2. Academic Validation
  3. Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression without inducing homologous recombination deficiency

Increased frequency of CHD1 deletions in prostate cancers of African American men is associated with rapid disease progression without inducing homologous recombination deficiency

  • Res Sq. 2024 Apr 1:rs.3.rs-3995251. doi: 10.21203/rs.3.rs-3995251/v1.
Zoltan Szallasi 1,  Miklos Diossy 2,  Viktoria Tisza 3,  Hua Li 4,  Pranshu Sahgal 5,  Jia Zhou 6,  Zsofia Sztupinszki 2,  Denise Young 7,  Darryl Nuosome 7,  Claire Kuo 7,  Jiji Jiang 7,  Yongmei Chen 8,  Reinhard Ebner 9,  Isabell Sesterhenn 10,  Joel Moncur 10,  Gregory Chesnut 8,  Gyorgy Petrovics 11,  Gregory T Klus 12,  Gábor Valcz 13,  Pier Nuzzo 14,  Dezso Ribli 15,  Judit Börcsök 2,  Aurél Prósz 16,  Marcin Krzystanek 2,  Thomas Ried 17,  Dávid Szüts 18,  Kinza Rizwan 19,  Salma Kaochar 19,  Shailja Pathania 20,  Alan D'Andrea 21,  István Csabai 22,  Shib Srivastava 7,  Matthew Freedman 14,  Albert Dobi 7,  Sandor Spisak 23
Affiliations

Affiliations

  • 1 Children's Hospital Boston.
  • 2 Danish Cancer Society Research Center.
  • 3 Institute of Enzymology, Research Centre for Natural Sciences.
  • 4 Center for Prostate Cancer Research.
  • 5 Dana-Farber Cancer Institute and Harvard Medical School.
  • 6 Department of Radiation Oncology, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA.
  • 7 Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD.
  • 8 Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department Uniformed Services University of the Health Sciences, Bethesda, MD.
  • 9 CytoTest Inc., Rockville, Maryland, USA.
  • 10 Joint Pathology Center, Silver Spring, Maryland, USA.
  • 11 Computational Health Informatics Program, Boston Children's Hospital, USA, Harvard Medical School, Boston, USA.
  • 12 Computational Health Informatics Program.
  • 13 ELKH Translational Extracellular Vesicle Research Group, Budapest, Hungary.
  • 14 Department of Medical Oncology, Dana-Farber Cancer Institute, Boston, Massachusetts.
  • 15 Department of Physics of Complex Systems, Eotvos Lorand University, Budapest, Hungary.
  • 16 Danish Cancer Institute.
  • 17 National Cancer Institute.
  • 18 HUN-REN Research Centre for Natural Sciences.
  • 19 Department of Medicine, Baylor College of Medicine, Houston, USA.
  • 20 University of Massachusetts Boston.
  • 21 Dana-Farber Cancer Institute.
  • 22 Eötvös Loránd University.
  • 23 Institute of Enzymology, Research Centre for Natural Sciences, Eötvös Loránd Research Network.
PMID: 38645014 DOI: 10.21203/rs.3.rs-3995251/v1
Abstract

We analyzed genomic data derived from the prostate Cancer of African and European American men in order to identify differences that may contribute to racial disparity of outcome and that could also define novel therapeutic strategies. In addition to analyzing patient derived next generation Sequencing data, we performed FISH based confirmatory studies of Chromodomain helicase DNA-binding protein 1 (CHD1) loss on prostate Cancer tissue microarrays. We created CRISPR edited, CHD1 deficient prostate Cancer cell lines for genomic, drug sensitivity and functional homologous recombination (HR) activity analysis. We found that subclonal deletion of CHD1 is nearly three times as frequent in prostate tumors of African American men than in men of European ancestry and it associates with rapid disease progression. We further showed that CHD1 deletion is not associated with homologous recombination deficiency associated mutational signatures in prostate Cancer. In prostate Cancer cell line models CHD1 deletion did not induce HR deficiency as detected by RAD51 foci formation assay or mutational signatures, which was consistent with the moderate increase of olaparib sensitivity. CHD1 deficient prostate Cancer cells, however, showed higher sensitivity to talazoparib. CHD1 loss may contribute to worse outcome of prostate Cancer in African American men. A deeper understanding of the interaction between CHD1 loss and PARP Inhibitor sensitivity will be needed to determine the optimal use of targeted agents such as talazoparib in the context of castration resistant prostate Cancer.

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