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Nat Commun. 2017 Jun 29;8(1):48. doi: 10.1038/s41467-017-00046-0.

Inherited determinants of early recurrent somatic mutations in prostate cancer.

Author information

1
Centre for Integrative Biology, University of Trento, Via Sommarive 9, 38123, Trento, Italy.
2
Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, 413 East 69th Street, New York, NY, 10021, USA.
3
Department of Physiology and Biophysics, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.
4
Department of Pathology and Laboratory Medicine, Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.
5
Sandra and Edward Meyer Cancer Center at Weill Cornell Medicine, 1300 York Avenue, New York, NY, 10065, USA.
6
Centre for Integrative Biology, University of Trento, Via Sommarive 9, 38123, Trento, Italy. f.demichelis@unitn.it.
7
Caryl and Israel Englander Institute for Precision Medicine, New York Presbyterian Hospital-Weill Cornell Medicine, 413 East 69th Street, New York, NY, 10021, USA. f.demichelis@unitn.it.

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.Prostate cancer is a heterogeneous disease, and many cases show somatic mutations of SPOP. Here, the authors show that a non-coding polymorphic regulatory element at 7p14.3 may predispose to SPOP mutant prostate cancer subclass through a hormone dependent DNA damage response.

PMID:
28663546
PMCID:
PMC5491529
DOI:
10.1038/s41467-017-00046-0
[Indexed for MEDLINE]
Free PMC Article

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