title: Genetic Progression of High Grade Prostatic Intraepithelial Neoplasia to Prostate Cancer.
abstract: Although high grade prostatic intraepithelial neoplasia (HGPIN) is considered a neoplastic lesion that precedes prostate cancer (PCA), the genomic structures of HGPIN remain unknown.
  
  
  
  Identification of the genomic landscape of HGPIN and the genomic differences between HGPIN and PCA that may drive the progression to PCA.
  
  
  
  We analyzed 20 regions of paired HGPIN and PCA from six patients using whole-exome sequencing and array-comparative genomic hybridization.
  
  
  
  Somatic mutation and copy number alteration (CNA) profiles of paired HGPIN and PCA were measured and compared.
  
  
  
  The number of total mutations and CNAs of HGPINs were significantly fewer than those of PCAs. Mutations in FOXA1 and CNAs (1q and 8q gains) were detected in both HGPIN and PCA ('common'), suggesting their roles in early PCA development. Mutations in SPOP, KDM6A, and KMT2D were 'PCA-specific', suggesting their roles in HGPIN progression to PCA. The 8p loss was either 'common' or 'PCA-specific'. In-silico estimation of evolutionary ages predicted that HGPIN genomes were much younger than PCA genomes. Our data show that PCAs are direct descendants of HGPINs in most cases that require more genomic alterations to progress to PCA. The nature of heterogeneous HGPIN population that might attenuate genomic signals should further be studied.
  
  
  
  HGPIN genomes harbor relatively fewer mutations and CNAs than PCA but require additional hits for the progression.
  
  
  
  In this study, we suggest a systemic diagram from high grade prostatic intraepithelial neoplasia (HGPIN) to prostate cancer (PCA). Our results provide a clue to explain the long latency from HGPIN to PCA and provide useful information for the genetic diagnosis of HGPIN and PCA.
authors.affiliation: Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea; Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Seung-Hyun
authors.initials: SH
authors.lastname: Jung
authors.affiliation: Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea; Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sun
authors.initials: S
authors.lastname: Shin
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Min Sung
authors.initials: MS
authors.lastname: Kim
authors.affiliation: Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea; Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: In-Pyo
authors.initials: IP
authors.lastname: Baek
authors.affiliation: Department of Urology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Ji Youl
authors.initials: JY
authors.lastname: Lee
authors.affiliation: Department of Hospital Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Sung Hak
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Medical Informatics, College of Medicine, The Catholic University of Korea, Seoul, Korea.
authors.forename: Tae-Min
authors.initials: TM
authors.lastname: Kim
authors.affiliation: Department of Pathology, College of Medicine, The Catholic University of Korea, Seoul, Korea. Electronic address: suhulee@catholic.ac.kr.
authors.forename: Sug Hyung
authors.initials: SH
authors.lastname: Lee
authors.affiliation: Department of Microbiology, College of Medicine, The Catholic University of Korea, Seoul, Korea; Integrated Research Center for Genome Polymorphism, College of Medicine, The Catholic University of Korea, Seoul, Korea. Electronic address: yejun@catholic.ac.kr.
authors.forename: Yeun-Jun
authors.initials: YJ
authors.lastname: Chung
mesh_terms: D000368:Aged; D002878:Chromosomes, Human, Pair 1; D002898:Chromosomes, Human, Pair 8; D055028:Comparative Genomic Hybridization; D003198:Computer Simulation; D056915:DNA Copy Number Variations; D004268:DNA-Binding Proteins / Q000235:genetics; D018450:Disease Progression; D019143:Evolution, Molecular; D051541:Hepatocyte Nuclear Factor 3-alpha / Q000235:genetics; D056466:Histone Demethylases / Q000235:genetics; D006801:Humans; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009363:Neoplasm Proteins / Q000235:genetics; D009687:Nuclear Proteins / Q000235:genetics; D019048:Prostatic Intraepithelial Neoplasia / Q000235:genetics* / Q000473:pathology*; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology*; D012097:Repressor Proteins / Q000235:genetics; D000073359:Exome Sequencing
chemical_list: D004268:DNA-Binding Proteins; C496499:FOXA1 protein, human; D051541:Hepatocyte Nuclear Factor 3-alpha; C120898:KMT2D protein, human; D009363:Neoplasm Proteins; D009687:Nuclear Proteins; D012097:Repressor Proteins; C509761:SPOP protein, human; D056466:Histone Demethylases; C523998:KDM6A protein, human
keywords: Prostate cancer genomes; Prostatic intraepithelial neoplasia