Abstract LB045: Pancancer meta-analysis of the genomic features associated with tandem duplication formation in cancer

Abstract Tandem Duplicator Phenotypes (TDPs) are a class of genome instability profiles characterized by the presence of hundreds of somatic head-to-tail tandem duplications (TDs) evenly distributed throughout the cancer genome. Different TDPs are characterized by distinct but recurrent TD span profiles, they manifest with different frequencies across different tumor types, and driven by distinct genetic perturbations (i.e., BRCA1 loss, activation of the CCNE1/CCNA2 pathways or CDK12 loss). Occurring in over 14% of all cancers, TDs in TDP disrupt tumor suppressors and duplicate oncogene. Thus, TDP is a genomic instability profile that enhances the oncogenic burden of a tumor. To better understand the potential mechanisms of TD formation in the context of the TDPs, we performed a pancancer meta-analysis of the local genomic features associated with somatic structural variation breakpoints. Specifically, we grouped, classified and characterized the four basic types of somatic structural variation breakpoints (TDs, deletions, inversions and translocations) based on their span size, their TDP context as well as its associated genetic perturbation. Using both a discovery and a validation datasets, comprising 3,084 and 4,784 independent cancer genomes, respectively, we found that cyclin-related TD breakpoints, from small (∼10 Kb), medium (∼200-330 Kb) and large (∼1-2Mb) TDs, consistently form in regions with the highest likelihood of generating a replication fork barrier due to either secondary DNA conformations or transcription-replication collisions. On the other hand, both small and medium BRCA1-linked TD breakpoints show significantly weaker enrichment in those same regions. This suggests that the signal of BRCA1-linked TD breakpoints mapping to these regions may be diluted by a more homogenous distribution of breakpoints throughout the genome, potentially reflecting attempted replication across ssDNA breaks in the parental template followed by their conversion to single ended breaks. Interestingly, neither the medium nor the large TDs linked to CDK12 deficiency associated with local DNA features indicative of replication fork stalling, suggesting a different mechanism for CDK12-linked TD formation. Converging results were obtained in a sample-based analysis, where each genome was classified based on its TDP/genetic driver status and analyzed as a unit: cyclin-related TDP genomes are enriched for TD breakpoints mapping to regions of early replication/replication origin, active chromatin, high transcription, G4 and Rloop formation and regions prone to double strand break, when compared to non-TDP genomes that are wild type for all drivers examined. Conversely, BRCA1-TDP and CDK12-TDP genomes show no enrichment of these genomic features at their TD breakpoints. Of interest, CCNE1 amplified genomes and FBXW7 mutated genomes that do not classify as TDP have different breakpoint profiles compared to their TDP counterparts, suggesting that additional genetic factors must be at play to synergize with cyclin driven replication stress in inducing TDP.Taken together, our analyses indicates that the different drivers for TDPs favor distinct genomic features for SV formation. This work provides novel insights in the mutational processes that shape the genomic landscape of cancer cells. Citation Format: Francesca Menghi, Edison T. Liu. Pancancer meta-analysis of the genomic features associated with tandem duplication formation in cancer [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2025; Part 2 (Late-Breaking, Clinical Trial, and Invited Abstracts); 2025 Apr 25-30; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2025;85(8_Suppl_2):Abstract nr LB045.