LAUSR

Prostate cancer (PCa) is a hormone-driven disease characterized by an abundance of structural variations (SV). Deconvolving the SV patterns can both inform on prior mutational processes leading to cancer, and be leveraged to identify patients with more aggressive disease. Under the auspices of the Pan Prostate Cancer Group (PPCG) consortium, we used whole genome sequencing of 812 treatment naive PCa patients to study both simple and complex SVs. In total, we classified 15,708 simple SVs and 1,448 complex SV events. Complex SVs such as chromothripsis, chromoplexy and templated insertion were found in more than half of the cohort. We also detected tandem duplicator phenotype (TDP) in a subset of the patients associated with CDK12 aberrations. Breakpoint recurrence analysis of driver genes revealed disruption of e.g. PTEN and formation of TMPRSS2-ERG fusion genes frequently coincide with occurrences of specific complex SV types, suggesting specific mutational processes driving these alterations of these cancer genes. Based on the simple and complex SV classifications we extracted six SV signatures, including two TDP-like signatures, distinct deletion-specific SV signatures and a signature characteristic of AR binding sites. We found signatures associated with disease markers, including Gleason score, risk scores, as well as age. Together, these findings provide insights into mechanisms driving SV formation and driver gene alterations in PCa, with potential for identifying markers of aggressive disease. Citation Format: André Olsen, Francesco Favero, Yilong Li, Etsehiwot Girma, Breon Feran, Tony Papenfuss, Kristian Helin, Jüri Reimand, Joachim Weischenfeldt. Panorama of complex structural variants in primary localized prostate cancer [abstract]. In: Proceedings of the AACR Special Conference: Advances in Prostate Cancer Research; 2023 Mar 15-18; Denver, Colorado. Philadelphia (PA): AACR; Cancer Res 2023;83(11 Suppl):Abstract nr A047.