06.053

M3 - Journal article

C2 - 25066126

SN - 2211-1247

VL - 8

SP - 798

EP - 806

JO - Cell Reports

JF - Cell Reports

IS - 3

ER -

Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer

Abstract

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