Intraindividual epigenetic heterogeneity underlying phenotypic subtypes of advanced prostate cancer
Abstract
Abstract Castration-resistant prostate cancer is a heterogeneous disease with variable phenotypes commonly observed in later stages of the disease. These include cases that retain expression of luminal markers and those that lose hormone dependence and acquire neuroendocrine features. While there are distinct transcriptomic and epigenomic differences between castration-resistant adenocarcinoma and neuroendocrine prostate cancer, the extent of overlap and degree of diversity across tumor metastases in individual patients has not been fully characterized. Here we perform combined DNA methylation, RNA-sequencing, H3K27ac, and H3K27me3 profiling across metastatic lesions from patients with CRPC/NEPC. Integrative analyses identify DNA methylation-driven gene links based on location (H3K27ac, H3K27me3, promoters, gene bodies) pointing to mechanisms underlying dysregulation of genes involved in tumor lineage (ASCL1, AR ) and therapeutic targets (PSMA, DLL3, STEAP1, B7-H3). Overall, these data highlight how integration of DNA methylation with RNA-sequencing and histone marks can inform intraindividual epigenetic heterogeneity and identify putative mechanisms driving transcriptional reprogramming in castration-resistant prostate cancer.
Article Details
Authors (23)
Kei Mizuno
Sheng-Yu Ku
Varadha Balaji Venkadakrishnan
Martin K. Bakht
Michael Sigouros
Joanna Chan
Anna Trigos
Jordan H. Driskill
Jyothi Manohar
Abigail King
Adam G. Presser
Min Jin Kim
Alok K. Tewari
Department of Medical Oncology, Dana-Farber Cancer Institute and Harvard Medical School
Henry W. Long
Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute
David Quigley
Department of Physics, University of Warwick 2 , Gibbet Hill Road, Coventry CV4 7AL,
Toni K. Choueiri
Department of Medical Oncology Dana‐Farber Cancer Institute Boston Massachusetts USA
Steven Balk
Sarah Hill
Juan Miguel Mosquera
David Einstein
Shahneen Sandhu
From the Sandra and Edward Meyer Cancer Center (J.D.W.) and the Department of Medicine (J.D.W., M.A.P.), Weill Cornell Medicine, and Memorial Sloan Kettering Cancer Center (M.A.P.) — both in New York; Istituto Oncologico Veneto, IRCCS, Padua (V.C.-S.), European Institute of Oncology, IRCCS, Milan (P.Q.), Istituto Scientifico Romagnolo per lo Studio e la Cura dei Tumori, IRCCS, Meldola (M.G.), University of Siena and the Center for Immuno-Oncology, University Hospital of Siena, Siena (M.M.), and Istituto Nazionale Tumori IRCCS Fondazione Pascale, Naples (P.A.A.) — all in Italy; Maria Sklodowska-Curie National Institute of Oncology, Warsaw, Poland (P.R.); Texas Oncology–Baylor Charles A. Sammons Cancer Center, Dallas (C.L.C.); University Hospital Essen, the German Cancer Consortium, the National Center for Tumor Diseases–West, the Research Alliance Ruhr, Research Center One Health, and University Duisburg-Essen — all in Essen, Germany (D.S.); the College of Medicine, Swansea University, Swansea (J.W.), Brist...
Mary-Ellen Taplin
Dana–Farber Cancer Institute, Boston
Himisha Beltran