title: Frequency of KLK3 gene deletions in the general population.
abstract: Background One of the kallikrein genes ( KLK3) encodes prostate-specific antigen, a key biomarker for prostate cancer. A number of factors, both genetic and non-genetic, determine variation of serum prostate-specific antigen concentrations in the population. We have recently found three KLK3 deletions in individuals with very low prostate-specific antigen concentrations, suggesting a link between abnormally reduced KLK3 expression and deletions of KLK3. Here, we aim to determine the frequency of kallikrein gene 3 deletions in the general population. Methods The frequency of KLK3 deletions in the general population was estimated from the 1958 Birth Cohort sample ( n = 3815) using amplification ratiometry control system. In silico analyses using PennCNV were carried out in the same cohort and in NBS-WTCCC2 in order to provide an independent estimation of the frequency of KLK3 deletions in the general population. Results Amplification ratiometry control system results from the 1958 cohort indicated a frequency of KLK3 deletions of 0.81% (3.98% following a less stringent calling criterion). From in silico analyses, we found that potential deletions harbouring the KLK3 gene occurred at rates of 2.13% (1958 Cohort, n = 2867) and 0.99% (NBS-WTCCC2, n = 2737), respectively. These results are in good agreement with our in vitro experiments. All deletions found were in heterozygosis. Conclusions We conclude that a number of individuals from the general population present KLK3 deletions in heterozygosis. Further studies are required in order to know if interpretation of low serum prostate-specific antigen concentrations in individuals with KLK3 deletions may offer false-negative assurances with consequences for prostate cancer screening, diagnosis and monitoring.
authors.affiliation: 1 MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Santiago
authors.initials: S
authors.lastname: Rodriguez
authors.affiliation: 2 Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.|3 School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Osama A
authors.initials: OA
authors.lastname: Al-Ghamdi
authors.affiliation: 1 MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Philip Ai
authors.initials: PA
authors.lastname: Guthrie
authors.affiliation: 1 MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Hashem A
authors.initials: HA
authors.lastname: Shihab
authors.affiliation: 3 School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Wendy
authors.initials: W
authors.lastname: McArdle
authors.affiliation: 1 MRC Integrative Epidemiology Unit (IEU), School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Tom
authors.initials: T
authors.lastname: Gaunt
authors.affiliation: 2 Clinical Laboratory Sciences Department, College of Applied Medical Sciences, King Saud University, Riyadh, Saudi Arabia.
authors.forename: Khalid K
authors.initials: KK
authors.lastname: Alharbi
authors.affiliation: 3 School of Social and Community Medicine, University of Bristol, Bristol, UK.
authors.forename: Ian Nm
authors.initials: IN
authors.lastname: Day
mesh_terms: D014408:Biomarkers, Tumor / Q000235:genetics*; D015331:Cohort Studies; D005188:False Negative Reactions; D017353:Gene Deletion; D015870:Gene Expression; D006579:Heterozygote; D006801:Humans; D007610:Kallikreins / Q000172:deficiency / Q000235:genetics*; D008297:Male; D008875:Middle Aged; D008991:Monitoring, Physiologic; D059645:Mutation Rate; D011379:Prognosis; D017430:Prostate-Specific Antigen / Q000172:deficiency / Q000235:genetics*; D011471:Prostatic Neoplasms / Q000175:diagnosis* / Q000235:genetics* / Q000473:pathology
chemical_list: D014408:Biomarkers, Tumor; C549870:KLK3 protein, human; D007610:Kallikreins; D017430:Prostate-Specific Antigen
keywords: KLK3; PennCNV; amplification ratiometry control system; deletions; prostate-specific antigen