Residual Metastatic Affinity Across Autopsy and Clinical Cohorts: Discovery in 332,195 Japanese Autopsies and External Validation in MSK-MET

Background: Metastatic-site frequencies reflect both how extensively a cancer spreads and how commonly an organ is involved across cancers. We assessed whether cancer–organ affinity beyond these overall effects is reproducible between autopsy and clinical cohorts. Methods: We analyzed 796,211 organ-involvement events from 332,195 Japanese malignant autopsy cases, covering 76 primary cancers and 48 target sites. We quantified observed-to-expected affinity with empirical-Bayes shrinkage and screened associations with multiple-testing correction. Robust associations underwent anatomical adjudication and fixed-margin testing. External validation compared 143 harmonized cancer–organ pairs (13 cancers, 11 targets) with an independently analyzed MSK-MET-derived clinical matrix. Results: We identified 176 robust enriched associations; 10 remained in a conservative analysis of patterns compatible with distant-organ spread. All 176 remained significant under exact fixed-margin tests. Among 5000 fixed-margin randomized matrices, none contained more than three robust associations, versus 176 observed (Monte Carlo p = 2.00 × 10−4). Conventional metastatic-site fractions were highly correlated across cohorts (Spearman ρ = 0.861). Residual affinities also showed concordance (Spearman ρ = 0.669; 95% bootstrap confidence interval, 0.416–0.839; Pearson r = 0.747), with matching enrichment or depletion directions in 76.9% of pairs. However, only three of the ten selected distant-organ associations could be compared individually across cohorts, and two showed enrichment in both datasets. Conclusions: Residual metastatic affinity captures partly reproducible population-level patterns beyond metastatic frequency. Validation was restricted to harmonizable categories; these aggregate findings neither estimate individual metastatic risk nor confirm lesion-level distant spread.