Identifying signatures of mutational mechanisms for tandem duplications found in breast cancers


Leila Shepard

Document Type


Publication Date

Summer 2022



JAX Location

In: Student Reports, Summer 2022, The Jackson Laboratory


Cancer is characterized by mutations that perturb genes associated with cell cycle regulation, which often result in rearrangements including duplications of regions of the genome. Tandem duplications (TDs) are a type of structural variation that consist of a head-to-tail duplication and are common in certain cancers. These mutations have the ability to disrupt or amplify genes, accelerating tumor progression. The tandem duplicator phenotype (TDP) is an enrichment for TDs grouped into distinct size classes, and it is found in about 50% of triple negative breast cancer, ovarian cancer, and endometrial cancers. Because the biological mechanisms of TD formation are largely unknown, we have applied long read sequencing to resolve the full structure of TDs, including breakpoints and small variants inside the nascent copy. From a call set of 649 fully reconstructed TDs to base pair resolution, we fully reconstructed 221 breakpoints spanning in size from a couple hundred to more than 200 kbp. We looked at the mutational signatures of each TD, focusing on unique SNV changes in each copy of the TD and found evidence for non-homologous end joining (NHEJ) and replication-based repair mechanisms. We also identified an enrichment for complex TD events that were previously unknown. These results provide a basis for future research in TD formation research, structural variant mechanism, and tumor progression.

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