Inherited Determinants Of Early Recurrent Somatic Mutations In Prostate Cancer

Background: Prostate cancer (PCa) is a clinically heterogeneous hormone regulated disease with a strong genetic component and characterized by distinct molecular subclasses. Since hormone levels and related transcription factors vary during individual’s lifetime, we hypothesized that inherited variants within regulatory elements of the human genome might act as facilitators of specific early somatic events in PCa in age/hormone dependent manner. Methods: We developed a computational approach to nominate heritable facilitators of somatic genomic events in the context of the Androgen Receptor (AR) signaling. Germline variants within functionally active regions of the genome (N=21,364) defined as per ENCODE data were ranked by the so called Trigger Score, which quantifies the fraction of the transcriptome putatively modulated by each variant leveraging individuals’ genotypes and transcript levels from a cohort of human benign prostate tissues. Results: We identified 300 polymorphic regulatory elements that associate with DNA repair and hormone regulated transcript levels. In a cohort of 539 PCa and more than 3,000 controls, a variant on 7p14.3 strongly associated with an early recurrent prostate cancer specific somatic mutation in the Speckle-Type POZ protein (SPOP) gene (OR=5.54, P=1.22e-08). Integrated computational analysis suggested a broad transcriptional regulatory impact of the variant. In vitro luciferase assay in PC-3 cells demonstrated allele-specific enhancer activity of the locus that is concomitantly modulated by AR and by CCAAT/Enhancer Binding Protein beta (CEBPB). ChIP assays experiments showed AR and CEBPB binding to the locus. Upon deletion of the genomic locus via CRISPR-Cas9 followed by transcriptome sequencing, we observed differential transcript levels along chromosome 7 between edited versus control cells, but not in edited versus edited or control versus control, and nominated genes that were also predicted to physically interact with the 7p14.3 locus by previously generated Hi-C data from prostate cells. Conclusions: Our study suggests a relevant role in cancer predisposition of non-coding variants that lead to allele specific transactivation with age dependent and tissue specific effect manifesting in early somatic genomic events. Citation Format: Alessandro Romanel, Sonia Iolanda Garritano, Blerta Stringa, Mirjam Blattner, Davide Dalfovo, Dimple Chakravarty, Kellie Cotter, Priyanka Dhingra, Paola Gasperini, Olivier Elemento, Andrea Sboner, Alberto Inga, Ekta Khurana, MarK Rubin, Francesca Demichelis. Inherited determinants of early recurrent somatic mutations in prostate cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2017; 2017 Apr 1-5; Washington, DC. Philadelphia (PA): AACR; Cancer Res 2017;77(13 Suppl):Abstract nr LB-232. doi:10.1158/1538-7445.AM2017-LB-232