ATM polymorphisms as risk factors for prostate cancer development.
The risk of prostate cancer is known to be elevated in carriers of germline mutations in BRCA2, and possibly also in carriers of BRCA1 and CHEK2 mutations. These genes are components of the ATM-dependent DNA damage signalling pathways. To evaluate the hypothesis that variants in ATM itself might be associated with prostate cancer risk, we genotyped five ATM variants in DNA from 637 prostate cancer patients and 445 controls with no family history of cancer. No significant differences in the frequency of the variant alleles at 5557G>A (D1853N), 5558A>T (D1853V), ivs38-8t>c and ivs38-15g>c were found between the cases and controls. The 3161G (P1054R) variant allele was, however, significantly associated with an increased risk of developing prostate cancer (any G vs CC OR 2.13, 95% CI 1.17-3.87, P=0.016). A lymphoblastoid cell line carrying both the 3161G and the 2572C (858L) variant in the homozygote state shows a cell cycle progression profile after exposure to ionising radiation that is significantly different to that seen in cell lines carrying a wild-type ATM gene. These results provide evidence that the presence of common variants in the ATM gene, may confer an altered cellular phenotype, and that the ATM 3161C>G variant might be associated with prostate cancer risk.
Angèle
S
S
DNA Repair Group, International Agency for Research on Cancer, 150 cours Albert Thomas, 69373 Lyon, France.
Falconer
A
A
Edwards
S M
SM
Dörk
T
T
Bremer
M
M
Moullan
N
N
Chapot
B
B
Muir
K
K
Houlston
R
R
Norman
A R
AR
Bullock
S
S
Hope
Q
Q
Meitz
J
J
Dearnaley
D
D
Dowe
A
A
Southgate
C
C
Ardern-Jones
A
A
Easton
D F
DF
Eeles
R A
RA
Hall
J
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D064007:Ataxia Telangiectasia Mutated Proteins; D016022:Case-Control Studies; D002453:Cell Cycle; D018797:Cell Cycle Proteins; D004268:DNA-Binding Proteins; D006801:Humans; D008297:Male; D008875:Middle Aged; D010375:Pedigree; D010641:Phenotype; D017354:Point Mutation; D011110:Polymorphism, Genetic; D011471:Prostatic Neoplasms / Q000235:genetics* / Q000473:pathology; D017346:Protein Serine-Threonine Kinases / Q000235:genetics*; D012307:Risk Factors; D015398:Signal Transduction; D014407:Tumor Cells, Cultured; D025521:Tumor Suppressor Proteins
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