Genomic architecture and evolution of clear cell renal cell carcinomas defined by multiregion sequencing.
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.
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK.
Marco
M
Gerlinger
Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London, UK.
Stuart
S
Horswell
Department of Medicine, Royal Marsden Hospital, London, UK.
James
J
Larkin
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK.
Andrew J
AJ
Rowan
Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London, UK.
Max P
MP
Salm
Instituto de Biomedicina y Biotecnología de Cantabria (CSIC-UC-Sodercan), Departamento de Biología Molecular, Universidad de Cantabria, Santander, Spain.
Ignacio
I
Varela
Department of Medicine, Royal Marsden Hospital, London, UK.
Rosalie
R
Fisher
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK.
Nicholas
N
McGranahan
Advanced Sequencing Facility, Cancer Research UK London Research Institute, London, UK.
Nicholas
N
Matthews
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK.
Claudio R
CR
Santos
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK.
Pierre
P
Martinez
Advanced Sequencing Facility, Cancer Research UK London Research Institute, London, UK.
Benjamin
B
Phillimore
Advanced Sequencing Facility, Cancer Research UK London Research Institute, London, UK.
Sharmin
S
Begum
Advanced Sequencing Facility, Cancer Research UK London Research Institute, London, UK.
Adam
A
Rabinowitz
Experimental Histopathology, Cancer Research UK London Research Institute, London, UK.
Bradley
B
Spencer-Dene
Biomolecular Modelling, Cancer Research UK London Research Institute, London, UK.
Sakshi
S
Gulati
Biomolecular Modelling, Cancer Research UK London Research Institute, London, UK.
Paul A
PA
Bates
Experimental Histopathology, Cancer Research UK London Research Institute, London, UK.
Gordon
G
Stamp
Department of Medicine, Royal Marsden Hospital, London, UK.
Lisa
L
Pickering
Department of Medicine, Royal Marsden Hospital, London, UK.
Martin
M
Gore
Department of Urology, Royal Marsden Hospital, London, UK.
David L
DL
Nicol
Department of Pathology, Royal Marsden Hospital, London, UK.
Steven
S
Hazell
Department of Genomic Medicine, MD Anderson Cancer Center, Houston, Texas, USA.
P Andrew
PA
Futreal
Bioinformatics and Biostatistics, Cancer Research UK London Research Institute, London, UK.
Aengus
A
Stewart
Translational Cancer Therapeutics Laboratory, Cancer Research UK London Research Institute, London, UK.|University College London Cancer Institute, University College London, London, UK.
Charles
C
Swanton
D002292:Carcinoma, Renal Cell / Q000235:genetics*; D058534:Class I Phosphatidylinositol 3-Kinases; D018899:CpG Islands; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins; D018450:Disease Progression; D019143:Evolution, Molecular; D059472:Exome; D023281:Genomics; D059014:High-Throughput Nucleotide Sequencing; D011495:Histone-Lysine N-Methyltransferase / Q000235:genetics; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics; D010802:Phylogeny; D020641:Polymorphism, Single Nucleotide; D014157:Transcription Factors / Q000235:genetics; D025521:Tumor Suppressor Proteins / Q000235:genetics; D043222:Ubiquitin Thiolesterase / Q000235:genetics; D051794:Von Hippel-Lindau Tumor Suppressor Protein / Q000235:genetics
D058534:Class I Phosphatidylinositol 3-Kinases; D004268:DNA-Binding Proteins; D011495:Histone-Lysine N-Methyltransferase; D009687:Nuclear Proteins; D019869:Phosphatidylinositol 3-Kinases; D014157:Transcription Factors; D025521:Tumor Suppressor Proteins; D043222:Ubiquitin Thiolesterase; D051794:Von Hippel-Lindau Tumor Suppressor Protein; C400134:BAP1 protein, human; C102195:PBRM1 protein, human; C521636:SETD2 protein, human; C484760:PIK3CA protein, human; C497446:VHL protein, human