title: Exome sequencing of prostate cancer supports the hypothesis of independent tumour origins.
abstract: BACKGROUND
  Prostate cancer (PCa) is a clinically and pathologically heterogeneous disease. The rapid development of sequencing technology has the potential to deliver new biomarkers with emphasis on aggressive disease and to revolutionise personalised cancer treatment. However, a prostate harbouring cancer commonly contains multiple separate tumour foci, with the potential to aggravate tumour sampling. The level of intraprostatic tumour heterogeneity remains to be determined.
  
  
  OBJECTIVE
  To determine the level of intraprostatic tumour heterogeneity through genome-wide, high-resolution profiling of multiple tumour samples from the same individual.
  
  
  METHODS
  Multiple tumour samples were obtained from four individuals following radical prostatectomy. One individual (SWE-1) contained >70% cancer cells in all tumour samples, whereas the other three (SWE-2 to SWE-4) required the use of laser capture microdissection for tumour cell enrichment. Subsequently, DNA was extracted from all tissue samples, and exome sequencing was performed. All tumour foci of SWE-1 were also profiled using a high-resolution array for the identification of copy number alterations (CNA).
  
  
  METHODS
  Shared somatic high-frequency single nucleotide variants (SNV) and CNAs were used to infer the level of intraprostatic tumour heterogeneity.
  
  
  CONCLUSIONS
  No high-frequency mutations, common for the three tumour samples of SWE-1, were identified. Ten randomly chosen positions were validated with Sanger sequencing in all foci, which verified the exome data. The high level of intraprostatic heterogeneity was consistent in all individuals. In total, three out of four individuals harboured tumours without an apparent common somatic denominator. Although we cannot exclude the presence of common structural rearrangements, a high-density array was used for the detection of deletions and amplifications in SWE-1, which agreed with the exome data.
  
  
  CONCLUSIONS
  We present evidence for the presence of somatically independent tumours within the same prostate. This finding will have implications for personalised cancer treatment and biomarker discovery.
authors.affiliation: Department of Medical Epidemiology and Biostatistics, Science for Life Laboratory, Karolinska Institutet, Stockholm, Sweden.
authors.forename: Johan
authors.initials: J
authors.lastname: Lindberg
authors.forename: Daniel
authors.initials: D
authors.lastname: Klevebring
authors.forename: Wennuan
authors.initials: W
authors.lastname: Liu
authors.forename: Mårten
authors.initials: M
authors.lastname: Neiman
authors.forename: Jianfeng
authors.initials: J
authors.lastname: Xu
authors.forename: Peter
authors.initials: P
authors.lastname: Wiklund
authors.forename: Fredrik
authors.initials: F
authors.lastname: Wiklund
authors.forename: Ian G
authors.initials: IG
authors.lastname: Mills
authors.forename: Lars
authors.initials: L
authors.lastname: Egevad
authors.forename: Henrik
authors.initials: H
authors.lastname: Grönberg
mesh_terms: D000368:Aged; D002277:Carcinoma / Q000235:genetics* / Q000473:pathology; D056915:DNA Copy Number Variations; D059472:Exome; D018740:Genetic Heterogeneity; D006801:Humans; D008297:Male; D008875:Middle Aged; D009378:Neoplasms, Multiple Primary / Q000235:genetics* / Q000473:pathology; D020641:Polymorphism, Single Nucleotide; D011468:Prostatectomy; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017422:Sequence Analysis, DNA