title: ATM missense variant P1054R predisposes to prostate cancer.
abstract: BACKGROUND
  Prostate cancer is associated with defective DNA strand break repair after DNA damage leading to genetic instability and prostate cancer progression. The ATM (ataxia-telangiectasia mutated) gene product is known to play an important role in cell cycle regulation and maintenance of genomic integrity. We investigated whether the prevalence of the ATM missense substitution P1054R is increased in a hospital-based series of prostate cancer patients and whether carriers are at increased risk for treatment-related side effects.
  
  
  METHODS
  A consecutive series of 261 patients treated for early-stage prostate cancer with I-125 brachytherapy (permanent seed implantation) between 10/2000 and 04/2006 at our institution and a comparison group of 460 male control individuals were screened for the presence of the P1054R variant. Outcome of therapy regarding morbidity was assessed prospectively and compared between carriers vs. non-carriers with the International Prostate Symptom Score (IPSS), a Quality-of-Life-index (QoL) and the International Index of Erectile Function (IIEF-15) with its subgroups (IIEF-5 and EF).
  
  
  RESULTS
  The proportion of carriers of the P1054R variant was significantly higher among prostate cancer patients than in the general population (25 out of 261 vs. 22 out of 460; OR 2.1; 95% CI 1.2-3.8, p<0.01). A subgroup of the carriers additionally harboured the ATM missense variant F858L that was associated with a similar risk (OR=2.2; 95% CI 1.1-4.6; p=0.03). After a mean follow-up of 18 months there were no statistically significant differences regarding IPSS (p=0.48), QoL (p=0.61), IIEF-15 score (p=0.78), IIEF-5 score (p=0.83), and EF score (p=0.80), respectively.
  
  
  CONCLUSIONS
  The ATM missense variant P1054R confers an about twofold increased risk for prostate cancer in our series. The subgroup of patients with the second-site variant F858L is not at significantly higher risk. After 18 months, there was no evidence for an increased adverse radiotherapy response in P1054R carriers.
authors.affiliation: Department of Radiation Oncology, Hannover Medical School, Germany. andie.meyer@gmx.net
authors.forename: Andreas
authors.initials: A
authors.lastname: Meyer
authors.forename: Bettina
authors.initials: B
authors.lastname: Wilhelm
authors.forename: Thilo
authors.initials: T
authors.lastname: Dörk
authors.forename: Michael
authors.initials: M
authors.lastname: Bremer
authors.forename: Rolf
authors.initials: R
authors.lastname: Baumann
authors.forename: Johann Hinrich
authors.initials: JH
authors.lastname: Karstens
authors.forename: Stefan
authors.initials: S
authors.lastname: Machtens
mesh_terms: D017668:Age of Onset; D019943:Amino Acid Substitution; D064007:Ataxia Telangiectasia Mutated Proteins; D018797:Cell Cycle Proteins / Q000235:genetics*; D004268:DNA-Binding Proteins / Q000235:genetics*; D005500:Follow-Up Studies; D020022:Genetic Predisposition to Disease; D006579:Heterozygote; D006801:Humans; D008297:Male; D008875:Middle Aged; D020125:Mutation, Missense; D011471:Prostatic Neoplasms / Q000235:genetics*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D025521:Tumor Suppressor Proteins / Q000235:genetics*
chemical_list: D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D025521:Tumor Suppressor Proteins; C576324:ATM protein, human; D064007:Ataxia Telangiectasia Mutated Proteins; D017346:Protein Serine-Threonine Kinases