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; Francesca Demichelis

doi:10.1038/s41467-017-00046-0

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, Francesca Demichelis

Genitourinary Medical Oncology

Research output: Contribution to journal › Article › peer-review

25 Scopus citations

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.

Original language	English (US)
Article number	48
Journal	Nature communications
Volume	8
Issue number	1
DOIs	https://doi.org/10.1038/s41467-017-00046-0
State	Published - Dec 1 2017

ASJC Scopus subject areas

General Chemistry
General Biochemistry, Genetics and Molecular Biology
General Physics and Astronomy

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Romanel, A., Garritano, S., Stringa, B., Blattner, M., Dalfovo, D., Chakravarty, DI., Soong, D., Cotter, K. A., Petris, G., Dhingra, P., Gasperini, P., Cereseto, A., Elemento, O., Sboner, A., Khurana, E., Inga, A., Rubin, M. A., & Demichelis, F. (2017). Inherited determinants of early recurrent somatic mutations in prostate cancer. Nature communications, 8(1), Article 48. https://doi.org/10.1038/s41467-017-00046-0

Romanel, A, Garritano, S, Stringa, B, Blattner, M, Dalfovo, D, Chakravarty, DI, Soong, D, Cotter, KA, Petris, G, Dhingra, P, Gasperini, P, Cereseto, A, Elemento, O, Sboner, A, Khurana, E, Inga, A, Rubin, MA & Demichelis, F 2017, 'Inherited determinants of early recurrent somatic mutations in prostate cancer', Nature communications, vol. 8, no. 1, 48. https://doi.org/10.1038/s41467-017-00046-0

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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.",

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AU - Chakravarty, DImple

AU - Soong, David

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AU - Dhingra, Priyanka

AU - Gasperini, Paola

AU - Cereseto, Anna

AU - Elemento, Olivier

AU - Sboner, Andrea

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AU - Rubin, Mark A.

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Inherited determinants of early recurrent somatic mutations in prostate cancer

Abstract

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