Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing

By M. Gerlinger, S. Horswell, J. Larkin, A. Rowan, M. Salm, I. Varela, R. Fisher, Nicholas McGranahan, N. Matthews, Claudio R. Santos and 15 more. Nature Genetics, 2014

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Clear cell renal carcinomas (ccRCCs) can display intratumor heterogeneity (ITH). We applied multiregion exome sequencing (M-seq) to resolve the genetic architecture and evolutionary histories of ten ccRCCs. Ultra-deep sequencing identified ITH in all cases. We found that 73–75% of identified ccRCC driver aberrations were subclonal, confounding estimates of driver mutation prevalence. ITH increased with the number of biopsies analyzed, without evidence of saturation in most tumors. Chromosome 3p loss and VHL aberrations were the only ubiquitous events. The proportion of C>T transitions at CpG sites increased during tumor progression. M-seq permits the temporal resolution of ccRCC evolution and refines mutational signatures occurring during tumor development.

Subfields: Cancer Research, Molecular Biology, Pulmonary and Respiratory Medicine

View Paper: https://www.semanticscholar.org/paper/515ad29fc833e0f50cfb213b92e4d2a21abf70ce

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Citations in the corpus

Clonal Heterogeneity and Tumor Evolution: Past, Present, and the Future. (2017, neutral): “…same patient, evidence for both contingency and convergence can be found; despite distinct secondary 3p loss of heterozygosity events and driver mutations in different cancers from the same patient, there was evidence for convergent PI3K signal transduction pathway activation (Fisher et al., 2014).”
Integrated Proteogenomic Characterization of Clear Cell Renal Cell Carcinoma (2019, result): “A uthor M anuscript A uthor M anuscript A uthor M anuscript A uthor M anuscript (D) Heatmap of “cell cycle” module expression with grade, BAP1 and chromosome 14 loss, and genome instability distribution annotated.”
Renal cell carcinoma (2017, background): “6 First, RCC proved to be an extremely heterogeneous disease [15]; beyond the seminal genetic alteration (mutation, deletion or hypermethylation) of the VHL tumour suppressor gene, which is present in the vast majority of sporadic RCCs, other genetic alterations may occur, especially over time [16],”
Tumor immune microenvironment characterization in clear cell renal cell carcinoma identifies prognostic and immunotherapeutically relevant messenger RNA signatures (2016, background): “[57] ccRCC multiregion tumor study (referred to as GERLINGER from here on).”
Renal cell carcinoma: ESMO Clinical Practice Guidelines for diagnosis, treatment and follow-up. (2010, background): “6 First, RCC proved to be an extremely heterogeneous disease [15]; beyond the seminal genetic alteration (mutation, deletion or hypermethylation) of the VHL tumour suppressor gene, which is present in the vast majority of sporadic RCCs, other genetic alterations may occur, especially over time [16],”
Intra-tumor Heterogeneity in Localized Lung Adenocarcinomas Delineated by Multi-region Sequencing (2014, neutral): “Studies in clear cell renal carcinoma (ccRCC) have demonstrated substantial ITH, with the majority of mutations in known cancer genes confined to spatially separated tumor regions except for VHL loss being a ubiquitous event (16, 17).”
Subclonal diversification of primary breast cancer revealed by multiregion sequencing (2015, neutral): “This contrasts with the profound heterogeneity seen almost universally in clear cell renal cell carcinoma (RCC), where subclonal diversification occurs early after VHL mutation 18,19 .”