Inherited determinants of early recurrent somatic mutations in prostate cancer

Alessandro Romanel, Sonia Garritano, Blerta Stringa, Mirjam Blattner, Davide Dalfovo, Dimple Chakravarty, David Soong, Kellie A. Cotter, Gianluca Petris, Priyanka Dhingra, Paola Gasperini, Anna Cereseto, Olivier Elemento, Andrea Sboner, Ekta Khurana, Alberto Inga, Mark A. Rubin and Francesca Demichelis ()
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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
Andrea Sboner: New York Presbyterian Hospital–Weill Cornell Medicine
Ekta Khurana: New York Presbyterian Hospital–Weill Cornell Medicine
Alberto Inga: University of Trento
Mark A. Rubin: New York Presbyterian Hospital–Weill Cornell Medicine
Francesca Demichelis: University of Trento

Nature Communications, 2017, vol. 8, issue 1, 1-10

Abstract: 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.

Date: 2017
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DOI: 10.1038/s41467-017-00046-0

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