Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal

Summary

Clear-cell renal cell carcinoma (ccRCC) exhibits a broad range of metastatic phenotypes that have not been systematically studied to date. Here, we analyzed 575 primary and 335 metastatic biopsies across 100 patients with metastatic ccRCC, including two cases sampledat post-mortem. Metastatic competence was afforded by chromosome complexity, and we identify 9p loss as a highly selected event driving metastasis and ccRCC-related mortality (p = 0.0014). Distinct patterns of metastatic dissemination were observed, including rapid progression to multiple tissue sites seeded by primary tumors of monoclonal structure. By contrast, we observed attenuated progression in cases characterized by high primary tumor heterogeneity, with metastatic competence acquired gradually and initial progression to solitary metastasis. Finally, we observed early divergence of primitive ancestral clones and protracted latency of up to two decades as a feature of pancreatic metastases.

Graphical Abstract

Highlights

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  Evolutionary study of matched primary metastasis biopsies from 100 ccRCC cases

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  Metastasis competence is afforded by chromosome complexity, but not driver mutation load

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  The hallmark genomic drivers of ccRCC metastasis are loss of 9p and 14q

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  Punctuated and branched evolution result in distinct patterns of metastases

Abstract

A multi-center prospective study and two validation cohorts of matched primary metastasis biopsies from 100 patients with clear-cell renal cell carcinoma provides a comprehensive picture of the genetic underpinnings and the evolutionary patterns of metastasis.