Genetic contribution of GADD45A to susceptibility to sporadic and non-BRCA1/2 familial breast cancers: a systematic evaluation in Chinese populations.
Growth arrest and DNA damage-induced 45, alpha (GADD45A) is a candidate breast cancer susceptibility gene because its product participates in DNA repair and it is a downstream gene of p53 and BRCA1, both of which are breast cancer susceptibility genes. We screened germline mutations of GADD45A in 185 non-BRCA1/2 familial breast cancer patients, but no deleterious mutation was found. Seven single-nucleotide-polymorphisms were identified in a subsample. Five common variants (minor allele frequency > 10%) were genotyped for association analyses to scrutinize the relationship between breast cancer and polymorphisms in GADD45A in two independent population sets (total n = 1,861). In the first case-control study (n = 1,457, cases 820, controls 637), a comparison of genotype frequencies between sporadic breast cancer patients and controls indicated the CT/TT-genotypes of +1506C>T and CG/CC-genotypes of +3204G>C were associated with decreased breast cancer risk (adjusted odds ratio (OR), 0.77; 95% confidence interval (CI), 0.62-0.96; and adjusted OR, 0.71; 95%CI, 0.57-0.88, respectively) compared with their wild-type homozygotes. A common haplotype CGTCC was also associated with reduced risk (P = 1.0 x 10(-4)). In a second familial breast cancer patient-based case-control study (n = 404, cases 185, controls 219), although +1506C>T and +3204G>C failed to be validated, the haplotype CGTCC showed a borderline significance. Notably, the combined P-values were robust for +3204G>C (P = 3.1 x 10(-4)) and CGTCC (P = 1.6 x 10(-5)). Moreover, CGTCC was correlated with a higher GADD45A expression in normal breast tissues. In conclusion, although germline mutations of GADD45A is not common in familial breast cancer patients, polymorphisms/haplotypes in GADD45A contribute to breast cancer risk, at least to sporadic breast cancer.
Yu
Ke-Da
KD
Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, Shanghai, People's Republic of China.
Di
Gen-Hong
GH
Li
Wen-Feng
WF
Rao
Nan-Yan
NY
Fan
Lei
L
Yuan
Wen-Tao
WT
Hu
Zhen
Z
Wu
Jiong
J
Shen
Zhen-Zhou
ZZ
Huang
Wei
W
Shao
Zhi-Ming
ZM
D044466:Asian People; D001943:Breast Neoplasms / Q000235:genetics*; D016022:Case-Control Studies; D018797:Cell Cycle Proteins / Q000235:genetics*; D004252:DNA Mutational Analysis; D005260:Female; D019398:Genes, BRCA1; D024522:Genes, BRCA2; D020022:Genetic Predisposition to Disease; D005838:Genotype; D018095:Germ-Line Mutation; D006239:Haplotypes; D006801:Humans; D015810:Linkage Disequilibrium; D008875:Middle Aged; D009687:Nuclear Proteins / Q000235:genetics*; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction; D000097642:GADD45 Proteins
D018797:Cell Cycle Proteins; D009687:Nuclear Proteins; C439070:GADD45A protein, human; D000097642:GADD45 Proteins