Studying mutational signatures in cancer is a powerful way to understand tumor evolution and etiology. These signatures are the patterns found in somatic mutations in cancer genomes, and they can guide therapeutic plans and inform cancer prevention efforts. To date, the bulk of the research in mutational signatures has been on single nucleotide polymorphisms or small indels in the genome. While larger-scale genomic rearrangements are common in tumors as well, their study in a systematic way has lagged. Although previous work has begun defining these signatures, many questions remain, including the underlying biological and pathological processes that lead to their formation.
This ASPIRE award will address these questions by comprehensively studying the various genetic alterations that shape cancer genomes. The project integrates advances from four leading labs, each contributing expertise in different aspects of cancer genomics analysis. The collaborative effort involves developing novel approaches to characterize the chronological sequence underlying somatic copy number alterations by incorporating structural and single nucleotide variant data to refine evolutionary trajectories. Critically, the project aims to redefine chromosomal instability signatures based on discrete evolutionary events, laying the groundwork for next-generation signatures of chromosomal instability. By doing so, researchers anticipate improving mechanistic insights into the origin and evolution of cancer, leading to the discovery of biomarkers for disease subtypes and informing treatment decisions.