The DNA methylation landscape of advanced prostate cancer.,Nature Genetics

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The DNA methylation landscape of advanced prostate cancer.
Nature Genetics ( IF 30.8 ) Pub Date : 2020-07-13 , DOI: 10.1038/s41588-020-0648-8
Shuang G Zhao _{1,

2,

3,

4,

5} , William S Chen _{3,

4,

6} , Haolong Li _{3,

4} , Adam Foye _{4,

7} , Meng Zhang _{3,

4} , Martin Sjöström _{3,

4} , Rahul Aggarwal _{4,

7} , Denise Playdle _{4,

7} , Arnold Liao ₈ , Joshi J Alumkal _{9,

10} , Rajdeep Das _{3,

4} , Jonathan Chou _{3,

4,

7} , Junjie T Hua ₁₁ , Travis J Barnard _{3,

4} , Adina M Bailey _{4,

7} , Eric D Chow _{12,

13} , Marc D Perry _{3,

4,

7} , Ha X Dang _{14,

15,

16} , Rendong Yang ₁₇ , Ruhollah Moussavi-Baygi _{3,

4} , Li Zhang _{4,

7} , Mohammed Alshalalfa ₃ , S Laura Chang ₃ , Kathleen E Houlahan _{18,

19,

20} , Yu-Jia Shiah ₁₈ , Tomasz M Beer _{9,

21} , George Thomas _{9,

22} , Kim N Chi _{23,

24} , Martin Gleave ₂₃ , Amina Zoubeidi ₂₃ , Robert E Reiter ₂₅ , Matthew B Rettig _{25,

26} , Owen Witte ₂₇ , M Yvonne Kim ₂₈ , Lawrence Fong _{4,

7} , Daniel E Spratt ₁ , Todd M Morgan _{2,

5,

29} , Rohit Bose _{4,

7,

30,

31} , Franklin W Huang _{4,

7} , Hui Li _{3,

4} , Lisa Chesner _{3,

4} , Tanushree Shenoy _{4,

7} , Hani Goodarzi _{12,

30} , Irfan A Asangani ₃₂ , Shahneen Sandhu ₃₃ , Joshua M Lang ₃₄ , Nupam P Mahajan _{16,

35} , Primo N Lara _{36,

37} , Christopher P Evans _{37,

38} , Phillip Febbo ₈ , Serafim Batzoglou ₈ , Karen E Knudsen ₃₉ , Housheng H He _{11,

19} , Jiaoti Huang ₄₀ , Wilbert Zwart ₄₁ , Joseph F Costello ₂₈ , Jianhua Luo ₄₂ , Scott A Tomlins ₅ , Alexander W Wyatt ₂₃ , Scott M Dehm _{43,

44} , Alan Ashworth _{4,

7} , Luke A Gilbert _{4,

30} , Paul C Boutros _{19,

20,

25} , Kyle Farh ₈ , Arul M Chinnaiyan _{2,

5,

29,

45,

46,

47} , Christopher A Maher _{14,

15,

16,

48} , Eric J Small _{4,

7} , David A Quigley _{4,

30,

49} , Felix Y Feng _{3,

4,

7,

30}

Affiliation

Department of Radiation Oncology, University of Michigan, Ann Arbor, MI, USA.
Rogel Cancer Center, University of Michigan, Ann Arbor, MI, USA.
Department of Radiation Oncology, University of California San Francisco, San Francisco, CA, USA.
Helen Diller Family Comprehensive Cancer Center, University of California San Francisco, San Francisco, CA, USA.
Michigan Center for Translational Pathology, University of Michigan, Ann Arbor, MI, USA.
Yale School of Medicine, New Haven, CT, USA.
Division of Hematology and Oncology, Department of Medicine, University of California San Francisco, San Francisco, CA, USA.
Illumina Inc., San Diego, CA, USA.
Knight Cancer Institute, Oregon Health & Science University, Portland, OR, USA.
Department of Molecular and Medical Genetics, Oregon Health & Science University, Portland, OR, USA.
Princess Margaret Cancer Centre, University Health Network, Toronto, Ontario, Canada.
Department of Biochemistry and Biophysics, University of California San Francisco, San Francisco, CA, USA.
Center for Advanced Technology, University of California San Francisco, San Francisco, CA, USA.
McDonnell Genome Institute, Washington University, St. Louis, MO, USA.
Department of Internal Medicine, Washington University, St. Louis, MO, USA.
Siteman Cancer Center, Washington University, St. Louis, MO, USA.
The Hormel Institute, University of Minnesota, Austin, MN, USA.
Ontario Institute for Cancer Research, Toronto, Ontario, Canada.
Department of Medical Biophysics, University of Toronto, Toronto, Ontario, Canada.
Department of Human Genetics, Institute for Precision Health, UCLA, Los Angeles, CA, USA.
Division of Hematology/Medical Oncology, Department of Medicine, Oregon Health & Science University, Portland, OR, USA.
Department of Pathology, Oregon Health & Science University, Portland, OR, USA.
Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
British Columbia Cancer Agency, Vancouver Centre, Vancouver, British Columbia, Canada.
Jonsson Comprehensive Cancer Center, Departments of Medicine and Urology, University of California Los Angeles, Los Angeles, CA, USA.
Department of Medicine, VA Greater Los Angeles Healthcare System, Los Angeles, CA, USA.
Department of Microbiology, Immunology, and Molecular Genetics at the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, CA, USA.
Department of Neurological Surgery, University of California San Francisco, San Francisco, CA, USA.
Department of Urology, University of Michigan, Ann Arbor, MI, USA.
Department of Urology, University of California San Francisco, San Francisco, CA, USA.
Department of Anatomy, University of California San Francisco, San Francisco, CA, USA.
Department of Cancer Biology, University of Pennsylvania, Philadelphia, PA, USA.
Peter MacCallum Cancer Centre, University of Melbourne, Melbourne, Victoria, Australia.
Department of Medicine, University of Wisconsin, Madison, WI, USA.
Department of Surgery, Washington University, St. Louis, MO, USA.
Division of Hematology Oncology, Department of Internal Medicine, University of California Davis, Sacramento, CA, USA.
Comprehensive Cancer Center, University of California Davis, Sacramento, CA, USA.
Department of Urologic Surgery, University of California Davis, Sacramento, CA, USA.
Department of Cancer Biology, Thomas Jefferson University, Philadelphia, PA, USA.
Department of Pathology, Duke University, Durham, NC, USA.
Netherlands Cancer Institute, Oncode Institute, Amsterdam, the Netherlands.
Department of Pathology, University of Pittsburgh, Pittsburgh, PA, USA.
Masonic Cancer Center, University of Minnesota, Minneapolis, MN, USA.
Department of Laboratory Medicine and Pathology, University of Minnesota, Minneapolis, MN, USA.
Department of Pathology, University of Michigan, Ann Arbor, MI, USA.
Department of Computational Medicine and Bioinformatics, University of Michigan, Ann Arbor, MI, USA.
Howard Hughes Medical Institute, University of Michigan Medical School, Ann Arbor, MI, USA.
Department of Biomedical Engineering, Washington University, St. Louis, MO, USA.
Department of Epidemiology and Biostatistics, University of California San Francisco, San Francisco, CA, USA.

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 in TET2, DNMT3B, IDH1 and BRAF. We also identified intergenic regions where methylation is associated with RNA expression of the oncogenic driver genes AR, MYC and ERG. 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.

中文翻译：

晚期前列腺癌的 DNA 甲基化景观。

尽管 DNA 甲基化是基因表达的关键调节因子，但从未定义过转移性癌症的全面甲基化景观。通过全基因组亚硫酸氢盐测序与深度全基因组和转录组测序对 100 个去势抵抗性前列腺转移瘤进行配对，我们发现了影响驱动基因的改变，这些改变只有通过整合的全基因组方法才能检测到。值得注意的是，我们观察到 22% 的肿瘤表现出与TET2、DNMT3B、IDH1和BRAF中的高甲基化和体细胞突变相关的新型表观基因组亚型。我们还确定了甲基化与致癌驱动基因AR的 RNA 表达相关的基因间区域，MYC和ERG。最后，我们发现进展过程中的差异甲基化优先发生在体细胞突变热点和假定的调节区域。本研究是对转移性癌症中全基因组、全甲基化组和全转录组测序的大型综合研究，全面概述了甲基化在转移性去势抵抗性前列腺癌中的重要调节作用。

更新日期：2020-07-13

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