Department of Breast Surgery, Cancer Hospital/Cancer Institute, Breast Cancer Institute, Fudan University, 399 Ling-Ling Road, Shanghai 200032, China.
Breast Cancer Res Treat. 2010 Jun;121(2):485-96. doi: 10.1007/s10549-009-0585-9. Epub 2009 Oct 24.
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.
Mu 类谷胱甘肽-S-转移酶 (GSTM) 基因排列在 1p13.3 染色体上的串联。GSTM1-5 基因簇中的遗传变异与乳腺癌之间的关系仍不明确。在本研究中，最初选择了 17 个覆盖 GSTMs 簇的标记单核苷酸多态性 (SNP)，并对 921 例病例和 711 例对照进行了 11 个验证 SNP 的基因分型。根据是否存在 GSTM1 进行关联分析。在 GSTM1-/-组中，GSTM3 中的一个 SNP 的等位基因频率在病例和对照之间存在显著差异 (P=2.0x10(-4)，校正 P=0.001)，优势比为 1.75(95%置信区间，1.26-2.44)。在另一个独立的人群样本（家族性/早发性乳腺癌病例，n=267；社区对照，n=667）中成功复制了 GSTM1-/-组中的观察到的关联。合并 P 值稳健（10(-6)），假阳性报告概率 (FPRP) 值较低。相比之下，当 GSTM1 基因存在时，没有确定易感等位基因/单倍型。基于流行病学观察，我们进一步鉴定了 GSTM3 基因座中的两个遗传变异，通过改变 RNA-pol-II 的结合来影响 GSTM3 在正常乳腺组织中的表达。保护基因型与较高的 GSTM3 表达水平相关。总之，当 GSTM1 缺失时，GSTM3 基因簇内的 SNP/单倍型可能导致乳腺癌风险增加。我们推断，正常乳腺组织中 GSTM3 的催化能力可能有助于预防乳腺癌的发生。
