title: An inherited NBN mutation is associated with poor prognosis prostate cancer.
abstract: BACKGROUND
  To establish the contribution of eight founder alleles in three DNA damage repair genes (BRCA1, CHEK2 and NBS1) to prostate cancer in Poland, and to measure the impact of these variants on survival among patients.
  
  
  METHODS
  Three thousand seven hundred fifty men with prostate cancer and 3956 cancer-free controls were genotyped for three founder alleles in BRCA1 (5382insC, 4153delA, C61G), four alleles in CHEK2 (1100delC, IVS2+1G>A, del5395, I157T), and one allele in NBS1 (657del5).
  
  
  RESULTS
  The NBS1 mutation was detected in 53 of 3750 unselected cases compared with 23 of 3956 (0.6%) controls (odds ratio (OR)=2.5; P=0.0003). A CHEK2 mutation was seen in 383 (10.2%) unselected cases and in 228 (5.8%) controls (OR=1.9; P<0.0001). Mutation of BRCA1 (three mutations combined) was not associated with the risk of prostate cancer (OR=0.9; P=0.8). In a subgroup analysis, the 4153delA mutation was associated with early-onset (age ≤ 60 years) prostate cancer (OR=20.3, P=0.004). The mean follow-up was 54 months. Mortality was significantly worse for carriers of a NBS1 mutation than for non-carriers (HR=1.85; P=0.008). The 5-year survival for men with an NBS1 mutation was 49%, compared with 72% for mutation-negative cases.
  
  
  CONCLUSIONS
  A mutation in NBS1 predisposes to aggressive prostate cancer. These data are relevant to the prospect of adapting personalised medicine to prostate cancer prevention and treatment.
authors.affiliation: Department of Genetics and Pathology, International Hereditary Cancer Center, Pomeranian Medical University, ul. Połabska 4, Szczecin 70-115, Poland.
authors.forename: C
authors.initials: C
authors.lastname: Cybulski
authors.forename: D
authors.initials: D
authors.lastname: Wokołorczyk
authors.forename: W
authors.initials: W
authors.lastname: Kluźniak
authors.forename: A
authors.initials: A
authors.lastname: Jakubowska
authors.forename: B
authors.initials: B
authors.lastname: Górski
authors.forename: J
authors.initials: J
authors.lastname: Gronwald
authors.forename: T
authors.initials: T
authors.lastname: Huzarski
authors.forename: A
authors.initials: A
authors.lastname: Kashyap
authors.forename: T
authors.initials: T
authors.lastname: Byrski
authors.forename: T
authors.initials: T
authors.lastname: Dębniak
authors.forename: A
authors.initials: A
authors.lastname: Gołąb
authors.forename: B
authors.initials: B
authors.lastname: Gliniewicz
authors.forename: A
authors.initials: A
authors.lastname: Sikorski
authors.forename: J
authors.initials: J
authors.lastname: Switała
authors.forename: T
authors.initials: T
authors.lastname: Borkowski
authors.forename: A
authors.initials: A
authors.lastname: Borkowski
authors.forename: A
authors.initials: A
authors.lastname: Antczak
authors.forename: L
authors.initials: L
authors.lastname: Wojnar
authors.forename: J
authors.initials: J
authors.lastname: Przybyła
authors.forename: M
authors.initials: M
authors.lastname: Sosnowski
authors.forename: B
authors.initials: B
authors.lastname: Małkiewicz
authors.forename: R
authors.initials: R
authors.lastname: Zdrojowy
authors.forename: P
authors.initials: P
authors.lastname: Sikorska-Radek
authors.forename: J
authors.initials: J
authors.lastname: Matych
authors.forename: J
authors.initials: J
authors.lastname: Wilkosz
authors.forename: W
authors.initials: W
authors.lastname: Różański
authors.forename: J
authors.initials: J
authors.lastname: Kiś
authors.forename: K
authors.initials: K
authors.lastname: Bar
authors.forename: P
authors.initials: P
authors.lastname: Bryniarski
authors.forename: A
authors.initials: A
authors.lastname: Paradysz
authors.forename: K
authors.initials: K
authors.lastname: Jersak
authors.forename: J
authors.initials: J
authors.lastname: Niemirowicz
authors.forename: P
authors.initials: P
authors.lastname: Słupski
authors.forename: P
authors.initials: P
authors.lastname: Jarzemski
authors.forename: M
authors.initials: M
authors.lastname: Skrzypczyk
authors.forename: J
authors.initials: J
authors.lastname: Dobruch
authors.forename: P
authors.initials: P
authors.lastname: Domagała
authors.forename: S A
authors.initials: SA
authors.lastname: Narod
authors.forename: J
authors.initials: J
authors.lastname: Lubiński
mesh_terms: D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D019313:BRCA1 Protein / Q000235:genetics; D014408:Biomarkers, Tumor / Q000235:genetics; D018797:Cell Cycle Proteins / Q000235:genetics*; D064447:Checkpoint Kinase 2; D019398:Genes, BRCA1; D020022:Genetic Predisposition to Disease; D005838:Genotype; D006801:Humans; D053208:Kaplan-Meier Estimate; D008297:Male; D008875:Middle Aged; D009154:Mutation; D009687:Nuclear Proteins / Q000235:genetics*; D011379:Prognosis; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000401:mortality*; D017346:Protein Serine-Threonine Kinases / Q000235:genetics
chemical_list: D019313:BRCA1 Protein; C492913:BRCA1 protein, human; D014408:Biomarkers, Tumor; D018797:Cell Cycle Proteins; C112156:NBN protein, human; D009687:Nuclear Proteins; D064447:Checkpoint Kinase 2; C578634:CHEK2 protein, human; D017346:Protein Serine-Threonine Kinases