The DNA methylation landscape of advanced prostate cancer

Shuang G. Zhao; William S. Chen; Haolong Li; Adam Foye; Meng Zhang; Martin Sjöström; Rahul Aggarwal; Denise Playdle; Arnold Liao; Joshi J. Alumkal; Rajdeep Das; Jonathan Chou; Junjie T. Hua; Travis J. Barnard; Adina M. Bailey; Eric D. Chow; Marc D. Perry; Ha X. Dang; Rendong Yang; Ruhollah Moussavi-Baygi; Li Zhang; Mohammed Alshalalfa; S. Laura Chang; Kathleen E. Houlahan; Yu Jia Shiah; Tomasz M. Beer; George Thomas; Kim N. Chi; Martin Gleave; Amina Zoubeidi; Robert E. Reiter; Matthew B. Rettig; Owen Witte; M. Yvonne Kim; Lawrence Fong; Daniel E. Spratt; Todd M. Morgan; Rohit Bose; Franklin W. Huang; Hui Li; Lisa Chesner; Tanushree Shenoy; Hani Goodarzi; Irfan A. Asangani; Shahneen Sandhu; Joshua M. Lang; Nupam P. Mahajan; Primo N. Lara; Christopher P. Evans; Phillip Febbo; Serafim Batzoglou; Karen E. Knudsen; Housheng H. He; Jiaoti Huang; Wilbert Zwart; Joseph F. Costello; Jianhua Luo; Scott A. Tomlins; Alexander W. Wyatt; Scott M. Dehm; Alan Ashworth; Luke A. Gilbert; Paul C. Boutros; Kyle Farh; Arul M. Chinnaiyan; Christopher A. Maher; Eric J. Small; David A. Quigley; Felix Y. Feng

doi:10.1038/s41588-020-0648-8

The DNA methylation landscape of advanced prostate cancer

Shuang G. Zhao, William S. Chen, Haolong Li, Adam Foye, Meng Zhang, Martin Sjöström, Rahul Aggarwal, Denise Playdle, Arnold Liao, Joshi J. Alumkal, Rajdeep Das, Jonathan Chou, Junjie T. Hua, Travis J. Barnard, Adina M. Bailey, Eric D. Chow, Marc D. Perry, Ha X. Dang, Rendong Yang, Ruhollah Moussavi-BaygiLi Zhang, Mohammed Alshalalfa, S. Laura Chang, Kathleen E. Houlahan, Yu Jia Shiah, Tomasz M. Beer, George Thomas, Kim N. Chi, Martin Gleave, Amina Zoubeidi, Robert E. Reiter, Matthew B. Rettig, Owen Witte, M. Yvonne Kim, Lawrence Fong, Daniel E. Spratt, Todd M. Morgan, Rohit Bose, Franklin W. Huang, Hui Li, Lisa Chesner, Tanushree Shenoy, Hani Goodarzi, Irfan A. Asangani, Shahneen Sandhu, Joshua M. Lang, Nupam P. Mahajan, Primo N. Lara, Christopher P. Evans, Phillip Febbo, Serafim Batzoglou, Karen E. Knudsen, Housheng H. He, Jiaoti Huang, Wilbert Zwart, Joseph F. Costello, Jianhua Luo, Scott A. Tomlins, Alexander W. Wyatt, Scott M. Dehm, Alan Ashworth, Luke A. Gilbert, Paul C. Boutros, Kyle Farh, Arul M. Chinnaiyan, Christopher A. Maher, Eric J. Small, David A. Quigley, Felix Y. Feng

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Abstract

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.

Original language	English (US)
Pages (from-to)	778-789
Number of pages	12
Journal	Nature Genetics
Volume	52
Issue number	8
DOIs	https://doi.org/10.1038/s41588-020-0648-8
State	Published - Aug 1 2020

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Publisher Copyright:
© 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.

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Zhao, S. G., Chen, W. S., Li, H., Foye, A., Zhang, M., Sjöström, M., Aggarwal, R., Playdle, D., Liao, A., Alumkal, J. J., Das, R., Chou, J., Hua, J. T., Barnard, T. J., Bailey, A. M., Chow, E. D., Perry, M. D., Dang, H. X., Yang, R., ... Feng, F. Y. (2020). The DNA methylation landscape of advanced prostate cancer. Nature Genetics, 52(8), 778-789. https://doi.org/10.1038/s41588-020-0648-8

Zhao, SG, Chen, WS, Li, H, Foye, A, Zhang, M, Sjöström, M, Aggarwal, R, Playdle, D, Liao, A, Alumkal, JJ, Das, R, Chou, J, Hua, JT, Barnard, TJ, Bailey, AM, Chow, ED, Perry, MD, Dang, HX, Yang, R, Moussavi-Baygi, R, Zhang, L, Alshalalfa, M, Laura Chang, S, Houlahan, KE, Shiah, YJ, Beer, TM, Thomas, G, Chi, KN, Gleave, M, Zoubeidi, A, Reiter, RE, Rettig, MB, Witte, O, Yvonne Kim, M, Fong, L, Spratt, DE, Morgan, TM, Bose, R, Huang, FW, Li, H, Chesner, L, Shenoy, T, Goodarzi, H, Asangani, IA, Sandhu, S, Lang, JM, Mahajan, NP, Lara, PN, Evans, CP, Febbo, P, Batzoglou, S, Knudsen, KE, He, HH, Huang, J, Zwart, W, Costello, JF, Luo, J, Tomlins, SA, Wyatt, AW, Dehm, SM, Ashworth, A, Gilbert, LA, Boutros, PC, Farh, K, Chinnaiyan, AM, Maher, CA, Small, EJ, Quigley, DA & Feng, FY 2020, 'The DNA methylation landscape of advanced prostate cancer', Nature Genetics, vol. 52, no. 8, pp. 778-789. https://doi.org/10.1038/s41588-020-0648-8

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title = "The DNA methylation landscape of advanced prostate cancer",

abstract = "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.",

author = "Zhao, {Shuang G.} and Chen, {William S.} and Haolong Li and Adam Foye and Meng Zhang and Martin Sj{\"o}str{\"o}m and Rahul Aggarwal and Denise Playdle and Arnold Liao and Alumkal, {Joshi J.} and Rajdeep Das and Jonathan Chou and Hua, {Junjie T.} and Barnard, {Travis J.} and Bailey, {Adina M.} and Chow, {Eric D.} and Perry, {Marc D.} and Dang, {Ha X.} and Rendong Yang and Ruhollah Moussavi-Baygi and Li Zhang and Mohammed Alshalalfa and {Laura Chang}, S. and Houlahan, {Kathleen E.} and Shiah, {Yu Jia} and Beer, {Tomasz M.} and George Thomas and Chi, {Kim N.} and Martin Gleave and Amina Zoubeidi and Reiter, {Robert E.} and Rettig, {Matthew B.} and Owen Witte and {Yvonne Kim}, M. and Lawrence Fong and Spratt, {Daniel E.} and Morgan, {Todd M.} and Rohit Bose and Huang, {Franklin W.} and Hui Li and Lisa Chesner and Tanushree Shenoy and Hani Goodarzi and Asangani, {Irfan A.} and Shahneen Sandhu and Lang, {Joshua M.} and Mahajan, {Nupam P.} and Lara, {Primo N.} and Evans, {Christopher P.} and Phillip Febbo and Serafim Batzoglou and Knudsen, {Karen E.} and He, {Housheng H.} and Jiaoti Huang and Wilbert Zwart and Costello, {Joseph F.} and Jianhua Luo and Tomlins, {Scott A.} and Wyatt, {Alexander W.} and Dehm, {Scott M.} and Alan Ashworth and Gilbert, {Luke A.} and Boutros, {Paul C.} and Kyle Farh and Chinnaiyan, {Arul M.} and Maher, {Christopher A.} and Small, {Eric J.} and Quigley, {David A.} and Feng, {Felix Y.}",

note = "Publisher Copyright: {\textcopyright} 2020, The Author(s), under exclusive licence to Springer Nature America, Inc.",

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AU - Foye, Adam

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AU - Sjöström, Martin

AU - Aggarwal, Rahul

AU - Playdle, Denise

AU - Liao, Arnold

AU - Alumkal, Joshi J.

AU - Das, Rajdeep

AU - Chou, Jonathan

AU - Hua, Junjie T.

AU - Barnard, Travis J.

AU - Bailey, Adina M.

AU - Chow, Eric D.

AU - Perry, Marc D.

AU - Dang, Ha X.

AU - Yang, Rendong

AU - Moussavi-Baygi, Ruhollah

AU - Zhang, Li

AU - Alshalalfa, Mohammed

AU - Laura Chang, S.

AU - Houlahan, Kathleen E.

AU - Shiah, Yu Jia

AU - Beer, Tomasz M.

AU - Thomas, George

AU - Chi, Kim N.

AU - Gleave, Martin

AU - Zoubeidi, Amina

AU - Reiter, Robert E.

AU - Rettig, Matthew B.

AU - Witte, Owen

AU - Yvonne Kim, M.

AU - Fong, Lawrence

AU - Spratt, Daniel E.

AU - Morgan, Todd M.

AU - Bose, Rohit

AU - Huang, Franklin W.

AU - Li, Hui

AU - Chesner, Lisa

AU - Shenoy, Tanushree

AU - Goodarzi, Hani

AU - Asangani, Irfan A.

AU - Sandhu, Shahneen

AU - Lang, Joshua M.

AU - Mahajan, Nupam P.

AU - Lara, Primo N.

AU - Evans, Christopher P.

AU - Febbo, Phillip

AU - Batzoglou, Serafim

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AU - He, Housheng H.

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AU - Wyatt, Alexander W.

AU - Dehm, Scott M.

AU - Ashworth, Alan

AU - Gilbert, Luke A.

AU - Boutros, Paul C.

AU - Farh, Kyle

AU - Chinnaiyan, Arul M.

AU - Maher, Christopher A.

AU - Small, Eric J.

AU - Quigley, David A.

AU - Feng, Felix Y.

PY - 2020/8/1

Y1 - 2020/8/1

N2 - 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.

AB - 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.

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The DNA methylation landscape of advanced prostate cancer

Abstract

Bibliographical note

UN SDGs

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