Abstract
SummaryClear-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.
Highlights
Large-scale sequencing initiatives, such as the cancer genome atlas (TCGA) and the international cancer genome consortium (ICGC), have profiled thousands of primary tumors across many cancer types
One-third of patients have metastases detected at pre-operative screening or surgery, termed ‘‘synchronous metastases.’’ Up to 50% develop metastases after the removal of the primary tumor, termed ‘‘metachronous metastases.’’ The spatial distribution of metastatic disease in Clear-cell renal cell carcinoma (ccRCC) varies from solitary, oligo (Weichselbaum and Hellman, 2011), and widespread
Overview of the Cohorts under Study ccRCC tumors exhibit a variety of progressive phenotypes, including invasion of the peri-renal and renal sinus fat (T3a), direct invasion through the renal capsule (Gerota’s fascia) and the adrenal gland (T4), intravascular tumor growth (T3a-T3c), and lymph node (N1/N2) and visceral metastases (M1), including indirect spread to the adrenal gland
Summary
Large-scale sequencing initiatives, such as the cancer genome atlas (TCGA) and the international cancer genome consortium (ICGC), have profiled thousands of primary tumors across many cancer types. Similar large-scale studies of metastases have been limited (Robinson et al, 2017; Zehir et al, 2017) and have not included matched primary tumors. Metastatic ccRCC, with its variable clinical presentation and natural history, is a compelling model for understanding the clonal evolution of metastasis. One-third of patients have metastases detected at pre-operative screening or surgery, termed ‘‘synchronous metastases.’’ Up to 50% develop metastases after the removal of the primary tumor (at least 3 months and as late as 30 years after primary surgery), termed ‘‘metachronous metastases.’’ The spatial distribution of metastatic disease in ccRCC varies from solitary (a single metastasis in a single location), oligo (limited in number and location; usually defined as %5 or %3 metastases) (Weichselbaum and Hellman, 2011), and widespread (multiple metastases in multiple sites)
Sign-in/Register to view highlights & summary 
Published Version (
Free)
Talk to us
Join us for a 30 min session where you can share your feedback and ask us any queries you have
Schedule a call