ATM haplotypes and cellular response to DNA damage: association with breast cancer risk and clinical radiosensitivity.
The ATM gene, mutated in the cancer-prone and radiation-sensitive syndrome ataxia-telangiectasia (AT), could predispose to breast cancer (BC) development and adverse radiotherapy responses. Sixteen ATM variants were genotyped in 254 BC cases, 70 of whom were adverse radiotherapy responders (RS-BC), and 312 control subjects and the ATM haplotypes were constructed. Constitutive ATM protein, cell survival, and the p53 response after exposure to ionizing radiation were compared in lymphoblastoid cell lines (LCLs) established from the BC cases, AT, and normal individuals. The tightly linked intronic ATM polymorphisms IVS22-77 T>C and IVS48 + 238 C>G, in the homozygote state were associated with increased BC risk [IVS22-77 CC versus TT odds ratio (OR), 1.67; 95% confidence interval (CI), 1.00-2.81], and in the heterozygote state with clinical radioprotection (IVS22-77 CT versus TT OR, 0.45; 95% CI, 0.24-0.85). Homozygote carriers of the G5557A variant were over-represented in RS-BC cases compared with non-RS-BC cases (OR, 6.76; 95% CI, 1.19-38.43). These three single nucleotide polymorphisms were associated with the three major ATM haplotypes present in >80% of the study population. BC LCLs treated with ionizing radiation exhibited an intermediate cell survival and p53 response between that of normal and AT LCLs, with the response in the RS-BC LCLs being more compromised than in the non-RS-BC LCLs. Our study suggests a general pattern of increased BC risk associated with carrying any one of the ATM variants studied, with a significant association being observed in individuals carrying variants on both ATM alleles (OR, 1.75; 95% CI, 1.09-2.81) and that ATM variants may impact on radiation sensitivity.
Angèle
Sandra
S
DNA Repair Group, International Agency for Research on Cancer, Lyon Cedex, France.
Romestaing
Pascale
P
Moullan
Norman
N
Vuillaume
Michèle
M
Chapot
Brigitte
B
Friesen
Marlin
M
Jongmans
Wim
W
Cox
David G
DG
Pisani
Paola
P
Gérard
Jean-Pierre
JP
Hall
Janet
J
D000328:Adult; D000368:Aged; D000369:Aged, 80 and over; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000532:radiotherapy*; D016022:Case-Control Studies; D002460:Cell Line; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins / Q000096:biosynthesis / Q000235:genetics; D004249:DNA Damage / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D006239:Haplotypes; D006801:Humans; D008214:Lymphocytes / Q000502:physiology; D008875:Middle Aged; D010641:Phenotype; D020641:Polymorphism, Single Nucleotide; D012333:RNA, Messenger / Q000096:biosynthesis / Q000235:genetics; D011836:Radiation Tolerance / Q000235:genetics; D016159:Tumor Suppressor Protein p53 / Q000096:biosynthesis / Q000235:genetics
C493956:CDKN1A protein, human; D050759:Cyclin-Dependent Kinase Inhibitor p21; D016213:Cyclins; D012333:RNA, Messenger; D016159:Tumor Suppressor Protein p53