The DNA methylation landscape of advanced prostate cancer

被引：240

作者：

Zhao, Shuang G. ^{[1
,2
,3
,4
]}

Chen, William S. ^{[3
,4
,6
]}

Li, Haolong ^{[3
,4
]}

Foye, Adam ^{[4
,7
]}

Zhang, Meng ^{[3
,4
]}

Sjostrom, Martin ^{[3
,4
]}

Aggarwal, Rahul ^{[4
,7
]}

Playdle, Denise ^{[4
,7
]}

Liao, Arnold ^{[8
]}

Alumkal, Joshi J. ^{[9
,10
]}

Das, Rajdeep ^{[3
,4
]}

Chou, Jonathan ^{[3
,4
,7
]}

Hua, Junjie T. ^{[11
]}

Barnard, Travis J. ^{[3
,4
]}

Bailey, Adina M. ^{[4
,7
]}

Chow, Eric D. ^{[12
,13
]}

Perry, Marc D. ^{[3
,4
,7
]}

Dang, Ha X. ^{[14
,15
,16
]}

Yang, Rendong ^{[17
]}

Moussavi-Baygi, Ruhollah ^{[3
,4
]}

Zhang, Li ^{[4
,7
]}

Alshalalfa, Mohammed ^{[3
]}

Chang, S. Laura ^{[3
]}

Houlahan, Kathleen E. ^{[18
,19
,20
]}

Shiah, Yu-Jia ^{[18
]}

Beer, Tomasz M. ^{[9
,21
]}

Thomas, George ^{[9
,22
]}

Chi, Kim N. ^{[23
,24
]}

Gleave, Martin ^{[23
]}

Zoubeidi, Amina ^{[23
]}

Reiter, Robert E. ^{[25
]}

Rettig, Matthew B. ^{[25
,26
]}

Witte, Owen ^{[27
]}

Kim, M. Yvonne ^{[28
]}

Fong, Lawrence ^{[4
,7
]}

Spratt, Daniel E. ^{[1
]}

Morgan, Todd M. ^{[2
,5
,29
]}

Bose, Rohit ^{[4
,7
,30
,31
]}

Huang, Franklin W. ^{[4
,7
]}

Li, Hui ^{[3
,4
]}

Chesner, Lisa ^{[3
,4
]}

Shenoy, Tanushree ^{[4
,7
]}

Goodarzi, Hani ^{[12
,30
]}

Asangani, Irfan A. ^{[32
]}

Sandhu, Shahneen ^{[33
]}

Lang, Joshua M. ^{[34
]}

Mahajan, Nupam P. ^{[16
,35
]}

Lara, Primo N. ^{[36
,37
]}

Evans, Christopher P. ^{[37
,38
]}

Febbo, Phillip ^{[8
]}

机构：

[1] Univ Michigan, Dept Radiat Oncol, Ann Arbor, MI 48109 USA

[2] Univ Michigan, Rogel Canc Ctr, Ann Arbor, MI 48109 USA

[3] Univ Calif San Francisco, Dept Radiat Oncol, San Francisco, CA 94143 USA

[4] Univ Calif San Francisco, Helen Diller Family Comprehens Canc Ctr, San Francisco, CA 94143 USA

[5] Univ Michigan, Michigan Ctr Translat Pathol, Ann Arbor, MI 48109 USA

[6] Yale Sch Med, New Haven, CT USA

[7] Univ Calif San Francisco, Dept Med, Div Hematol & Oncol, San Francisco, CA 94143 USA

[8] Illumina Inc, San Diego, CA USA

[9] Oregon Hlth & Sci Univ, Knight Canc Inst, Portland, OR 97201 USA

[10] Oregon Hlth & Sci Univ, Dept Mol & Med Genet, Portland, OR 97201 USA

[11] Univ Hlth Network, Princess Margaret Canc Ctr, Toronto, ON, Canada

[12] Univ Calif San Francisco, Dept Biochem & Biophys, San Francisco, CA USA

[13] Univ Calif San Francisco, Ctr Adv Technol, San Francisco, CA 94143 USA

[14] Washington Univ, McDonnell Genome Inst, St Louis, MO 63110 USA

[15] Washington Univ, Dept Internal Med, St Louis, MO 63110 USA

[16] Washington Univ, Siteman Canc Ctr, St Louis, MO 63110 USA

[17] Univ Minnesota, Hormel Inst, 801 16th Ave NE, Austin, MN 55912 USA

[18] Ontario Inst Canc Res, Toronto, ON, Canada

[19] Univ Toronto, Dept Med Biophys, Toronto, ON, Canada

[20] Univ Calif Los Angeles, Inst Precis Hlth, Dept Human Genet, Los Angeles, CA USA

[21] Oregon Hlth & Sci Univ, Dept Med, Div Hematol Med Oncol, Portland, OR 97201 USA

[22] Oregon Hlth & Sci Univ, Dept Pathol, Portland, OR 97201 USA

[23] Univ British Columbia, Vancouver Prostate Ctr, Dept Urol Sci, Vancouver, BC, Canada

[24] British Columbia Canc Agcy, Vancouver Ctr, Vancouver, BC, Canada

[25] Univ Calif Los Angeles, Jonsson Comprehens Canc Ctr, Dept Med & Urol, Los Angeles, CA 90024 USA

[26] VA Greater Los Angeles Healthcare Syst, Dept Med, Los Angeles, CA USA

[27] Univ Calif Los Angeles, David Geffen Sch Med, Dept Microbiol Immunol & Mol Genet, Los Angeles, CA 90095 USA

[28] Univ Calif San Francisco, Dept Neurol Surg, San Francisco, CA USA

[29] Univ Michigan, Dept Urol, Ann Arbor, MI 48109 USA

[30] Univ Calif San Francisco, Dept Urol, San Francisco, CA 94143 USA

[31] Univ Calif San Francisco, Dept Anat, San Francisco, CA 94143 USA

[32] Univ Penn, Dept Canc Biol, Philadelphia, PA 19104 USA

[33] Univ Melbourne, Peter MacCallum Canc Ctr, Victoria, Australia

[34] Univ Wisconsin, Dept Med, Madison, WI USA

[35] Washington Univ, Dept Surg, St Louis, MO 63110 USA

[36] Univ Calif Davis, Div Hematol Oncol, Dept Internal Med, Sacramento, CA 95817 USA

[37] Univ Calif Davis, Comprehens Canc Ctr, Sacramento, CA 95817 USA

[38] Univ Calif Davis, Dept Urol Surg, Sacramento, CA 95817 USA

[39] Thomas Jefferson Univ, Dept Canc Biol, Philadelphia, PA 19107 USA

[40] Duke Univ, Dept Pathol, Durham, NC 27706 USA

[41] Netherlands Canc Inst, Oncode Inst, Amsterdam, Netherlands

[42] Univ Pittsburgh, Dept Pathol, Pittsburgh, PA USA

[43] Univ Minnesota, Masonic Canc Ctr, Minneapolis, MN USA

[44] Univ Minnesota, Dept Lab Med & Pathol, Minneapolis, MN 55455 USA

[45] Univ Michigan, Dept Pathol, Ann Arbor, MI 48109 USA

[46] Univ Michigan, Dept Computat Med & Bioinformat, Ann Arbor, MI 48109 USA

[47] Univ Michigan, Howard Hughes Med Inst, Med Sch, Ann Arbor, MI 48109 USA

[48] Washington Univ, Dept Biomed Engn, St Louis, MO 63110 USA

[49] Univ Calif San Francisco, Dept Epidemiol & Biostat, San Francisco, CA USA

来源：

NATURE GENETICS | 2020年 / 52卷 / 08期

基金：

瑞典研究理事会; 美国国家卫生研究院;

关键词：

CPG ISLAND HYPERMETHYLATION; TET2; MUTATIONS; ANDROGEN RECEPTOR; TRANSCRIPTION FACTORS; EPIGENOMIC ANALYSIS; CLONAL EVOLUTION; GENE; GENOME; DNMT3A; HYPOMETHYLATION;

D O I：

10.1038/s41588-020-0648-8

中图分类号：

Q3 [遗传学];

学科分类号：

071007 ; 090102 ;

摘要：

Although DNA methylation is a key regulator of gene expression, the comprehensive methylation landscape of metastatic cancer has never been defined. Through whole-genome bisulfite sequencing paired with deep whole-genome and transcriptome sequencing of 100 castration-resistant prostate metastases, we discovered alterations affecting driver genes that were detectable only with integrated whole-genome approaches. Notably, we observed that 22% of tumors exhibited a novel epigenomic subtype associated with hypermethylation and somatic mutations inTET2,DNMT3B,IDH1andBRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genesAR,MYCandERG. Finally, we showed that differential methylation during progression preferentially occurs at somatic mutational hotspots and putative regulatory regions. This study is a large integrated study of whole-genome, whole-methylome and whole-transcriptome sequencing in metastatic cancer that provides a comprehensive overview of the important regulatory role of methylation in metastatic castration-resistant prostate cancer. Whole-genome bisulfite sequencing along with whole-genome and transcriptome sequencing of 100 prostate cancer metastases identifies genomic regions that are differentially methylated during disease progression and a novel epigenomic subtype.

引用

页码：778 / +

页数：14

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