Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with distinct homologous recombination deficiency associated DNA aberration profiles
Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with distinct homologous recombination deficiency associated DNA aberration profiles
Abstract BackgroundAfrican American (AA) men have significantly higher mortality rates from prostate cancer (PC) than individuals of European ancestry (EA). Therapeutically targetable molecular differences may hold the potential to reduce this disparity. ObjectiveTo investigate chromodomain helicase DNA-binding protein 1 (CHD1) deletion both as a cause of aggressive disease and therapeutic vulnerability in the prostate cancer of AA men. Design, setting, and participants91 AA and 109 EA prostate cancer cases were analyzed by fluorescence in situ hybridization (FISH) for the deletion of CHD1. Whole exome and whole genome sequencing data from prostate adenocarcinoma cases were analyzed for mutational signatures from AA and EA individuals. Outcome measurements and statistical analysisAssociations with biochemical recurrence were evaluated using Cox proportional hazard regression models. Association between mutational signatures and CHD1 deletion were assessed by Wilcoxon ranked sum tests. Results and limitationsSubclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of men than in EA men. CHD1 deletion is associated with some of the homologous recombination deficiency associated mutational signatures in prostate cancer. In a cell line model CHD1 deletion induced 1-10 kb deletions resembling those induced by BRCA2 deficiency. CHD1 deficient cells showed markedly increased sensitivity to both talazoparib and the radiomimetic bleomycin. ConclusionsCHD1 is more frequently deleted in the prostate cancer of AA men. This deletion is both associated with and induces mutational signatures characteristic of BRCA2 deficiency. CHD1 deficient prostate cancer is more sensitive to talazoparib or bleomycin treatment. Patient summarySubclonal deletion of CHD1 is more frequent in the prostate cancer of AA men and this could be one of the reasons behind more aggressive disease. CHD1 deletion, however, also constitutes a therapeutic vulnerability to the PARP inhibitor talazoparib. This treatment may significantly improve the outcome of disease in AA men.
Srivastava Shiv、Diossy Miklos、Zhou Jia、Young Denise、Ebner Reinhard、Spisak Sandor、Krzystanek Marcin、Klus Gregory T.、B?rcs?k Judit、Ribli Dezso、D?ˉAndrea Alan D.、Moncur Joel T.、Szuts David、Ried Thomas、Csabai Istvan、Sesterhenn Isabell A.、Schina Aimilia、Freedman Matthew L、Petrovics Gyorgy、Tisza Viktoria、Valcz Gabor、Nuzzo Pier Vitale、Szallasi Zoltan、Pathania Shailja、Kaochar Salma、Dobi Albert、Chen Yongmei、Chesnut Gregory T.、Li Hua、Kuo Claire、Nousome Darryl、Sztupinszki Zsofia、Prosz Aurel
Center for Prostate Disease Research, Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health Sciences||Department of Biochemistry and Molecular & Cell Biology, Georgetown University School of MedicineDanish Cancer Society Research CenterDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical SchoolCenter for Prostate Disease Research, Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health Sciences||The Henry M. Jackson Foundation for the Advancement of Military MedicineCytoTest Inc., RockvilleDepartment of Medical Oncology, Dana-Farber Cancer Institute||Center for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteDanish Cancer Society Research CenterComputational Health Informatics Program, Boston Children?ˉs Hospital, USA, Harvard Medical School||Genetics Branch, Center for Cancer Research, National Cancer InstituteDanish Cancer Society Research CenterDepartment of Physics of Complex Systems, E?tv?s Lor¨￠nd UniversityDepartment of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School||Center for DNA Damage and Repair, Dana-Farber Cancer InstituteJoint Pathology Center, Silver SpringInstitute of Enzymology, Research Centre for Natural SciencesGenetics Branch, Center for Cancer Research, National Cancer InstituteDepartment of Physics of Complex Systems, E?tv?s Lor¨￠nd UniversityJoint Pathology Center, Silver SpringDanish Cancer Society Research Center||National Center for Cancer Immune TherapyDepartment of Medical Oncology, Dana-Farber Cancer Institute||Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute||The Eli and Edythe L. Broad InstituteCenter for Prostate Disease Research, Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health Sciences||The Henry M. Jackson Foundation for the Advancement of Military MedicineComputational Health Informatics Program, Boston Children?ˉs Hospital, USA, Harvard Medical School||Department of Medical Oncology, Dana-Farber Cancer InstituteMTA-SE Molecular Medicine Research Group, Hungarian Academy of SciencesDepartment of Medical Oncology, Dana-Farber Cancer Institute||Center for Functional Cancer Epigenetics, Dana-Farber Cancer InstituteDanish Cancer Society Research Center||Computational Health Informatics Program, Boston Children?ˉs Hospital, USA, Harvard Medical School||2nd Department of Pathology, SE NAP, Brain Metastasis Research Group, Hungarian Academy of Sciences, Semmelweis UniversityCenter for Personalized Cancer Therapy, University of Massachusetts||Department of Biology, University of MassachusettsDepartment of Medicine, Baylor College of MedicineDepartment of Medical Oncology, Dana-Farber Cancer Institute||Center for Prostate Disease Research, Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health SciencesCenter for Prostate Disease Research, Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health Sciences||The Henry M. Jackson Foundation for the Advancement of Military MedicineCenter for Prostate Disease Research, Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health SciencesCenter for Prostate Disease Research, Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health Sciences||The Henry M. Jackson Foundation for the Advancement of Military MedicineCenter for Prostate Disease Research, Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health Sciences||The Henry M. Jackson Foundation for the Advancement of Military MedicineCenter for Prostate Disease Research, Murtha Cancer Center / Research Program, Department of Surgery, Uniformed Services University of the Health Sciences||The Henry M. Jackson Foundation for the Advancement of Military MedicineDanish Cancer Society Research CenterDanish Cancer Society Research Center
肿瘤学医学研究方法基础医学
Srivastava Shiv,Diossy Miklos,Zhou Jia,Young Denise,Ebner Reinhard,Spisak Sandor,Krzystanek Marcin,Klus Gregory T.,B?rcs?k Judit,Ribli Dezso,D?ˉAndrea Alan D.,Moncur Joel T.,Szuts David,Ried Thomas,Csabai Istvan,Sesterhenn Isabell A.,Schina Aimilia,Freedman Matthew L,Petrovics Gyorgy,Tisza Viktoria,Valcz Gabor,Nuzzo Pier Vitale,Szallasi Zoltan,Pathania Shailja,Kaochar Salma,Dobi Albert,Chen Yongmei,Chesnut Gregory T.,Li Hua,Kuo Claire,Nousome Darryl,Sztupinszki Zsofia,Prosz Aurel.Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with distinct homologous recombination deficiency associated DNA aberration profiles[EB/OL].(2025-03-28)[2025-04-30].https://www.medrxiv.org/content/10.1101/2021.02.08.21251199.点此复制
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