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.
This is a preview of subscription content, access via your institution
Access options
Access Nature and 54 other Nature Portfolio journals
Get Nature+, our best-value online-access subscription
$29.99 / 30 days
cancel any time
Subscribe to this journal
Receive 12 print issues and online access
$209.00 per year
only $17.42 per issue
Buy this article
- Purchase on Springer Link
- Instant access to full article PDF
Prices may be subject to local taxes which are calculated during checkout
Similar content being viewed by others
Code availability
All code used in the manuscript is available at https://github.com/DavidQuigley/WCDT_WGBS.
References
Jones, P. A. & Baylin, S. B. The fundamental role of epigenetic events in cancer. Nat. Rev. Genet. 3, 415–428 (2002).
Feinberg, A. P., Koldobskiy, M. A. & Gondor, A. Epigenetic modulators, modifiers and mediators in cancer aetiology and progression. Nat. Rev. Genet. 17, 284–299 (2016).
Okano, M., Bell, D. W., Haber, D. A. & Li, E. DNA methyltransferases Dnmt3a and Dnmt3b are essential for de novo methylation and mammalian development. Cell 99, 247–257 (1999).
Rechache, N. S. et al. DNA methylation profiling identifies global methylation differences and markers of adrenocortical tumors. J. Clin. Endocrinol. Metab. 97, E1004–E1013 (2012).
Skvortsova, K. et al. DNA hypermethylation encroachment at CpG island borders in cancer is predisposed by H3K4 monomethylation patterns. Cancer Cell 35, 297–314.e8 (2019).
Saghafinia, S., Mina, M., Riggi, N., Hanahan, D. & Ciriello, G. Pan-cancer landscape of aberrant DNA methylation across human tumors. Cell Rep. 25, 1066–1080.e8 (2018).
Kobayashi, Y. et al. DNA methylation profiling reveals novel biomarkers and important roles for DNA methyltransferases in prostate cancer. Genome Res. 21, 1017–1027 (2011).
Kim, J. H. et al. Deep sequencing reveals distinct patterns of DNA methylation in prostate cancer. Genome Res. 21, 1028–1041 (2011).
Maruyama, R. et al. Aberrant promoter methylation profile of prostate cancers and its relationship to clinicopathological features. Clin. Cancer Res. 8, 514–519 (2002).
Bhasin, J. M. et al. Methylome-wide sequencing detects DNA hypermethylation distinguishing indolent from aggressive prostate Cancer. Cell Rep. 13, 2135–2146 (2015).
Yu, Y. P. et al. Whole-genome methylation sequencing reveals distinct impact of differential methylations on gene transcription in prostate cancer. Am. J. Pathol. 183, 1960–1970 (2013).
Cancer Genome Atlas Research Network The molecular taxonomy of primary prostate cancer. Cell 163, 1011–1025 (2015).
Borno, S. T. et al. Genome-wide DNA methylation events in TMPRSS2–ERG fusion-negative prostate cancers implicate an EZH2-dependent mechanism with miR-26a hypermethylation. Cancer Discov. 2, 1024–1035 (2012).
Gerhauser, C. et al. Molecular evolution of early-onset prostate cancer identifies molecular risk markers and clinical trajectories. Cancer Cell 34, 996–1011.e8 (2018).
Yegnasubramanian, S. et al. Hypermethylation of CpG islands in primary and metastatic human prostate cancer. Cancer Res. 64, 1975–1986 (2004).
Robinson, D. et al. Integrative clinical genomics of advanced prostate cancer. Cell 161, 1215–1228 (2015).
Quigley, D. A. et al. Genomic hallmarks and structural variation in metastatic prostate. Cell 174, 758–769.e9 (2018).
Viswanathan, S. R. et al. Structural alterations driving castration-resistant prostate cancer revealed by linked-read genome sequencing. Cell 174, 433–447.e19 (2018).
Fraser, M. et al. Genomic hallmarks of localized, non-indolent prostate cancer. Nature 541, 359–364 (2017).
Beltran, H. et al. Divergent clonal evolution of castration-resistant neuroendocrine prostate cancer. Nat. Med. 22, 298–305 (2016).
Aryee, M. J. et al. DNA methylation alterations exhibit intraindividual stability and interindividual heterogeneity in prostate cancer metastases. Sci. Transl. Med. 5, 169ra10 (2013).
Hama, N. et al. Epigenetic landscape influences the liver cancer genome architecture. Nat. Commun. 9, 1643 (2018).
Kretzmer, H. et al. DNA methylome analysis in Burkitt and follicular lymphomas identifies differentially methylated regions linked to somatic mutation and transcriptional control. Nat. Genet. 47, 1316–1325 (2015).
Kulis, M. et al. Epigenomic analysis detects widespread gene-body DNA hypomethylation in chronic lymphocytic leukemia. Nat. Genet. 44, 1236–1242 (2012).
Berman, B. P. et al. Regions of focal DNA hypermethylation and long-range hypomethylation in colorectal cancer coincide with nuclear lamina-associated domains. Nat. Genet. 44, 40–46 (2011).
Klughammer, J. et al. The DNA methylation landscape of glioblastoma disease progression shows extensive heterogeneity in time and space. Nat. Med. 24, 1611–1624 (2018).
Queiros, A. C. et al. Decoding the DNA methylome of mantle cell lymphoma in the light of the entire B cell lineage. Cancer Cell 30, 806–821 (2016).
Hovestadt, V. et al. Decoding the regulatory landscape of medulloblastoma using DNA methylation sequencing. Nature 510, 537–541 (2014).
McDonald, O. G. et al. Epigenomic reprogramming during pancreatic cancer progression links anabolic glucose metabolism to distant metastasis. Nat. Genet. 49, 367–376 (2017).
Chun, H. E. et al. Genome-wide profiles of extra-cranial malignant rhabdoid tumors reveal heterogeneity and dysregulated developmental pathways. Cancer Cell 29, 394–406 (2016).
Spencer, D. H. et al. CpG island hypermethylation mediated by DNMT3A is a consequence of AML progression. Cell 168, 801–816.e13 (2017).
Hughes, L. A. et al. The CpG island methylator phenotype: what’s in a name? Cancer Res. 73, 5858–5868 (2013).
Takeda, D. Y. et al. A somatically acquired enhancer of the androgen receptor is a noncoding driver in advanced prostate cancer. Cancer Cell 174, 422–432.e13 (2018).
Kron, K. J. et al. TMPRSS2–ERG fusion co-opts master transcription factors and activates NOTCH signaling in primary prostate cancer. Nat. Genet. 49, 1336–1345 (2017).
Stelloo, S. et al. Integrative epigenetic taxonomy of primary prostate cancer. Nat. Commun. 9, 4900 (2018).
Sharma, N. L. et al. The androgen receptor induces a distinct transcriptional program in castration-resistant prostate cancer in man. Cancer Cell 23, 35–47 (2013).
Pomerantz, M. M. et al. The androgen receptor cistrome is extensively reprogrammed in human prostate tumorigenesis. Nat. Genet. 47, 1346–1351 (2015).
Yu, J. et al. An integrated network of androgen receptor, polycomb, and TMPRSS2–ERG gene fusions in prostate cancer progression. Cancer Cell 17, 443–454 (2010).
Zhang, Z. et al. An AR-ERG transcriptional signature defined by long-range chromatin interactomes in prostate cancer cells. Genome Res. 29, 223–235 (2019).
Sun, W. et al. The association between copy number aberration, DNA methylation and gene expression in tumor samples. Nucleic Acids Res. 46, 3009–3018 (2018).
Gardiner-Garden, M. & Frommer, M. CpG islands in vertebrate genomes. J. Mol. Biol. 196, 261–282 (1987).
Saxonov, S., Berg, P. & Brutlag, D. L. A genome-wide analysis of CpG dinucleotides in the human genome distinguishes two distinct classes of promoters. Proc. Natl Acad. Sci. USA 103, 1412–1417 (2006).
Ioshikhes, I. P. & Zhang, M. Q. Large-scale human promoter mapping using CpG islands. Nat. Genet. 26, 61–63 (2000).
Aggarwal, R. R. et al. Whole-genome and transcriptional analysis of treatment-emergent small-cell neuroendocrine prostate cancer demonstrates intraclass heterogeneity. Mol. Cancer Res. 17, 1235–1240 (2019).
Aggarwal, R. et al. Clinical and genomic characterization of treatment-emergent small-cell neuroendocrine prostate cancer: a multi-institutional prospective study. J. Clin. Oncol. 36, 2492–2503 (2018).
Hennig, C. Cluster-wise assessment of cluster stability. Comput. Stat. Data Anal. 52, 258–271 (2007).
Weisenberger, D. J. et al. CpG island methylator phenotype underlies sporadic microsatellite instability and is tightly associated with BRAF mutation in colorectal cancer. Nat. Genet. 38, 787–793 (2006).
Figueroa, M. E. et al. Leukemic IDH1 and IDH2 mutations result in a hypermethylation phenotype, disrupt TET2 function, and impair hematopoietic differentiation. Cancer Cell 18, 553–567 (2010).
Buscarlet, M. et al. DNMT3A and TET2 dominate clonal hematopoiesis and demonstrate benign phenotypes and different genetic predispositions. Blood 130, 753–762 (2017).
Delhommeau, F. et al. Mutation in TET2 in myeloid cancers. N. Engl. J. Med 360, 2289–2301 (2009).
Langemeijer, S. M. et al. Acquired mutations in TET2 are common in myelodysplastic syndromes. Nat. Genet. 41, 838–842 (2009).
Dong, C. et al. Comparison and integration of deleteriousness prediction methods for nonsynonymous SNVs in whole exome sequencing studies. Hum. Mol. Genet. 24, 2125–2137 (2015).
Wong, T. N. et al. Cellular stressors contribute to the expansion of hematopoietic clones of varying leukemic potential. Nat. Commun. 9, 455 (2018).
Odejide, O. et al. A targeted mutational landscape of angioimmunoblastic T-cell lymphoma. Blood 123, 1293–1296 (2014).
Coolen, M. W. et al. Consolidation of the cancer genome into domains of repressive chromatin by long-range epigenetic silencing (LRES) reduces transcriptional plasticity. Nat. Cell Biol. 12, 235–246 (2010).
Bert, S. A. et al. Regional activation of the cancer genome by long-range epigenetic remodeling. Cancer Cell 23, 9–22 (2013).
Zhou, W. et al. DNA methylation loss in late-replicating domains is linked to mitotic cell division. Nat. Genet. 50, 591–602 (2018).
Brinkman, A. B. et al. Partially methylated domains are hypervariable in breast cancer and fuel widespread CpG island hypermethylation. Nat. Commun. 10, 1749 (2019).
Xie, W. et al. Epigenomic analysis of multilineage differentiation of human embryonic stem cells. Cell 153, 1134–1148 (2013).
Jeong, M. et al. Large conserved domains of low DNA methylation maintained by Dnmt3a. Nat. Genet. 46, 17–23 (2014).
Li, Y. et al. Genome-wide analyses reveal a role of Polycomb in promoting hypomethylation of DNA methylation valleys. Genome Biol. 19, 18 (2018).
Kumar, A. et al. Substantial interindividual and limited intraindividual genomic diversity among tumors from men with metastatic prostate cancer. Nat. Med. 22, 369–378 (2016).
Mu, P. et al. SOX2 promotes lineage plasticity and antiandrogen resistance in TP53- and RB1-deficient prostate cancer. Science 355, 84–88 (2017).
Beltran, H. et al. The role of lineage plasticity in prostate cancer therapy resistance. Clin. Cancer Res. 25, 6916–6924 (2019).
Jones, P. A. Functions of DNA methylation: islands, start sites, gene bodies and beyond. Nat. Rev. Genet. 13, 484–492 (2012).
Pacis, A. et al. Gene activation precedes DNA demethylation in response to infection in human dendritic cells. Proc. Natl Acad. Sci. USA 116, 6938–6943 (2019).
Teschendorff, A. E. et al. DNA methylation outliers in normal breast tissue identify field defects that are enriched in cancer. Nat. Commun. 7, 10478 (2016).
Yang, X. et al. Gene body methylation can alter gene expression and is a therapeutic target in cancer. Cancer Cell 26, 577–590 (2014).
Massie, C. E., Mills, I. G. & Lynch, A. G. The importance of DNA methylation in prostate cancer development. J. Steroid Biochem. Mol. Biol. 166, 1–15 (2017).
Gery, S., Sawyers, C. L., Agus, D. B., Said, J. W. & Koeffler, H. P. TMEFF2 is an androgen-regulated gene exhibiting antiproliferative effects in prostate cancer cells. Oncogene 21, 4739–4746 (2002).
Qian, X. et al. Spondin-2 (SPON2), a more prostate-cancer-specific diagnostic biomarker. PLoS One 7, e37225 (2012).
Boormans, J. L. et al. Identification of TDRD1 as a direct target gene of ERG in primary prostate cancer. Int. J. Cancer 133, 335–345 (2013).
Xu, J. et al. Identification and characterization of prostein, a novel prostate-specific protein. Cancer Res. 61, 1563–1568 (2001).
Prensner, J. R. et al. RNA biomarkers associated with metastatic progression in prostate cancer: a multi-institutional high-throughput analysis of SChLAP1. Lancet Oncol. 15, 1469–1480 (2014).
White, N. M. et al. Multi-institutional analysis shows that low PCAT-14 expression associates with poor outcomes in prostate cancer. Eur. Urol. 71, 257–266 (2017).
Eisenberg, E. & Levanon, E. Y. Human housekeeping genes, revisited. Trends Genet. 29, 569–574 (2013).
Liberzon, A. et al. The Molecular Signatures Database (MSigDB) hallmark gene set collection. Cell Syst. 1, 417–425 (2015).
Zhao, S. G. et al. The immune landscape of prostate cancer and nomination of PD-L2 as a potential therapeutic target. J. Natl. Cancer Inst. 111, 301–310 (2019).
Tomlins, S. A. et al. Role of the TMPRSS2–ERG gene fusion in prostate cancer. Neoplasia 10, 177–188 (2008).
Domcke, S. et al. Competition between DNA methylation and transcription factors determines binding of NRF1. Nature 528, 575–579 (2015).
Feldmann, A. et al. Transcription factor occupancy can mediate active turnover of DNA methylation at regulatory regions. PLoS Genet. 9, e1003994 (2013).
Yin, Y. et al. Impact of cytosine methylation on DNA binding specificities of human transcription factors.Science 356, eaaj2239 (2017).
Cho, S. W. et al. Promoter of lncRNA gene PVT1 is a tumor-suppressor DNA boundary element. Cell 173, 1398–1412.e22 (2018).
Bell, R. E. et al. Enhancer methylation dynamics contribute to cancer plasticity and patient mortality. Genome Res. 26, 601–611 (2016).
Yegnasubramanian, S. et al. DNA hypomethylation arises later in prostate cancer progression than CpG island hypermethylation and contributes to metastatic tumor heterogeneity. Cancer Res. 68, 8954–8967 (2008).
Kulis, M. & Esteller, M. DNA methylation and cancer. Adv. Genet. 70, 27–56 (2010).
Chen, R. Z., Pettersson, U., Beard, C., Jackson-Grusby, L. & Jaenisch, R. DNA hypomethylation leads to elevated mutation rates. Nature 395, 89–93 (1998).
Zhao, S. G. et al. Associations of luminal and basal subtyping of prostate cancer with prognosis and response to androgen deprivation therapy. JAMA Oncol. 3, 1663–1672 (2017).
Yamazaki, J. et al. TET2 mutations affect non-CpG island DNA methylation at enhancers and transcription factor-binding sites in chronic myelomonocytic leukemia. Cancer Res. 75, 2833–2843 (2015).
Yamazaki, J. et al. Effects of TET2 mutations on DNA methylation in chronic myelomonocytic leukemia. Epigenetics 7, 201–207 (2012).
Ko, M. et al. Impaired hydroxylation of 5-methylcytosine in myeloid cancers with mutant TET2. Nature 468, 839–843 (2010).
Rasmussen, K. D. et al. Loss of TET2 in hematopoietic cells leads to DNA hypermethylation of active enhancers and induction of leukemogenesis. Genes Dev. 29, 910–922 (2015).
Liao, J. et al. Targeted disruption of DNMT1, DNMT3A and DNMT3B in human embryonic stem cells. Nat. Genet. 47, 469–478 (2015).
Duymich, C. E., Charlet, J., Yang, X., Jones, P. A. & Liang, G. DNMT3B isoforms without catalytic activity stimulate gene body methylation as accessory proteins in somatic cells. Nat. Commun. 7, 11453 (2016).
Itzykson, R. et al. Impact of TET2 mutations on response rate to azacitidine in myelodysplastic syndromes and low blast count acute myeloid leukemias. Leukemia 25, 1147–1152 (2011).
Bejar, R. et al. TET2 mutations predict response to hypomethylating agents in myelodysplastic syndrome patients. Blood 124, 2705–2712 (2014).
Brocks, D. et al. Intratumor DNA methylation heterogeneity reflects clonal evolution in aggressive prostate cancer. Cell Rep. 8, 798–806 (2014).
Krueger, F. & Andrews, S. R. Bismark: a flexible aligner and methylation caller for Bisulfite-Seq applications. Bioinformatics 27, 1571–1572 (2011).
Burger, L., Gaidatzis, D., Schubeler, D. & Stadler, M. B. Identification of active regulatory regions from DNA methylation data. Nucleic Acids Res. 41, e155 (2013).
Liao, Y., Smyth, G. K. & Shi, W. featureCounts: an efficient general purpose program for assigning sequence reads to genomic features. Bioinformatics 30, 923–930 (2014).
Roller, E., Ivakhno, S., Lee, S., Royce, T. & Tanner, S. Canvas: versatile and scalable detection of copy number variants. Bioinformatics 32, 2375–2377 (2016).
Yoshihara, K. et al. Inferring tumour purity and stromal and immune cell admixture from expression data. Nat. Commun. 4, 2612 (2013).
Sanchez-Vega, F. et al. Oncogenic signaling pathways in The Cancer Genome Atlas. Cell 173, 321–337.e10 (2018).
Bailey, M. H. et al. Comprehensive characterization of cancer driver genes and mutations. Cell 173, 371–385.e18 (2018).
Goldman, M. et al. The UCSC Cancer Genomics Browser: update 2015. Nucleic Acids Res. 43, D812–D817 (2015).
Faraway, J. J Linear Models with R (Taylor & Francis, 2014).
Wu, H. et al. Detection of differentially methylated regions from whole-genome bisulfite sequencing data without replicates. Nucleic Acids Res. 43, e141 (2015).
Acknowledgements
We thank the patients who selflessly contributed samples to this study and without whom this research would not have been possible. We would also like to acknowledge the assistance of Steven Kronenberg and Barbara Panning. This research was supported by a Stand Up To Cancer-Prostate Cancer Foundation Prostate Cancer Dream Team Award (SU2C-AACR-DT0812 to E.J.S.) and by the Movember Foundation. Stand Up To Cancer is a division of the Entertainment Industry Foundation. This research grant was administered by the American Association for Cancer Research, the scientific partner of SU2C. S.G.Z., D.A.Q., Hui Li, R.A., J.T.H., R.B. and R.Y. were funded by Prostate Cancer Foundation Young Investigator Awards. F.Y.F. was funded by Prostate Cancer Foundation Challenge Awards. Additional funding was provided by a UCSF Benioff Initiative for Prostate Cancer Research award. F.Y.F. and A.A. were supported by National Institutes of Health (NIH)/National Cancer Institute (NCI) 1R01CA230516-01. F.Y.F. and N.M. were supported by NIH/NCI 1R01CA227025 and Prostate Cancer Foundation (PCF) 17CHAL06. F.Y.F. and A.M.C. were supported by NIH P50CA186786. A.M.C. is supported by NIH R35CA231996 and U01CA214170. D.A.Q. was funded by a BRCA Foundation Young Investigator Award. M.S. was supported by the Swedish Research Council (Vetenskapsrådet) with grant number 2018–00382 and the Swedish Society of Medicine (Svenska Läkaresällskapet). L.A.G. was supported by K99/R00 CA204602 and DP2 CA239597, as well as the Goldberg-Benioff Endowed Professorship in Prostate Cancer Translational Biology. P.C.B. was supported by the NIH/NCI under award number P30CA016042 and by an operating grant from the National Cancer Institute Early Detection Research Network (1U01CA214194-01).
Author information
Authors and Affiliations
Contributions
S.G.Z., W.S.C., E.J.S., D.A.Q. and F.Y.F. conceived and designed the study. S.G.Z., Haolong Li, A.F., R.A., D.P., J.J.A., R.D., T.J.B., A.M.B., E.C., T.M.B., G.T., K.N.C., M.G., A.Z., R.E.R., M.B.R., O.W., M.Y.K., P.N.L., C.P.E., P.F., S.B., J.H., J.F.C., J.L., A.W.W., K.F., E.J.S., D.A.Q. and F.Y.F. acquired the data. S.G.Z., W.S.C., Haolong Li, M.Z., M.S., R.A., A.L., R.D., J.C., J.T.H., M.P., H.X.D., R.Y., R.M.-B., L.Z., M.A., S.L.C., K.E.H., Y.J.S., M.Y.K., L.F., D.E.S., T.M.M., R.B., F.W.H., Hui Li, L.C., T.S., H.G., I.A.A., S.S., J.M.L., N.M., K.E.K., H.H.H., W.Z., S.A.T., A.W.W., S.M.D., A.A., L.A.G., P.C.B., A.M.C., C.A.M., E.J.S., D.A.Q. and F.Y.F. analysed and interpreted the data. All authors drafted the article or revised it critically for important intellectual content. All authors approved the final version of the manuscript.
Corresponding author
Ethics declarations
Competing interests
P.F., S.B., K.F. and A.L. are employees of Illumina Inc., which provided material support for this project. No other commercial entities contributed to or played a role in the writing of this article. J.M.L. holds equity in Salus Discovery, LLC. L.F. has funding from BMS, Abbvie, Janssen, Roche/Genentech and Merck. O.W. currently has consulting, equity and/or board relationships with Trethera Corporation, Kronos Biosciences, Sofie Biosciences, Breakthrough Properties, Vida Ventures, Nanmi Therapeutics and Allogene Therapeutics. The University of Michigan and Brigham and Women’s Hospital have been issued patents on ETS gene fusions in prostate cancer, on which S.A.T. is a co-inventor. The diagnostic field of use was licensed to Hologic/Gen-Probe Inc., which has sublicensed rights to Roche/Ventana Medical Systems. S.A.T. has served as a consultant for and received honoraria from Janssen, AbbVie, Sanofi, Almac Diagnostics and Astellas/Medivation. S.A.T. has sponsored research agreements with Astellas/Medivation and GenomeDX. S.A.T. is a cofounder, previous consultant for and current employee of Strata Oncology. T.M.B. has research funding from Alliance Foundation Trials, Boehringer Ingelheim, Concept Therapeutics, Endocyte Inc., Janssen R&D, Medivation Inc./Astellas, oncoGenex, Sotio and Theraclone Sciences/OncoResponse. T.M.B. has received consulting fees from AbbVie, AstraZeneca, Astellas Pharma, Bayer, Boehringer Ingelheim, Clovis Oncology, GlaxoSmithKline, Janssen Biotech, Janssen Japan, Merck and Pfizer. T.M.B. holds stock in Salarius Pharmaceuticals. M.R. reports consulting and Speakers’ Bureau for Johnson & Johnson, research funding from Novartis, research support from Merck and Astellas/Medivation, and a provisional patent with UCLA on the development of small-molecule inhibitors of the androgen receptor N-terminal domain. J.J.A. has consulted for or held advisory roles at Astellas Pharma, Bayer and Janssen Biotech Inc. He has received research funding from Aragon Pharmaceuticals Inc., Astellas Pharma, Novartis, Zenith Epigenetics Ltd. and Gilead Sciences Inc. A.A. is a co-founder of Tango Therapeutics, Azkarra Therapeutics and Ovibio Corporation; is a consultant for SPARC, Bluestar, ProLynx, Earli, Cura, GenVivo and GSK; is a member of the SAB of Genentech and GLAdiator; receives grant/research support from SPARC and AstraZeneca; and holds patents on the use of PARP inhibitors held jointly with AstraZeneca, from which he has benefitted financially (and may do so in the future). F.Y.F. has consulted for Astellas, Bayer, BlueEarth Diagnostics, Celgene, Clovis, EMD Serono, Genentech, Janssen, Myovant, Ryovant and Sanofi, and is a co-founder and has an ownership stake in PFS Genomics. S.L.C. is in a leadership role at PFS Genomics. S.G.Z., S.L.C. and F.Y.F. have patent applications with Decipher Biosciences on molecular signatures in prostate cancer unrelated to this work. S.G.Z. and F.Y.F. have a patent application for a molecular signature in breast cancer unrelated to this work and licensed to PFS Genomics. S.G.Z. and F.Y.F. have patent applications with Celgene unrelated to this work.
Additional information
Publisher’s note Springer Nature remains neutral with regard to jurisdictional claims in published maps and institutional affiliations.
Supplementary information
Supplementary Information
Supplementary Figures 1–10
Supplementary Table
Supplementary Tables 1–10
Rights and permissions
About this article
Cite this article
Zhao, S.G., Chen, W.S., Li, H. et al. The DNA methylation landscape of advanced prostate cancer. Nat Genet 52, 778–789 (2020). https://doi.org/10.1038/s41588-020-0648-8
Received:
Accepted:
Published:
Issue Date:
DOI: https://doi.org/10.1038/s41588-020-0648-8
This article is cited by
-
Transcending frontiers in prostate cancer: the role of oncometabolites on epigenetic regulation, CSCs, and tumor microenvironment to identify new therapeutic strategies
Cell Communication and Signaling (2024)
-
TP63–TRIM29 axis regulates enhancer methylation and chromosomal instability in prostate cancer
Epigenetics & Chromatin (2024)
-
An integrated ceRNA network identifies miR-375 as an upregulated miRNA playing a tumor suppressive role in aggressive prostate cancer
Oncogene (2024)
-
Single cell-transcriptomic analysis informs the lncRNA landscape in metastatic castration resistant prostate cancer
npj Genomic Medicine (2024)
-
Omics-based molecular classifications empowering in precision oncology
Cellular Oncology (2024)
