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. CONCLUSION: 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.
Subject(s)
Cell Cycle Proteins/genetics , Nuclear Proteins/genetics , Prostatic Neoplasms/genetics , Prostatic Neoplasms/mortality , Adult , Aged , Aged, 80 and over , BRCA1 Protein/genetics , Biomarkers, Tumor/genetics , Checkpoint Kinase 2 , Genes, BRCA1 , Genetic Predisposition to Disease , Genotype , Humans , Kaplan-Meier Estimate , Male , Middle Aged , Mutation , Prognosis , Protein Serine-Threonine Kinases/geneticsABSTRACT
Platelet is blood's morphotic element in which intense energy metabolism takes place, which makes it possible to participate in the complex processes of the organism's homeostasis. The aim of the study was to analyse aerobic metabolism in the platelets, taking into consideration lipids peroxidation in patients with bladder cancer treated with the bacillus Calmette-Guerin (BCG) Mycobacterium suspension. The determination of superoxide dismutase (SOD-1) and malonyl dialdehyde (MDA) concentration activity constituted this evaluation's parameters. A group of 12 patients (4 women and 8 men) aged 54-67 years (average age 61) in which superficial bladder cancer was diagnosed were included in the study. Electroresection was carried out and subsequently, after 14 days, BCG Mycobacterium suspension was administered in intravesical instillations, in a 6-week cycle according to Morales. The material for the study was venous blood taken from the patients in three periods (before treatment, after the last clyster and 30 days after treatment) into the tubes with the addition of 1% EDTA in the ratio of 9 blood volumes to anticoagulant's one volume. Superoxide dismutase activity (Cu Zn--SOD) was determined according to Misra and Fridovich. The values were expressed in lamellar protein U/g protein. MDA concentration in platelet's TBARS was determined according to Pansa et al. MDA concentration included in TBARS was expressed in nmol/109 platelets. The controls were healthy volunteers in the same age range. In unaided studies a significant rise in superoxide dismutase (SOD-1) activity was obtained with the 1574.606 average before treatment > 2137.03 after treatment and 2646.4 after a month observation. Whereas MDA concentration increased in non-treated patients to 1.97, after treatment it dropped down significantly to 1.55 and sustained the downward trend after 30-day observation 1.4 nmol/109 platelets. The use of BCG intravesical clysters causes lipids peroxidation inhibition (decrease in MDA concentration) and the increase of SOD-1 activity results in smaller aggregation of platelets, preventing the formation of neoplastic metastases.