Genetic variants in GSTM3 gene within GSTM4-GSTM2-GSTM1-GSTM5-GSTM3 cluster influence breast cancer susceptibility depending on GSTM1.
Mu class of Glutathione-S-transferase (GSTM) genes arrange in a tandem on chromosome 1p13.3. The relationship between genetic variants in the GSTM1-5 gene cluster and breast cancer is still ambiguous. In the present study, 17 tagging single-nucleotide polymorphisms (SNPs) covering the GSTMs cluster were originally selected and 11 validated SNPs were used for genotyping 921 cases and 711 controls. The association analyses were performed according to the absence or presence of GSTM1. In the GSTM1-/- group, the allele frequency of one SNP in GSTM3 was significantly different between cases and controls (P = 2.0 x 10(-4), corrected P = 0.001), with odds ratio of 1.75 (95% confidence interval, 1.26-2.44). The observed association in the GSTM1-/- group was successfully replicated in an independent population set (familial/early-onset breast cancer cases, n = 267; community-based controls, n = 667). The combined P values were robust (10(-6)) and the false positive report probability (FPRP) values were low. In contrast, no susceptibility allele/haplotype was identified when the GSTM1 gene was present. Based on epidemiological observations, we further identified two genetic variants in the GSTM3 locus accounting for differential expression of GSTM3 in normal breast tissues by such means as altering binding of RNA-pol-II. Protective genotypes were correlated with higher GSTM3 expression levels. In conclusion, SNPs/haplotypes in the GSTM3 gene within the GSTMs gene cluster are likely to contribute to breast cancer risk when the GSTM1 is absent. We infer that GSTM3 catalyzing ability in normal breast tissue might protect against breast carcinogenesis.
Yu
Ke-Da
KD
Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai 200032, China.
Fan
Lei
L
Di
Gen-Hong
GH
Yuan
Wen-Tao
WT
Zheng
Ying
Y
Huang
Wei
W
Chen
Ao-Xiang
AX
Yang
Chen
C
Wu
Jiong
J
Shen
Zhen-Zhou
ZZ
Shao
Zhi-Ming
ZM
D001943:Breast Neoplasms / Q000235:genetics*; D005260:Female; D020022:Genetic Predisposition to Disease; D005838:Genotype; D005982:Glutathione Transferase / Q000235:genetics*; D006239:Haplotypes; D006801:Humans; D008875:Middle Aged; D005810:Multigene Family; D020641:Polymorphism, Single Nucleotide; D020133:Reverse Transcriptase Polymerase Chain Reaction
D005982:Glutathione Transferase; C483009:GSTM3 protein, human; C514654:GSTM4 protein, human; C524366:GSTM5 protein, human; C412602:glutathione S-transferase Mu 2