Abstract 5381: Understanding the genesis and oncogenic consequences of tandem duplicator phenotypes in human cancers

Abstract

Abstract Genome-scale instability configurations in cancer genomes are commonly found across different types of cancers. We and others have described an enrichment of head-to-tail somatic segmental tandem duplications (TDs) in primarily breast and ovarian cancers, a configuration known as the Tandem Duplicator Phenotype (TDP). Here, we perform a meta-analysis of 2,717 human cancer genomes, representing 30 different tumor types and refine the TDP classification based on the identification of highly specific and recurrent TD span profiles. Overall, we identify the TDP as a highly recurrent chromosomal instability configuration, occurring in 14% of the cancer genomes examined. The TDP is remarkably prevalent in triple negative breast cancer (50%), ovarian cancer (55%), and uterine cancers (45%), but is infrequent in most other cancer types. In TDP tumors, TD span sizes can be classified into three major discrete intervals with modal values of 10 Kb, 230 Kb, and 1.7 Mb. TDPs with a dominant TD modal span size of 10 Kb are strongly associated with conjoint TP53 mutations and BRCA1 deficiency across different tumor types. TDPs with larger span sizes (230 Kb and 1.7 Mb) are associated with CCNE1 pathway activation and CRKRS/CDK12 gene disruptions. We proved the driver role of the conjoint abrogation of the BRCA1 and TP53 genes for the induction of TDP cancers with the 10 Kb predominant span peak by generating mammary cancers with a Tandem Duplicator Phenotype of the ~10 Kb TD span configuration type in genetically modified mouse models harboring deleterious mutations in only these same two genes. Lastly, we describe how heterogeneous combinations of tumor suppressors and chromatin topologically associating domains are disrupted, and oncogene and tissue-specific super enhancers are duplicated as a consequence of TD formation in TDP tumors. In summary, our work unifies a number of observations around a specific cancer genomic signature, shows how a number of genetic drivers converge on creating the tandem duplicator phenotype, and how the downstream consequences of the TDs generate oncogenic diversity that allows for further formation of genetic subgroups. The implications of TDP-based stratification for therapy response are currently under investigation. Citation Format: Francesca Menghi, Floris Barthel, Vinod Yadav, Ming Tang, Bo Ji, Gregory Carter, Jos Jonkers, Roel Verhaak, Ralph Scully, Ed Liu. Understanding the genesis and oncogenic consequences of tandem duplicator phenotypes in human cancers [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 5381.