title: Development of synchronous VHL syndrome tumors reveals contingencies and constraints to tumor evolution.
abstract: BACKGROUND
  Genomic analysis of multi-focal renal cell carcinomas from an individual with a germline VHL mutation offers a unique opportunity to study tumor evolution.
  
  
  RESULTS
  We perform whole exome sequencing on four clear cell renal cell carcinomas removed from both kidneys of a patient with a germline VHL mutation. We report that tumors arising in this context are clonally independent and harbour distinct secondary events exemplified by loss of chromosome 3p, despite an identical genetic background and tissue microenvironment. We propose that divergent mutational and copy number anomalies are contingent upon the nature of 3p loss of heterozygosity occurring early in tumorigenesis. However, despite distinct 3p events, genomic, proteomic and immunohistochemical analyses reveal evidence for convergence upon the PI3K-AKT-mTOR signaling pathway. Four germline tumors in this young patient, and in a second, older patient with VHL syndrome demonstrate minimal intra-tumor heterogeneity and mutational burden, and evaluable tumors appear to follow a linear evolutionary route, compared to tumors from patients with sporadic clear cell renal cell carcinoma.
  
  
  CONCLUSIONS
  In tumors developing from a germline VHL mutation, the evolutionary principles of contingency and convergence in tumor development are complementary. In this small set of patients with early stage VHL-associated tumors, there is reduced mutation burden and limited evidence of intra-tumor heterogeneity.
authors.forename: Rosalie
authors.initials: R
authors.lastname: Fisher
authors.forename: Stuart
authors.initials: S
authors.lastname: Horswell
authors.forename: Andrew
authors.initials: A
authors.lastname: Rowan
authors.forename: Maximilian P
authors.initials: MP
authors.lastname: Salm
authors.forename: Elza C
authors.initials: EC
authors.lastname: de Bruin
authors.forename: Sakshi
authors.initials: S
authors.lastname: Gulati
authors.forename: Nicholas
authors.initials: N
authors.lastname: McGranahan
authors.forename: Mark
authors.initials: M
authors.lastname: Stares
authors.forename: Marco
authors.initials: M
authors.lastname: Gerlinger
authors.forename: Ignacio
authors.initials: I
authors.lastname: Varela
authors.forename: Andrew
authors.initials: A
authors.lastname: Crockford
authors.forename: Francesco
authors.initials: F
authors.lastname: Favero
authors.forename: Virginie
authors.initials: V
authors.lastname: Quidville
authors.forename: Fabrice
authors.initials: F
authors.lastname: André
authors.forename: Carolina
authors.initials: C
authors.lastname: Navas
authors.forename: Eva
authors.initials: E
authors.lastname: Grönroos
authors.forename: David
authors.initials: D
authors.lastname: Nicol
authors.forename: Steve
authors.initials: S
authors.lastname: Hazell
authors.forename: David
authors.initials: D
authors.lastname: Hrouda
authors.forename: Tim
authors.initials: T
authors.lastname: O'Brien
authors.forename: Nik
authors.initials: N
authors.lastname: Matthews
authors.forename: Ben
authors.initials: B
authors.lastname: Phillimore
authors.forename: Sharmin
authors.initials: S
authors.lastname: Begum
authors.forename: Adam
authors.initials: A
authors.lastname: Rabinowitz
authors.forename: Jennifer
authors.initials: J
authors.lastname: Biggs
authors.forename: Paul A
authors.initials: PA
authors.lastname: Bates
authors.forename: Neil Q
authors.initials: NQ
authors.lastname: McDonald
authors.forename: Gordon
authors.initials: G
authors.lastname: Stamp
authors.forename: Bradley
authors.initials: B
authors.lastname: Spencer-Dene
authors.forename: James J
authors.initials: JJ
authors.lastname: Hsieh
authors.forename: Jianing
authors.initials: J
authors.lastname: Xu
authors.forename: Lisa
authors.initials: L
authors.lastname: Pickering
authors.forename: Martin
authors.initials: M
authors.lastname: Gore
authors.forename: James
authors.initials: J
authors.lastname: Larkin
authors.forename: Charles
authors.initials: C
authors.lastname: Swanton
mesh_terms: D000328:Adult; D000368:Aged; D002292:Carcinoma, Renal Cell / Q000235:genetics* / Q000473:pathology; D002872:Chromosome Deletion; D002893:Chromosomes, Human, Pair 3 / Q000235:genetics; D059472:Exome; D015972:Gene Expression Regulation, Neoplastic; D018740:Genetic Heterogeneity; D018095:Germ-Line Mutation; D006801:Humans; D007680:Kidney Neoplasms / Q000235:genetics*; D020935:MAP Kinase Signaling System; D008297:Male; D008875:Middle Aged; D008958:Models, Molecular; D010802:Phylogeny; D017422:Sequence Analysis, DNA; D006623:von Hippel-Lindau Disease / Q000150:complications / Q000235:genetics* / Q000473:pathology