Deciphering genomic evolution of metastatic organotropism with 535 paired primary lung cancers and metastases.

Metastasis is the leading cause of death in lung cancer patients, yet our understanding of its genomic determinants and evolution remains limited. Here, we analyzed whole-exome sequencing data from 535 paired primary and metastatic tumors from 223 non-small cell lung cancer patients, including brain (BM), distant extracranial (ExM), and lymph node (LNM) metastases. BMs harbored the most somatic alterations compared to metastases in other sites. Despite the high concordance of putative driver alterations between paired primary tumors and metastases, PTPRD and FAT1 were highly enriched in BM-associated primary tumors. We discovered loss of early driver mutations by specific loss of heterozygosity in BMs. Monoclonal seeding is common in BMs (89%, 84/94) but relatively rarer in LNMs (41%, 74/179) and ExMs (49%, 19/39). Metastatic timing estimates indicated that BMs occur relatively later than LNMs. Collectively, our systematic analysis reveals distinct genomic features and evolutionary trajectories of BMs.