title: Very low PSA concentrations and deletions of the KLK3 gene.
abstract: BACKGROUND
  Prostate-specific antigen (PSA), a widely used biomarker for prostate cancer (PCa), is encoded by a kallikrein gene (KLK3, kallikrein-related peptidase 3). Serum PSA concentrations vary in the population, with PCa patients generally showing higher PSA concentrations than control individuals, although a small proportion of individuals in the population display very low PSA concentrations. We hypothesized that very low PSA concentrations might reflect gene-inactivating mutations in KLK3 that lead to abnormally reduced gene expression.
  
  
  METHODS
  We have sequenced all KLK3 exons and the promoter and searched for gross deletions or duplications in KLK3 in the 30 individuals with the lowest observed PSA concentrations in a sample of approximately 85 000 men from the Prostate Testing for Cancer and Treatment (ProtecT) study. The ProtecT study examines a community-based population of men from across the UK with little prior PSA testing.
  
  
  RESULTS
  We observed no stop codons or frameshift mutations, but we did find 30 single-base genetic variants, including 3 variants not described previously. These variants included missense variants that could be functionally inactivating and splicing variants. At this stage, however, we cannot confidently conclude whether these variants markedly lower PSA concentration or activity. More importantly, we identified 3 individuals with different large heterozygous deletions that encompass all KLK3 exons. The absence of a functional copy of KLK3 in these individuals is consistent with their reduced serum PSA concentrations.
  
  
  CONCLUSIONS
  The clinical interpretation of the PSA test for individuals with KLK3 gene inactivation could lead to false-negative PSA findings used for screening, diagnosis, or monitoring of PCa.
authors.affiliation: MRC Centre for Causal Analyses in Translational Epidemiology-CAiTE and Bristol Genetic Epidemiology Laboratories-BGEL, University of Bristol, Bristol, UK. santi.rodriguez@bristol.ac.uk
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodriguez
authors.forename: Osama A
authors.initials: OA
authors.lastname: Al-Ghamdi
authors.forename: Kimberley
authors.initials: K
authors.lastname: Burrows
authors.forename: Philip A I
authors.initials: PA
authors.lastname: Guthrie
authors.forename: J Athene
authors.initials: JA
authors.lastname: Lane
authors.forename: Michael
authors.initials: M
authors.lastname: Davis
authors.forename: Gemma
authors.initials: G
authors.lastname: Marsden
authors.forename: Khalid K
authors.initials: KK
authors.lastname: Alharbi
authors.forename: Angela
authors.initials: A
authors.lastname: Cox
authors.forename: Freddie C
authors.initials: FC
authors.lastname: Hamdy
authors.forename: David E
authors.initials: DE
authors.lastname: Neal
authors.forename: Jenny L
authors.initials: JL
authors.lastname: Donovan
authors.forename: Ian N M
authors.initials: IN
authors.lastname: Day
mesh_terms: D005091:Exons; D017353:Gene Deletion; D006801:Humans; D007610:Kallikreins / Q000235:genetics*; D008297:Male; D009154:Mutation; D016133:Polymerase Chain Reaction; D017430:Prostate-Specific Antigen / Q000097:blood* / Q000235:genetics
chemical_list: C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen