Molecular underpinnings of metastatic small renal masses.

Metastases in renal cell carcinoma (RCC) typically arise from large primary tumors. However, a subset of patients with small renal masses (SRMs; ≤4 cm) can develop metastatic disease. Identifying these tumors is clinically important, as many SRMs are managed with active surveillance, and their study may provide insight into the early acquisition of metastatic competence. It remains unclear whether these tumors acquire distinct metastatic programs or instead show premature activation of the same aggressive programs typically associated with larger tumors. Here, we performed integrated morphological and molecular profiling of a multiinstitutional cohort of metastatic SRMs, including whole-exome sequencing and RNA-Seq, using nonmetastatic primary tumors as controls. Among metastatic, non-clear cell SRMs, we identified NF2-altered tumors, ELOC-mutated RCC, and an mTOR-driven eosinophilic vacuolated tumor. Metastatic clear cell SRMs were enriched by multi-hit aggressive genotypes, including recurrent losses of chromosomes 8p, 9, and 14q, as well as co-occurring driver alterations (≥2 events), including BAP1 and mTOR pathway genes. Transcriptomic analyses revealed enrichment of the non-negative matrix factorization 3 (NMF3) subtype from the IMmotion151 trial-based taxonomy, along with metabolic rewiring and reduced cytotoxic immune effector function. Collectively, these findings identify molecular programs associated with metastatic competence in SRMs, highlight the importance of genomic studies of equivocal non-clear cell SRMs, and provide a biological framework for risk stratification in patients often considered for active surveillance.