title: How should clinicians address intratumour heterogeneity in clear cell renal cell carcinoma?
abstract: OBJECTIVE
  Despite the availability of multiple targeted therapies, the 5-year survival rate of patients with metastatic clear cell renal cell carcinoma (ccRCC) rarely exceeds 10%. Recent insights into the mutational landscape and evolutionary dynamics of ccRCC have offered up a plausible explanation for these outcomes. The purpose of this review is to link the research findings to potential changes in clinical practice.
  
  
  RESULTS
  Intratumour heterogeneity (ITH) dominates the evolutionary landscape in ccRCC at the genetic, transcriptomic and proteomic level. Spatial and temporal separation of tumour subclones within the primary tumour as well as between primary and metastatic sites has been demonstrated at single nucleotide resolution. In the cases analysed to date, approximately two-thirds of somatic mutations are not shared between multiple biopsies from the same primary tumour. Very few of the key disease-driving events are shared across all primary tumour regions (with the exception of VHL and loss of chromosome 3p), whereas the majority are restricted to one or more tumour regions (TP53, SETD2, BAP1, PTEN, mTOR, PIK3CA and KDM5C).
  
  
  CONCLUSIONS
  ITH must be considered in the management of ccRCC with respect to diagnostic procedures, prognostic and predictive biomarkers and drug development.
authors.affiliation: aGuys and St Thomas NHS Foundation Trust bThe Francis Crick Institute, 44 Lincoln's Inn Fields, London cUCL Cancer Institute, CRUK Lung Cancer Centre of Excellence, Huntley Street dRenal Unit, The Royal Marsden Hospital, London, UK.
authors.forename: Aspasia
authors.initials: A
authors.lastname: Soultati
authors.forename: Mark
authors.initials: M
authors.lastname: Stares
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Samra
authors.initials: S
authors.lastname: Turajlic
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001706:Biopsy; D002292:Carcinoma, Renal Cell / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000556:secondary; D004252:DNA Mutational Analysis; D020869:Gene Expression Profiling; D020022:Genetic Predisposition to Disease; D006801:Humans; D007680:Kidney Neoplasms / Q000188:drug therapy / Q000235:genetics* / Q000378:metabolism / Q000473:pathology; D058990:Molecular Targeted Therapy; D009154:Mutation; D010641:Phenotype; D057285:Precision Medicine; D011237:Predictive Value of Tests; D012307:Risk Factors; D015398:Signal Transduction / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D014408:Biomarkers, Tumor