title: Parallel evolution of tumour subclones mimics diversity between tumours.
abstract: Intratumour heterogeneity (ITH) may foster tumour adaptation and compromise the efficacy of personalized medicine approaches. The scale of heterogeneity within a tumour (intratumour heterogeneity) relative to genetic differences between tumours (intertumour heterogeneity) is unknown. To address this, we obtained 48 biopsies from eight stage III and IV clear cell renal cell carcinomas (ccRCCs) and used DNA copy-number analyses to compare biopsies from the same tumour with 440 single tumour biopsies from the Cancer Genome Atlas (TCGA). Unsupervised hierarchical clustering of TCGA and multi-region ccRCC samples revealed segregation of samples from the same tumour into unrelated clusters; 25% of multi-region samples appeared more similar to unrelated samples than to any other sample originating from the same tumour. We found that the majority of recurrent DNA copy number driver aberrations in single biopsies were not present ubiquitously in late-stage ccRCCs and were likely to represent subclonal events acquired during tumour progression. Such heterogeneous subclonal genetic alterations within individual tumours may impair the identification of robust ccRCC molecular subtypes classified by distinct copy number alterations and clinical outcomes. The co-existence of distinct subclonal copy number events in different regions of individual tumours reflects the diversification of individual ccRCCs through multiple evolutionary routes and may contribute to tumour sampling bias and impact upon tumour progression and clinical outcome.
authors.affiliation: Cancer Research UK London Research Institute, London, UK.
authors.forename: Pierre
authors.initials: P
authors.lastname: Martinez
authors.forename: Nicolai Juul
authors.initials: NJ
authors.lastname: Birkbak
authors.forename: Marco
authors.initials: M
authors.lastname: Gerlinger
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.forename: Rebecca A
authors.initials: RA
authors.lastname: Burrell
authors.forename: Andrew J
authors.initials: AJ
authors.lastname: Rowan
authors.forename: Tejal
authors.initials: T
authors.lastname: Joshi
authors.forename: Rosalie
authors.initials: R
authors.lastname: Fisher
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Zoltan
authors.initials: Z
authors.lastname: Szallasi
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D001706:Biopsy; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D043171:Chromosomal Instability; D002999:Clone Cells; D016000:Cluster Analysis; D019295:Computational Biology; D056915:DNA Copy Number Variations; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling / Q000379:methods; D053263:Gene Regulatory Networks; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D009154:Mutation; D009367:Neoplasm Staging; D020411:Oligonucleotide Array Sequence Analysis; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D011379:Prognosis
chemical_list: D014408:Biomarkers, Tumor
keywords: biomarker; chromosomal instability; copy number; intratumour heterogeneity; personalized medicine; tumour evolution