Evolutionary dynamics of early and late mutational signatures in metastatic cancer.

Cancer genomes accumulate somatic mutations over time, influenced by both intrinsic and extrinsic mutational processes. In metastatic cancer, disseminated tumor cells may acquire additional mutations at metastatic sites, shaped by extrinsic factors distinct from those at the primary tumor. As a result, cancer genomes at metastatic sites may bear mutational signatures originating from both primary and metastatic environments. However, the patterns and relative contributions of mutational signatures specific to metastatic sites remain poorly understood. To investigate this, we analyzed mutational signatures from seven metastatic cancer patients. We observed distinct mutational patterns between early and late mutation profiles within individual patients, where the early and late categories were based on their relative timing during tumor evolution. Early mutations were often dominated by a single mutational signature that accounted for more than half of the total signature burden. These dominant signatures tended to be shared among tumors of the same cancer type, suggesting that early mutations in metastatic cancers may be shaped by a single, highly active mutational process at the primary tumor site. In contrast, late mutations were often more poorly decomposed into distinct mutational signatures, reflecting more complex and diverse compositions. Overall, early mutations tended to preserve clearer signals of their origin.