According to the seed and soil hypothesis, the organ specificity of metastasis is not a random process and depends on multiple tumor-intrinsic and microenvironmental factors. In this study, we characterized the mutational landscape of a large cohort of human metastatic samples to investigate whether mutational trends determine metastatic dissemination. Genomic data from nine cancer types (bladder, breast, colorectal, endometrial, melanoma, non-small cell lung cancer, ovarian, pancreatic, and prostate) including 19827 patients were obtained from a pan-cancer study. When restricting the analysis to driver mutations, no robust, recurrent mutational patterns associated with metastatic locations were identified across cancer types. However, when cancer types were analyzed separately, mutational trends associated with specific metastatic locations emerged. Considering the total tumor mutational burden (TMB), central nervous system (CNS)/brain and lung metastases harbored a higher TMB than other metastatic locations. Since higher TMB in CNS/brain metastases was also associated with improved prognosis, these findings may be pivotal in refining immunotherapy strategies. Indeed, this observation was confirmed in an independent dataset including patients treated with immunotherapy. In conclusion, our findings suggest that TMB may have greater influence on metastatic organotropism than driver mutational background.
Candeal et al. (2026) studied this question.