LAUSR

Somatic rearrangements are a part of mutational landscape of human cancer genomes. We systematically investigated the distribution of the somatic rearrangements in 560 breast cancer genomes and highlight 33 rearrangement hotspots associated with a signature of Homologous Recombinational repair deficiency, characterized mainly by large (>100kb) tandem duplications. Remarkably, these tandem duplication hotspots are enriched for breast cancer germline susceptibility loci (OR 4.28) and breast-specific “super-enhancer” regulatory elements (OR 3.54). They likely represent sites of selective susceptibility to double-strand break damage due to high transcriptional activity. However, through incrementally increasing the number of copies of these functionally active loci, they could inadvertently come under some level of selective pressure. Indeed, transcriptomic consequences range from strong individual oncogene effects through to weak but quantifiable multigene expression effects. We thus present a passenger somatic rearrangement mutational process that has the ability to create secondary driver events. It exerts its influence through coding sequences and non-coding regulatory elements, contributing a continuum of driver consequences, from modest through to strong effects, making this mutational process a particularly deleterious one. Citation Format: Dominik Glodzik, Sandro Morganella, Helen Davies, Serena Nik-Zainal, ICGC Breast Cancer Consortium. A somatic-mutational process in breast cancer genomes recurrently duplicates germline susceptibility loci and tissue-specific super-enhancers [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-262. doi:10.1158/1538-7445.AM2017-LB-262