2. Academic Validation
  3. Frequent CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression

Frequent CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression

  • NPJ Precis Oncol. 2024 Sep 19;8(1):208. doi: 10.1038/s41698-024-00705-8.
Miklos Diossy # 1 2,  Viktoria Tisza # 2 3,  Hua Li # 4 5,  Pranshu Sahgal 2 3 6,  Jia Zhou 7,  Zsofia Sztupinszki 1 2,  Denise Young 4 5,  Darryl Nousome 4 5,  Claire Kuo 4 5,  Jiji Jiang 4 5,  Yongmei Chen 4 5,  Reinhard Ebner 8,  Isabell A Sesterhenn 9,  Joel T Moncur 9,  Gregory T Chesnut 4,  Gyorgy Petrovics 4 5,  Gregory T Klus 2 10,  Gabor Valcz 11,  Pier Vitale Nuzzo 3 12,  Dezso Ribli 13,  Judit Börcsök 1,  Aurel Prosz 1,  Marcin Krzystanek 1,  Thomas Ried 10,  David Szuts 14,  Kinza Rizwan 15,  Salma Kaochar 15,  Shailja Pathania 16 17,  Alan D D'Andrea 7 18,  Istvan Csabai 13,  Shiv Srivastava 4 19,  Matthew L Freedman 20 21 22,  Albert Dobi 23 24,  Sandor Spisak 25,  Zoltan Szallasi 26 27 28
Affiliations

Affiliations

  • 1 Danish Cancer Institute, Copenhagen, Denmark.
  • 2 Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA.
  • 3 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 4 Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA.
  • 5 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA.
  • 6 The Eli and Edythe L. Broad Institute, Cambridge, MA, USA.
  • 7 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 8 CytoTest Inc., Rockville, MD, USA.
  • 9 Joint Pathology Center, Silver Spring, MD, USA.
  • 10 Genetics Branch, Center for Cancer Research, National Cancer Institute, Bethesda, MD, USA.
  • 11 MTA-SE Molecular Medicine Research Group, Hungarian Academy of Sciences, Budapest, 1051, Hungary.
  • 12 Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 13 Department of Physics of Complex Systems, Eötvös Loránd University, Budapest, Hungary.
  • 14 Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary.
  • 15 Department of Medicine, Baylor College of Medicine, Houston, TX, USA.
  • 16 Center for Personalized Cancer Therapy, University of Massachusetts, Boston, MA, USA.
  • 17 Department of Biology, University of Massachusetts, Boston, MA, USA.
  • 18 Center for DNA Damage and Repair, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, 02215, USA.
  • 19 Department of Biochemistry and Molecular & Cell Biology, Georgetown University School of Medicine, Washington, DC, USA.
  • 20 Department of Medical Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. freedman@broadinstitute.org.
  • 21 The Eli and Edythe L. Broad Institute, Cambridge, MA, USA. freedman@broadinstitute.org.
  • 22 Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. freedman@broadinstitute.org.
  • 23 Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. adobi@cpdr.org.
  • 24 The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA. adobi@cpdr.org.
  • 25 Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary. Spisak.sandor@ttk.hu.
  • 26 Danish Cancer Institute, Copenhagen, Denmark. Zoltan.Szallasi@childrens.harvard.edu.
  • 27 Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. Zoltan.Szallasi@childrens.harvard.edu.
  • 28 2nd Department of Pathology and Department of Bioinformatics, Semmelweis University, Budapest, Hungary. Zoltan.Szallasi@childrens.harvard.edu.
  • # Contributed equally.
PMID: 39294262 DOI: 10.1038/s41698-024-00705-8
Abstract

We analyzed genomic data from the prostate Cancer of African- and European American men to identify differences contributing to racial disparity of outcome. We also performed FISH-based studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate Cancer tissue microarrays. We created CHD1-deficient prostate Cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. Subclonal deletion of CHD1 was nearly three times as frequent in prostate tumors of African American than in European American men and it associates with rapid disease progression. CHD1 deletion was not associated with HR deficiency associated mutational signatures or HR deficiency as detected by RAD51 foci formation. This was consistent with the moderate increase of olaparib and talazoparib sensitivity with several CHD1 deficient cell lines showing talazoparib sensitivity in the clinically relevant concentration range. CHD1 loss may contribute to worse disease outcome in African American men.

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