Germline Mutation Landscape Of Dna Repair Genes In African American Prostate Cancer Patients Highlight Potentially Targetable Rad Genes

You have accessJournal of UrologyProstate Cancer: Detection & Screening VII (PD65)1 Sep 2021PD65-12 GERMLINE MUTATION LANDSCAPE OF DNA REPAIR GENES IN AFRICAN AMERICAN PROSTATE CANCER PATIENTS HIGHLIGHT POTENTIALLY TARGETABLE RAD GENES Indu Kohaar, Xijun Zhang, Shyh-Han Tan, Darryl Nousome, Kevin Babcock, Lakshmi Ravindranath, Gauthaman Sukumar, Elisa Mcgrath-Martinez, John Rosenberger, Camille Alba, Amina Ali, Denise Young, Yongmei Chen, Jennifer Cullen, Inger Rosner Bethesda, Isabell Sesterhenn, Albert Dobi, Gregory Chesnut, Clesson Turner, Clifton Dalgard, Matthew Wilkerson, Harvey Pollard, Shiv Srivastava, and Gyorgy Petrovics Indu KohaarIndu Kohaar More articles by this author , Xijun ZhangXijun Zhang More articles by this author , Shyh-Han TanShyh-Han Tan More articles by this author , Darryl NousomeDarryl Nousome More articles by this author , Kevin BabcockKevin Babcock More articles by this author , Lakshmi RavindranathLakshmi Ravindranath More articles by this author , Gauthaman SukumarGauthaman Sukumar More articles by this author , Elisa Mcgrath-MartinezElisa Mcgrath-Martinez More articles by this author , John RosenbergerJohn Rosenberger More articles by this author , Camille AlbaCamille Alba More articles by this author , Amina AliAmina Ali More articles by this author , Denise YoungDenise Young More articles by this author , Yongmei ChenYongmei Chen More articles by this author , Jennifer CullenJennifer Cullen More articles by this author , Inger Rosner BethesdaInger Rosner Bethesda More articles by this author , Isabell SesterhennIsabell Sesterhenn More articles by this author , Albert DobiAlbert Dobi More articles by this author , Gregory ChesnutGregory Chesnut More articles by this author , Clesson TurnerClesson Turner More articles by this author , Clifton DalgardClifton Dalgard More articles by this author , Matthew WilkersonMatthew Wilkerson More articles by this author , Harvey PollardHarvey Pollard More articles by this author , Shiv SrivastavaShiv Srivastava More articles by this author , and Gyorgy PetrovicsGyorgy Petrovics More articles by this author View All Author Informationhttps://doi.org/10.1097/JU.0000000000002109.12AboutPDF ToolsAdd to favoritesDownload CitationsTrack CitationsPermissionsReprints ShareFacebookLinked InTwitterEmail Abstract INTRODUCTION AND OBJECTIVE: DNA damage repair genes (DDRGs) play a critical role in genomic stability and their dysfunction contributes to mutagenesis in several cancer types. In prostate cancer (CaP), the association with disease progression and therapeutic stratification based on inherited mutations of DDRGs remains to be defined in African American (AA) CaP patients. Our objective was to genomically profile all known annotated DDRGs in AA and Caucasian American (CA) CaP patient to determine whether DDRG germline variation status can refine patient stratification for targeted therapeutic options. METHODS: Germline mutations in all DDRGs (N=276) was evaluated by whole genome sequence (WGS) analysis of archived blood DNA samples from 600 CaP patients (300 AA and 300 CA) who underwent primary treatment at Walter Reed National Military Medical Center. The WGS mean coverage exceeded 37x. Principal Component Analysis (PCA) was used infer axes of genetic variation within AA men and examine individual and population clustering to predict ancestry of each sample using the Peddy program. Variant frequencies in CPDR CaP patients were compared to variant frequencies available from the Exome Aggregation Consortium (ExAC) controls with no CaP. Data analysis approaches included single variant association, gene-based total frequency test and clinico-pathological associations for germline mutations. All statistical tests were two-sided, and FDR adjusted. FDR < 0.05 was set as significance threshold. RESULTS: Interrogation of the complete known DDRG set of 276 genes revealed that the pathogenic/likely pathogenic (P/LP) variant carrier rate was higher than reported before (23.5%) in both AA and CA patients. 2/3 of the 46 DDRGs with germline mutations were different between AA and CA patients. Importantly, RAD family genes (RAD51, RAD54L, RAD54B), as well as PMS2 and BRCA1, were among the most frequently mutated DDRGs in AA. Germline mutations in RAD51 and PMS2 genes were enriched in AA cohort as compared to CA men with P values of 0.0063 and 0.0271, respectively, while germline mutations in FANCA gene were significantly enriched in CA cohort (P = 0.0075). AA patients with germline mutations in DDRGs showed association with future biochemical recurrence (p=0.044). CONCLUSIONS: Our findings clearly highlight distinct racial differences and addresses the clinical utility of available genetic tests across AA and CA men. The percentage of patients with DDRG germline variation is of suitable threshold (23%) to consider early genetic testing for them in both AA and CA patients. Source of Funding: This research was supported by intramural DOD grant DHA-16-CRII-PMRA to S.S., G.P and Center for Prostate Disease Research, Uniformed Services University Grant HU0001-10-2-0002 to G.T.C © 2021 by American Urological Association Education and Research, Inc.FiguresReferencesRelatedDetails Volume 206Issue Supplement 3September 2021Page: e1157-e1157 Advertisement Copyright & Permissions© 2021 by American Urological Association Education and Research, Inc.MetricsAuthor Information Indu Kohaar More articles by this author Xijun Zhang More articles by this author Shyh-Han Tan More articles by this author Darryl Nousome More articles by this author Kevin Babcock More articles by this author Lakshmi Ravindranath More articles by this author Gauthaman Sukumar More articles by this author Elisa Mcgrath-Martinez More articles by this author John Rosenberger More articles by this author Camille Alba More articles by this author Amina Ali More articles by this author Denise Young More articles by this author Yongmei Chen More articles by this author Jennifer Cullen More articles by this author Inger Rosner Bethesda More articles by this author Isabell Sesterhenn More articles by this author Albert Dobi More articles by this author Gregory Chesnut More articles by this author Clesson Turner More articles by this author Clifton Dalgard More articles by this author Matthew Wilkerson More articles by this author Harvey Pollard More articles by this author Shiv Srivastava More articles by this author Gyorgy Petrovics More articles by this author Expand All Advertisement Loading ...