Laboratory of Translational Genomics, Division of Cancer Epidemiology and Genetics, National Cancer Institute, National Institutes of Health, Bethesda, MD, USA.
Mol Cancer. 2010 May 19;9:113. doi: 10.1186/1476-4598-9-113.
A recent genome-wide association study (GWAS) has identified a single nucleotide polymorphism (SNP) rs11249433 in the 1p11.2 region as a novel genetic risk factor for breast cancer, and this association was stronger in patients with estrogen receptor (ER)+ versus ER- cancer.
We found association between SNP rs11249433 and expression of the NOTCH2 gene located in the 1p11.2 region. Examined in 180 breast tumors, the expression of NOTCH2 was found to be lowest in tumors with TP53 mutations and highest in TP53 wild-type/ER+ tumors (p = 0.0059). In the latter group, the NOTCH2 expression was particularly increased in carriers of the risk genotypes (AG/GG) of rs11249433 when compared to the non-risk AA genotype (p = 0.0062). Similar association between NOTCH2 expression and rs11249433 was observed in 60 samples of purified monocytes from healthy controls (p = 0.015), but not in total blood samples from 302 breast cancer patients and 76 normal breast tissue samples. We also identified the first possible dominant-negative form of NOTCH2, a truncated version of NOTCH2 consisting of only the extracellular domain.
This is the first study to show that the expression of NOTCH2 differs in subgroups of breast tumors and by genotypes of the breast cancer-associated SNP rs11249433. The NOTCH pathway has key functions in stem cell differentiation of ER+ luminal cells in the breast. Therefore, increased expression of NOTCH2 in carriers of rs11249433 may promote development of ER+ luminal tumors. Further studies are needed to investigate possible mechanisms of regulation of NOTCH2 expression by rs11249433 and the role of NOTCH2 splicing forms in breast cancer development.
最近的全基因组关联研究（GWAS）已经确定了 1p11.2 区域中的单核苷酸多态性（SNP）rs11249433 是乳腺癌的新遗传风险因素，并且这种关联在雌激素受体（ER）+与 ER- 癌症患者中更强。
我们发现 SNP rs11249433 与位于 1p11.2 区域的 NOTCH2 基因的表达之间存在关联。在 180 例乳腺癌肿瘤中，NOTCH2 的表达在具有 TP53 突变的肿瘤中最低，在 TP53 野生型/ER+肿瘤中最高（p = 0.0059）。在后一组中，与非风险基因型（AA）相比，rs11249433 的风险基因型（AG / GG）的携带者中 NOTCH2 的表达特别增加（p = 0.0062）。在来自健康对照的 60 个纯化单核细胞样本中也观察到了 NOTCH2 表达与 rs11249433 之间的类似关联（p = 0.015），但在 302 例乳腺癌患者和 76 例正常乳腺组织样本的总血液样本中则没有观察到这种关联。我们还鉴定了 NOTCH2 的第一个可能的显性负形式，即仅由细胞外结构域组成的 NOTCH2 的截断形式。
这是第一项表明 NOTCH2 的表达在乳腺癌相关 SNP rs11249433 的亚组和基因型中存在差异的研究。NOTCH 途径在乳腺 ER+ 腔细胞的干细胞分化中具有关键功能。因此，rs11249433 携带者中 NOTCH2 的表达增加可能会促进 ER+ 腔肿瘤的发展。需要进一步研究以探讨 rs11249433 对 NOTCH2 表达的调节的可能机制以及 NOTCH2 剪接形式在乳腺癌发展中的作用。
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