Origins and Timing of Emerging Lesions in Advanced Renal Cell Carcinoma

Renal cell carcinoma (RCC) with venous tumor thrombus (VTT) arising from the primary tumor occurs in approximately 10% of cases and is thought to represent more advanced disease. The intravascular nature of VTT suggests that it may serve as a source for hematogenous metastases. RCC with VTT and distant metastasis provides unique opportunities to examine the origins and emergence timing of these distinct tumor lesions, and to identify molecular correlates with disease state. We performed multi-region exome and RNA-sequencing analysis of 16 patients with RCC with VTT, with eight patients also having sequenced metastasis, to identify genomic alterations, biological pathways, and evolutionary processes contributing to VTT and metastasis, and to ask whether metastasis arises directly from or independent of VTT. No specific genomic alterations were associated with VTT. Hallmark copy-number alterations (deletions of 14q, 8p, and 4q) were associated with metastasis and disease recurrence, and secondary driver alterations tended to accumulate in metastatic lineages. Mismatch repair mutational signatures co-occurred across most tumors, suggesting a role for intracellular DNA damage in RCC. Robust phylogenetic timing analysis indicated that metastasis typically emerged before VTT, rather than deriving from it, with the earliest metastases predicted to emerge years before diagnosis. As a result, VTT in metastatic cases frequently derived from a metastatic lineage. Relative to the primary tumor, VTT upregulated immediate-early genes and transcriptional targets of the TNF alpha/NF-kappa B pathway, whereas metastases upregulated MTOR and transcriptional targets downstream of mTORC1 activation.

Automated summary

This study analyzed the genomic alterations and molecular pathways associated with renal cell carcinoma (RCC) with venous tumor thrombus (VTT) and distant metastasis. The results showed that VTT did not have specific genomic alterations, while metastasis and disease recurrence were associated with certain copy-number alterations and secondary driver alterations. The study also found that metastasis generally occurred before VTT, with the earliest metastases predicted to emerge years before diagnosis. Furthermore, VTT upregulated immediate-early genes and transcriptional targets of the TNF alpha/NF-kappa B pathway, while metastases upregulated MTOR and transcriptional targets downstream of mTORC1 activation.