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.
Bibliographical noteFunding Information:
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.
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).
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