title: Genetic profiling to determine risk of relapse-free survival in high-risk localized prostate cancer.
abstract: OBJECTIVE
  The characterization of actionable mutations in human tumors is a prerequisite for the development of individualized, targeted therapy. We examined the prevalence of potentially therapeutically actionable mutations in patients with high-risk clinically localized prostate cancer.
  
  
  METHODS
  Forty-eight samples of formalin-fixed paraffin-embedded prostatectomy tissue from a neoadjuvant chemotherapy trial were analyzed. DNA extracted from microdissected tumor was analyzed for 643 common solid tumor mutations in 53 genes using mass spectroscopy-based sequencing. In addition, PTEN loss and erythroblast transformation-specific-related gene (ERC) translocations were examined using immunohistochemistry (IHC) in associated tissue microarrays. Association with relapse during 5 years of follow-up was examined in exploratory analyses of the potential clinical relevance of the genetic alterations.
  
  
  RESULTS
  Of the 40 tumors evaluable for mutations, 10% had point mutations in potentially actionable cancer genes. Of the 47 tumors evaluable for IHC, 36% had PTEN loss and 40% had ERG rearrangement. Individual mutations were not frequent enough to determine associations with relapse. Using Kaplan-Meier analysis with a log-rank test, the 16 patients who had PTEN loss had a significantly shorter median relapse-free survival, 19 versus 106 months (P = 0.01).
  
  
  CONCLUSIONS
  This study confirms that point mutations in the most common cancer regulatory genes in prostate cancer are rare. However, the PIK3CA/AKT pathway was mutated in 10% of our samples. Although point mutations alone did not have a statistically significant association with relapse, PTEN loss was associated with an increased relapse in high-risk prostate cancer treated with chemotherapy followed by surgery.
authors.affiliation: Authors' Affiliations: Knight Cancer Institute; Department of Public Health and Preventive Medicine; Knight Diagnostic Laboratories, Oregon Health and Science University; Portland VA Medical Center, Portland, Oregon; and Puget Sound Oncology Consortium, Seattle Cancer Care Alliance, University of Washington, Seattle, Washington.
authors.forename: Christine M
authors.initials: CM
authors.lastname: Barnett
authors.forename: Michael C
authors.initials: MC
authors.lastname: Heinrich
authors.forename: Jeong
authors.initials: J
authors.lastname: Lim
authors.forename: Dylan
authors.initials: D
authors.lastname: Nelson
authors.forename: Carol
authors.initials: C
authors.lastname: Beadling
authors.forename: Andrea
authors.initials: A
authors.lastname: Warrick
authors.forename: Tanaya
authors.initials: T
authors.lastname: Neff
authors.forename: Celestia S
authors.initials: CS
authors.lastname: Higano
authors.forename: Mark
authors.initials: M
authors.lastname: Garzotto
authors.forename: David
authors.initials: D
authors.lastname: Qian
authors.forename: Christopher L
authors.initials: CL
authors.lastname: Corless
authors.forename: George V
authors.initials: GV
authors.lastname: Thomas
authors.forename: Tomasz M
authors.initials: TM
authors.lastname: Beer
mesh_terms: D000328:Adult; D000368:Aged; D058534:Class I Phosphatidylinositol 3-Kinases; D006801:Humans; D007150:Immunohistochemistry; D008207:Lymphatic Metastasis; D008297:Male; D008875:Middle Aged; D009154:Mutation; D060787:Neoplasm Grading; D009367:Neoplasm Staging; D015514:Oncogene Proteins, Fusion / Q000235:genetics / Q000378:metabolism; D051059:PTEN Phosphohydrolase / Q000235:genetics / Q000378:metabolism; D019869:Phosphatidylinositol 3-Kinases / Q000235:genetics / Q000378:metabolism; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality* / Q000473:pathology; D012008:Recurrence
chemical_list: D015514:Oncogene Proteins, Fusion; C515553:TMPRSS2-ERG fusion protein, human; D019869:Phosphatidylinositol 3-Kinases; D058534:Class I Phosphatidylinositol 3-Kinases; C484760:PIK3CA protein, human; D051059:PTEN Phosphohydrolase