Tracking Cancer Evolution Reveals Constrained Routes to Metastases: TRACERx Renal

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.

Clonal evolution through genetic bottlenecks and telomere attrition: Potential threats to in vitro data reproducibility

“…(D) Population bottleneck caused by an external factor, such as single cell cloning or extensive killing of cells, that reduces the number of genetic variants that are allowed to be transmitted further, here limited to a single clone (blue), that evolved further to form a single subclone (yellow). (E) Population bottleneck caused by an endogenous factor resulting from a growth failure of all cells but a specific, small population (blue), which subsequently generates a subclone (brown) samples from the same tumor and to compare in detail the clonal landscapes of primary tumours with their recurrences, metastases, [19][20][21] and with tumor cells populating the bloodstream. 22 We now know that in malignant neoplasms intratumor genetic heterogeneity due to branching evolution is the rule rather than the exception.…”

Clear cell renal cell carcinoma with wild‐type von Hippel‐Lindau gene: a non‐existent or new tumour entity?

“…ccRCC cases with two active copies of VHL (‘truly’ wt VHL ccRCC) were also shown to also have significantly lower survival compared to those with a single or bi‐allelic inactivation of VHL . The aggressive nature of wt VHL ccRCC was further confirmed in another study by Turajlic et al ., in which they examined the routes and timing of ccRCC tumour metastasis. The result was the division of their cohort, made up of 575 primary and 335 metastatic biopsies across 100 patients, into two groups: cases with rapid progression and those with attenuated progression.…”

“…The result was the division of their cohort, made up of 575 primary and 335 metastatic biopsies across 100 patients, into two groups: cases with rapid progression and those with attenuated progression. They found that the rapid progression group was enriched with wt VHL tumours, associated with lower intratumor heterogeneity and increased genomic instability …”

CINSARC signature as a prognostic marker for clinical outcome in sarcomas and beyond

“…The prognostic value of CINSARC is thus supported mechanistically by (1) the pathway enrichment of the gene set restricted to mitosis and chromosome integrity and (2) the driver role of chromosomal instability in metastatic spread. Moreover, it is now clear that metastatic competence is afforded by chromosome complexity in other cancers . Therefore, the CINSARC signature could serve as an important biomarker for stratifying patients for systemic therapy in almost every type of malignant tumor.…”