IDENTIFICATION OF CHROMATIN SIGNATURES PREDICTIVE OF PROSTATE CANCER PROGRESSION

You have accessJournal of UrologyCME1 May 2022PD07-12 IDENTIFICATION OF CHROMATIN SIGNATURES PREDICTIVE OF PROSTATE CANCER PROGRESSION Michael Rothberg, Jacob Enders, Cheyenne Williams, Michael Daneshvar, Nitin Yerram, Sohyoung Kim, Saori Fujiwara, Lorenzo Rinaldi, Songjoon Baek, Luke O'Connor, Qizong Kim, Patrick Gomella, Maria Merino, Bradford Wood, Peter Choyke, Baris Turkbey, Gordon Hager, and Peter Pinto Michael RothbergMichael Rothberg More articles by this author , Jacob EndersJacob Enders More articles by this author , Cheyenne WilliamsCheyenne Williams More articles by this author , Michael DaneshvarMichael Daneshvar More articles by this author , Nitin YerramNitin Yerram More articles by this author , Sohyoung KimSohyoung Kim More articles by this author , Saori FujiwaraSaori Fujiwara More articles by this author , Lorenzo RinaldiLorenzo Rinaldi More articles by this author , Songjoon BaekSongjoon Baek More articles by this author , Luke O'ConnorLuke O'Connor More articles by this author , Qizong KimQizong Kim More articles by this author , Patrick GomellaPatrick Gomella More articles by this author , Maria MerinoMaria Merino More articles by this author , Bradford WoodBradford Wood More articles by this author , Peter ChoykePeter Choyke More articles by this author , Baris TurkbeyBaris Turkbey More articles by this author , Gordon HagerGordon Hager More articles by this author , and Peter PintoPeter Pinto More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002526.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: Alterations of androgen receptor (AR) binding across the human genome and subsequent reprogramming of active regulatory sites are associated with prostate tumorigenesis and cancer progression. It is unknown whether early AR alterations are predictive of future aggressiveness of prostate cancer. We sought to identify chromatin landscape signatures predictive for low-grade, high-grade, and progressed prostate cancer to characterize patients at risk for aggressive disease after initial biopsy. METHODS: Samples from 42 patients with biopsy-confirmed prostate cancer were included in this study. Patients underwent MRI fusion-guided biopsies to obtain tissue from both prostate tumors and paired adjacent normal tissue at the time of diagnosis. Thirteen patients had low grade (grade group (GG) 1) lesions, 21 patients had high-grade (GG ≥ 4) lesions, and 8 patients had initial GG ≤ 2 lesions which later progressed to GG ≥ 3 at follow-up biopsy. Median follow-up was 42 months (IQR: 28-54). Transposase-Accessible Chromatin sequencing (ATAC-Seq) of each fresh biopsy sample obtained genome-wide chromatin accessibility as a readout of active regulatory sites. Ultimately, 98 high-quality ATAC-Seq data sets (52 tumor, 47 adjacent normal) were obtained and analyzed. RESULTS: ATAC-Seq revealed two groups of regulatory sites possessing contrasting activities between low-grade and high-grade/progressed cancer. 2,078 sites were predominantly active in low-grade cancer, and 2,655 sites were predominantly active in high-grade/progressed cancer. Analysis of AR motifs showed similar levels of AR motifs in both groups. However, a comparison of AR binding in prostate primary tumors revealed that the high-grade/progressed sites had higher AR binding than the low-grade sites indicating additional co-factors may facilitate AR binding in the high-grade/progressed cancer. Binding motifs for ETS Transcription Factor (ERG) and Grainyhead Like Transcription Factor 2 (GRHL2) were enriched exclusively in the high-grade/progressed sites (enrichment P= 1e-94, 1e-54 for ERG and GRHL2 respectively in high-grade/progressed, and P= 1e-2, 1e-15 for ERG and GRHL2 respectively in low-grade). CONCLUSIONS: We identified regulatory sites commonly active among high-grade and initially low-grade but later progressed PCa. Among high grade/progressed cancer, enriched ERG and GRHL2 binding motifs are associated with elevated AR binding, indicating the roles of ERG and GRHL2 as cofactors modulating AR binding. This suggests that ERG and GRHL2 modulating AR reprogramming may be an early event in PCa predictive of future progression. Source of Funding: The National Institute of Health (NIH) Medical Research Scholars Program, Foundation for the NIH, NIH Intramural Research Program © 2022 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 207Issue Supplement 5May 2022Page: e103 Advertisement Copyright & Permissions© 2022 by American Urological Association Education and Research, Inc.MetricsAuthor Information Michael Rothberg More articles by this author Jacob Enders More articles by this author Cheyenne Williams More articles by this author Michael Daneshvar More articles by this author Nitin Yerram More articles by this author Sohyoung Kim More articles by this author Saori Fujiwara More articles by this author Lorenzo Rinaldi More articles by this author Songjoon Baek More articles by this author Luke O'Connor More articles by this author Qizong Kim More articles by this author Patrick Gomella More articles by this author Maria Merino More articles by this author Bradford Wood More articles by this author Peter Choyke More articles by this author Baris Turkbey More articles by this author Gordon Hager More articles by this author Peter Pinto More articles by this author Expand All Advertisement PDF DownloadLoading ...