scholarly journals Spatial patterns of tumour growth impact clonal diversification in a computational model and the TRACERx Renal study

2021 ◽  
Author(s):  
Xiao Fu ◽  
Yue Zhao ◽  
Jose I. Lopez ◽  
Andrew Rowan ◽  
Lewis Au ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Time Course ◽  
Tumour Growth ◽  
Clear Cell ◽  
Early Stage ◽  
Clonal Evolution ◽  
Growth Surface ◽  
Cell Renal Cell Carcinoma

AbstractGenetic intra-tumour heterogeneity fuels clonal evolution, but our understanding of clinically relevant clonal dynamics remain limited. We investigated spatial and temporal features of clonal diversification in clear cell renal cell carcinoma through a combination of modelling and real tumour analysis. We observe that the mode of tumour growth, surface or volume, impacts the extent of subclonal diversification, enabling interpretation of clonal diversity in patient tumours. Specific patterns of proliferation and necrosis explain clonal expansion and emergence of parallel evolution and microdiversity in tumours. In silico time-course studies reveal the appearance of budding structures before detectable subclonal diversification. Intriguingly, we observe radiological evidence of budding structures in early-stage clear cell renal cell carcinoma, indicating that future clonal evolution may be predictable from imaging. Our findings offer a window into the temporal and spatial features of clinically relevant clonal evolution.

scholarly journals VHL and HIF-1α: gene variations and prognosis in early-stage clear cell renal cell carcinoma

2014 ◽  
Vol 31 (3) ◽  
Author(s):  
Francesca Lessi ◽  
Chiara Maria Mazzanti ◽  
Sara Tomei ◽  
Claudio Di Cristofano ◽  
Andrea Minervini ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Renal Cell ◽  
Clear Cell ◽  
Early Stage ◽  
Cell Renal Cell Carcinoma

Genomic instability and DNA damage repair in clear cell renal cell carcinoma.

2017 ◽  
Vol 35 (15_suppl) ◽  
pp. 4581-4581
Author(s):  
Patrick Glen Pilie ◽  
Lijun Zhou ◽  
Pan Tong ◽  
Surena F. Matin ◽  
Kanishka Sircar ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Dna Damage ◽  
Cell Carcinoma ◽  
Genomic Instability ◽  
Renal Cell ◽  
Clear Cell ◽  
Early Stage ◽  
Cell Renal Cell Carcinoma ◽  
Mutator Phenotype ◽  
Damage Repair

4581 Background: Kidney cancer accounts for 2-3% of all new cancers with clear cell renal cell carcinoma (ccRCC) the most common subtype. ccRCC is characterized by a high level of genomic instability, suggesting defective DNA damage repair (DDR). The most frequent genomic alteration in ccRCC involves loss of the 3p chromosomal arm which harbors the von Hippel Lindau gene ( VHL), in addition to nearby genes SETD2, BAP1, and PBRM. We hypothesized that VHL loss leads to defective DDR as an early event in ccRCC carcinogenesis, giving way to a mutator phenotype. We posited that assessment of very early ccRCC tumors would inform us regarding the core mutations required to drive tumorigenesis in ccRCC, and that we could confirm these findings in appropriate model systems. Methods: We performed whole-exome (WES) DNA sequencing on 11 early-stage ccRCC tumors from 5 individuals, along with their matched normal DNA. We then analyzed ccRCC samples with and without somatic VHL mutations from the Cancer Genome Atlas (TCGA) for mutational load. Finally we assessed DDR signaling activity in renal proximal tubular cell lines (RPTEC) with VHL/SETD2 knockdown and in murine embryo fibroblasts (MEFs) from Vhl and Setd2knockout mice treated with etoposide via γH2AX expression and direct repeat-green fluorescent protein reporter assay. Results: All 11 samples revealed loss of 3p with pathogenic germline or somatic mutation in remaining VHL allele. No mutations were found in genes frequently mutated in larger ccRCC, including PBRM1, BAP1 or SETD2. WES revealed ~100 mutations/tumor, with no shared mutations across samples, even within the same individual. TCGA analysis showed similar mutational loads across ccRCC samples. MEFs with biallelic loss of Vhl and monoallelic loss of Setd2 and RPTEC with VHL and SETD2knockdown displayed increased DNA damage with impaired homologous repair and increased non-homologous end joining (NHEJ). Conclusions: Early stage ccRCC tumors with loss of VHL and chr 3p demonstrate genomic instability and a mutator phenotype similar to more advanced ccRCC. Cell line models of early ccRCC show increased DNA damage with a greater reliance on error-prone NHEJ machinery. These defects could be targeted for synthetic lethal treatment strategies.

Homologous repair deficiency in VHL-mutated clear cell renal cell carcinoma.

2018 ◽  
Vol 36 (6_suppl) ◽  
pp. 585-585 ◽  
Author(s):  
Patrick Glen Pilie ◽  
Lijun Zhou ◽  
Christine B Peterson ◽  
Yang Peng ◽  
Guang Peng ◽  
...  
Keyword(s):  
Renal Cell Carcinoma ◽  
Cell Carcinoma ◽  
Proteomic Analysis ◽  
In Silico ◽  
Renal Cell ◽  
Clear Cell ◽  
Early Stage ◽  
Gene Signature ◽  
Cell Renal Cell Carcinoma ◽  
Tumor Stages

585 Background: Clear cell renal cell carcinoma (ccRCC) displays genomic instability across all tumor stages, indicative of increased replicative stress and defects in DNA damage response (DDR) pathways including homologous repair (HR); however ccRCC does not display mutations in canonical DDR genes and advanced ccRCC is not traditionally sensitive to DNA damaging agents. We hypothesized that biallelic VHL loss is sufficient to cause HR deficiency (HRD) and that early stage ccRCC is more likely to display HRD than late stage disease. Methods: We performed whole-exome (WES) sequencing of 15 small ccRCC tumors to assess for mutational burden, mutational signature, and cancer-related driver gene mutations. We performed in silico genomic, transcriptomic, and proteomic analysis of tumors in KIRC TCGA to assess for HRD. Finally, we assessed HR efficiency as a product of biallelic VHL loss in engineered cell line models. Results: 15/15 early stage ccRCC had VHL mutations, approximately 100 additional mutations per tumor, but no common mutations found in KIRC TCGA. In silico analysis showed 67% of KIRC TCGA displayed HRD gene signature, and was significantly higher in stage I disease (p = 2.21e-08). Patients with VHL-mutated tumors are more commonly HRD than HR intact (HRI) (p = 0.03), with frameshift/nonsense variants in VHL more likely to result in HRD than missense variants (p = 0.02). Multivariate analysis showed HRD predicted for better overall survival compared to HRI (p < 0.0001). Proteomic analysis of KIRC TCGA revealed HRI samples had significantly higher protein expression of Rad51 and RAPTOR when compared to HRD samples. Lastly, etoposide-treated MEF Vhl-/- cell lines displayed reduced HR efficiency when compared to Vhl intact controls. Conclusions: Biallelic loss of VHL is sufficient to cause HRD. HRD gene signature predicts for significantly better OS in ccRCC patients, and early stage ccRCC is more likely to be HRD. mTOR/PI3K signaling pathway proteins are differentially expressed in HRI patient samples from TCGA compared to HRD, suggesting a possible role for these oncogenes driving a HRI phenotype. Treatment strategies combining PARP inhibitors with PI3K/mTOR inhibitors should be tested in advanced VHL-mutated ccRCC.

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