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

Miklos Diossy; Viktoria Tisza; Hua Li; Pranshu Sahgal; Jia Zhou; Zsofia Sztupinszki; Denise Young; Darryl Nousome; Claire Kuo; Jiji Jiang; Yongmei Chen; Reinhard Ebner; Isabell A Sesterhenn; Joel T Moncur; Gregory T Chesnut; Gyorgy Petrovics; Gregory T Klus; Gabor Valcz; Pier Vitale Nuzzo; Dezso Ribli; Judit Börcsök; Aurel Prosz; Marcin Krzystanek; Thomas Ried; David Szuts; Kinza Rizwan; Salma Kaochar; Shailja Pathania; Alan D D'Andrea; Istvan Csabai; Shiv Srivastava; Matthew L Freedman; Albert Dobi; Sandor Spisak; Zoltan Szallasi

doi:10.1038/s41698-024-00705-8

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.

Authors

Miklos Diossy^#^{1

2}, Viktoria Tisza^#^{2

3}, Hua Li^#^{4

5}, Pranshu Sahgal^{2

3

6}, Jia Zhou⁷, 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 Ebner⁸, Isabell A Sesterhenn⁹, Joel T Moncur⁹, Gregory T Chesnut⁴, Gyorgy Petrovics^{4

5}, Gregory T Klus^{2

10}, Gabor Valcz¹¹, Pier Vitale Nuzzo^{3

12}, Dezso Ribli¹³, Judit Börcsök¹, Aurel Prosz¹, Marcin Krzystanek¹, Thomas Ried¹⁰, David Szuts¹⁴, Kinza Rizwan¹⁵, Salma Kaochar¹⁵, Shailja Pathania^{16

17}, Alan D D'Andrea^{7

18}, Istvan Csabai¹³, Shiv Srivastava^{4

19}, Matthew L Freedman^{20

21

22}, Albert Dobi^{23

24}, Sandor Spisak²⁵, Zoltan Szallasi^{26

27

28}

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. [email protected].
²¹ The Eli and Edythe L. Broad Institute, Cambridge, MA, USA. [email protected].
²² Center for Functional Cancer Epigenetics, Dana-Farber Cancer Institute, Harvard Medical School, Boston, MA, USA. [email protected].
²³ Center for Prostate Disease Research, Murtha Cancer Center Research Program, Department of Surgery, Uniformed Services University of the Health Sciences, Bethesda, MD, USA. [email protected].
²⁴ The Henry M. Jackson Foundation for the Advancement of Military Medicine, Inc, Bethesda, MD, USA. [email protected].
²⁵ Institute of Molecular Life Sciences, HUN-REN Research Centre for Natural Sciences, Budapest, Hungary. [email protected].
²⁶ Danish Cancer Institute, Copenhagen, Denmark. [email protected].
²⁷ Computational Health Informatics Program, Boston Children's Hospital, Harvard Medical School, Boston, MA, USA. [email protected].
²⁸ 2nd Department of Pathology and Department of Bioinformatics, Semmelweis University, Budapest, Hungary. [email protected].

^# Contributed equally.

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.

Abstract

Grants and funding