Clonal architectures predict clinical outcome in clear cell renal cell carcinoma

Abstract

The genetic landscape of clear cell renal cell carcinoma (ccRCC) had been investigated extensively but its evolution patterns remained unclear. Here we analyze the clonal architectures of 473 patients from three different populations. We find that the mutational signatures vary substantially across different populations and evolution stages. The evolution patterns of ccRCC have great inter-patient heterogeneities, with del(3p) being regarded as the common earliest event followed by three early departure points: VHL and PBRM1 mutations, del(14q) and other somatic copy number alterations (SCNAs) including amp(7), del(1p) and del(6q). We identify three prognostic subtypes of ccRCC with distinct clonal architectures and immune infiltrates: long-lived patients, enriched with VHL but depleted of BAP1 mutations, have high levels of Th17 and CD8+ T cells while short-lived patients with high burden of SCNAs have high levels of Tregs and Th2 cells, highlighting the importance of evaluating evolution patterns in the clinical management of ccRCC.

Immune evasion in renal cell carcinoma: biology, clinical translation, future directions

“…• Secrete suppressive cytokines such as transforming growth factor-β (TGFβ) and IL-10, express CTLA-4 and promote tumor progression. • Presence of high Tregs is associated with a poor prognosis in RCC 48,49 , and a higher T effector/Treg ratio is associated with a lower recurrence rate 50…”

Ankhd1enhances polycystic kidney disease development via promoting proliferation and fibrosis

“…Our findings are likely to be relevant to human ADPKD because ANKHD1 inhibition also attenuated proliferation of human ADPKD renal cells and importantly ANKHD1 protein is highly expressed in human ADPKD biopsies at all stages of disease progression. Since ANKHD1 controls the ability of cells to divide, it is possible that its inhibition may slow the growth of cyst in additional ciliopathies 23,24 and other kidney diseases defined by epithelial overgrowth such as renal cancer 25 , besides ADPKD.…”

Targeting the Deterministic Evolutionary Trajectories of Clear Cell Renal Cell Carcinoma

“…In comparison to other malignancies, ccRCC is characterized by a high prevalence of somatic copy number alterations (SCNAs) and a low burden of somatic substitutions [6,8,11,12]. The integrative analysis of the genetic and clinical data led to the identification of certain alterations with prognostic value, such as mutually exclusive mutations of BAP1 and PBRM1 [13][14][15]. These studies, although conducted on large cohorts of patients, did not determine the prognostic values of genetic alterations according to whether they were clonal or subclonal.…”

“…These studies, although conducted on large cohorts of patients, did not determine the prognostic values of genetic alterations according to whether they were clonal or subclonal. Huang et al were among the first to demonstrate the possibility of genomic subtyping of ccRCC [13]. Recently, Turajlic and colleagues provided a comprehensive model of ccRCC evolution [14], which might lay the foundation for the development of precision clinical management.…”