Maqueda Real, A.; Olle Monras, L.; Park, S.

Metastatic cancer, a major cause of mortality, has been understudied compared to primary tumors, leaving gaps in our understanding of how cancer genes adapt between these states. We analyzed the association between mutations and copy-number alterations in 25,000 tumor samples from both primary and metastatic cancers. Our findings show that cancer genes display distinct interaction strengths across these states, with 27.45% of genes, including ARID1A, FBXW7, and SMARCA4, shifting between one-hit and two-hit drivers. Interaction strengths varied by cancer state and treatment conditions, revealing seven state-specific interactions. We also identified 38 primary-specific and 21 metastatic-specific high-order interactions, enriched in cancer hallmarks, indicating unique tumor progression mechanisms. These findings highlight dynamic tumor progression mechanisms and under-score the importance of considering cancer state in research and treatment strategies for precise therapeutic interventions.