Intratumor DNA Methylation Heterogeneity Reflects Clonal Evolution in Aggressive Prostate Cancer

被引：230

作者：

Brocks, David ^{[1
]}

Assenov, Yassen ^{[1
]}

Minner, Sarah ^{[2
]}

Bogatyrova, Olga ^{[1
]}

Simon, Ronald ^{[2
]}

Koop, Christina ^{[2
]}

Oakes, Christopher ^{[1
]}

Zucknick, Manuela ^{[3
]}

Lipka, Daniel Bernhard ^{[1
,4
]}

Weischenfeldt, Joachim ^{[5
]}

Feuerbach, Lars ^{[6
]}

Lari, Richard Cowper-Sal ^{[7
]}

Lupien, Mathieu ^{[7
,8
,9
]}

Brors, Benedikt ^{[6
]}

Korbel, Jan ^{[5
,10
]}

Schlomm, Thorsten ^{[11
,12
]}

Tanay, Amos ^{[13
,14
]}

Sauter, Guido ^{[2
]}

Gerhaeuser, Clarissa ^{[1
]}

Plass, Christoph ^{[1
,15
]}

机构：

[1] German Canc Res Ctr, Div Epigen & Canc Risk Factors, D-69120 Heidelberg, Germany

[2] Univ Med Ctr Hamburg Eppendorf, Inst Pathol, D-20246 Hamburg, Germany

[3] German Canc Res Ctr, Div Biostat, D-69120 Heidelberg, Germany

[4] Univ Med Ctr, Dept Hematol & Oncol, D-39120 Magdeburg, Germany

[5] European Mol Biol Lab, Genome Biol Unit, D-69117 Heidelberg, Germany

[6] German Canc Res Ctr, Div Theoret Bioinformat, D-69120 Heidelberg, Germany

[7] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON M5G 1L7, Canada

[8] Ontario Inst Canc Res, Toronto, ON M5G 0A3, Canada

[9] Univ Toronto, TMDT, Dept Med Biophys, Toronto, ON M5G 1L7, Canada

[10] European Bioinformat Inst, Cambridge CB10 1SD, England

[11] Univ Med Ctr Hamburg Eppendorf, Prostate Canc Ctr, Martini Clin, D-20246 Hamburg, Germany

[12] Univ Med Ctr Hamburg Eppendorf, Dept Urol, Sect Translat Prostate Canc Res, D-20246 Hamburg, Germany

[13] Weizmann Inst Sci, Dept Comp Sci & Appl Math, IL-76100 Rehovot, Israel

[14] Weizmann Inst Sci, Dept Regulat Biol, IL-76100 Rehovot, Israel

[15] German Canc Consortium, D-69120 Heidelberg, Germany

来源：

CELL REPORTS | 2014年 / 8卷 / 03期

关键词：

CHRONIC LYMPHOCYTIC-LEUKEMIA; ANDROGEN RECEPTOR; TUMOR EVOLUTION; REVEALS; MUTATIONS; GLIOBLASTOMA; CHEMOTHERAPY; THERAPY; DENSITY;

D O I：

10.1016/j.celrep.2014.06.053

中图分类号：

Q2 [细胞生物学];

学科分类号：

071013 [干细胞生物学];

摘要：

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.

引用

页码：798 / 806

页数：9

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