Deciphering Mutational Signature Dynamics in Hormone-Sensitive Breast Cancer During Treatment Adaptation.

Abstract The DNA accumulates somatic changes before and after tumor initiation. These changes have been classified into mutational signatures (1) but only recently have studies begun to experimentally validate and functionally dissect these signatures. The role of the underlying functional annotation of DNA and long-term exposure to endocrine therapies in shaping signatures in breast cancer remains to be elucidated. In this study we use novel patients- and in vitro-derived longitudinal datasets to dissect the dynamic nature of mutational processes throughout the evolution of hormone-sensitive breast cancer. We demonstrate that chromatin and epigenetic cues can actively shape the local mutational processes, with significant impact on regulatory elements and cancer drivers. We also conclude that the etiology of APOBEC and clock-like SBS5 signatures needs further experimental corroboration. In conclusion, our research illuminates the dynamic nature of mutational processes and their direct influence on tumor evolution