Inherited determinants of early recurrent somatic mutations in prostate cancer.

Romanel, Alessandro; Garritano, Sonia; Stringa, Blerta; Blattner, Mirjam; Dalfovo, Davide; Chakravarty, Dimple; Soong, David; Cotter, Kellie Anne; Petris, Gianluca; Dhingra, Priyanka; Gasperini, Paola; Cereseto, Anna; Elemento, Olivier; Sboner, Andrea; Khurana, Ekta; Inga, Alberto; Rubin, Mark Andrew; Demichelis, Francesca (2017). Inherited determinants of early recurrent somatic mutations in prostate cancer. Nature communications, 8(1), p. 48. Nature Publishing Group 10.1038/s41467-017-00046-0

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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.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie
04 Faculty of Medicine > Pre-clinic Human Medicine > BioMedical Research (DBMR) > DBMR Forschung Mu35 > Forschungsgruppe Präzisionsonkologie

UniBE Contributor:

Cotter, Kellie Anne and Rubin, Mark Andrew

Subjects:

500 Science
500 Science > 570 Life sciences; biology

ISSN:

2041-1723

Publisher:

Nature Publishing Group

Language:

English

Submitter:

Marla Rittiner

Date Deposited:

02 Feb 2018 12:47

Last Modified:

23 Oct 2019 01:33

Publisher DOI:

10.1038/s41467-017-00046-0

PubMed ID:

28663546

BORIS DOI:

10.7892/boris.110780

URI:

https://boris.unibe.ch/id/eprint/110780

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