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Inherited determinants of early recurrent somatic mutations in prostate cancer

Author

Listed:
  • Alessandro Romanel

    (University of Trento)

  • Sonia Garritano

    (University of Trento)

  • Blerta Stringa

    (University of Trento)

  • Mirjam Blattner

    (University of Trento)

  • Davide Dalfovo

    (University of Trento)

  • Dimple Chakravarty

    (New York Presbyterian Hospital–Weill Cornell Medicine)

  • David Soong

    (Weill Cornell Medicine)

  • Kellie A. Cotter

    (New York Presbyterian Hospital–Weill Cornell Medicine)

  • Gianluca Petris

    (University of Trento)

  • Priyanka Dhingra

    (Weill Cornell Medicine)

  • Paola Gasperini

    (University of Trento)

  • Anna Cereseto

    (University of Trento)

  • Olivier Elemento

    (New York Presbyterian Hospital–Weill Cornell Medicine
    Weill Cornell Medicine)

  • Andrea Sboner

    (New York Presbyterian Hospital–Weill Cornell Medicine)

  • Ekta Khurana

    (New York Presbyterian Hospital–Weill Cornell Medicine
    Weill Cornell Medicine)

  • Alberto Inga

    (University of Trento)

  • Mark A. Rubin

    (New York Presbyterian Hospital–Weill Cornell Medicine
    Weill Cornell Medicine
    Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine)

  • Francesca Demichelis

    (University of Trento
    New York Presbyterian Hospital–Weill Cornell Medicine)

Abstract

Prostate cancer is a highly heritable molecularly and clinically heterogeneous disease. To discover germline events involved in prostate cancer predisposition, we develop a computational approach to nominate heritable facilitators of somatic genomic events in the context of the androgen receptor signaling. Here, we use a ranking score and benign prostate transcriptomes to identify a non-coding polymorphic regulatory element at 7p14.3 that associates with DNA repair and hormone-regulated transcript levels and with an early recurrent prostate cancer-specific somatic mutation in the Speckle-Type POZ protein (SPOP) gene. The locus shows allele-specific activity that is concomitantly modulated by androgen receptor and by CCAAT/enhancer-binding protein (C/EBP) beta (CEBPB). Deletion of this locus via CRISPR-Cas9 leads to deregulation of the genes predicted to interact with the 7p14.3 locus by Hi-C chromosome conformation capture data. This study suggests that a polymorphism at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone-dependent DNA damage response.

Suggested Citation

  • Alessandro Romanel & Sonia Garritano & Blerta Stringa & Mirjam Blattner & Davide Dalfovo & Dimple Chakravarty & David Soong & Kellie A. Cotter & Gianluca Petris & Priyanka Dhingra & Paola Gasperini & , 2017. "Inherited determinants of early recurrent somatic mutations in prostate cancer," Nature Communications, Nature, vol. 8(1), pages 1-10, December.
    • Handle: RePEc:nat:natcom:v:8:y:2017:i:1:d:10.1038_s41467-017-00046-0
    DOI: 10.1038/s41467-017-00046-0
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