Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma
Common SNP in pre-miR-146a decreases mature miR expression and predisposes to papillary thyroid carcinoma
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DOI：
10.1073/pnas.0802682105
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发表时间：
2008-05-20
影响因子：
11.1
通讯作者：
de la Chapelle, Albert
中科院分区：
文献类型：
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作者：
Jazdzewski, Krystian;Murray, Elizabeth L.;de la Chapelle, Albert
虽然乳头状甲状腺癌（PTC）显示出很强的遗传性，没有诱发生殖系突变已经found. We表明，一个共同的G/C多态性（rs 2910164）的前miR-146 a序列内减少前和成熟的miR-146 a的C等位基因的数量分别为1.9和1.8倍，相比G等位基因。这与在体外加工反应中从相应的pri-miR-146 a产生的每种pre-miR的量的类似减少相匹配。C等位基因还干扰核因子与pre-miR-146 a的结合。miR-146 a的减少导致对参与Toll样受体和细胞因子信号传导途径（TRAF 6，IRAK 1）的靶基因和PTC 1（也称为CCDC 6或1-14）的抑制效率降低，PTC中的基因经常与RET原癌基因重排。在对608名PTC患者和901名对照者的关联研究中，我们发现rs 2910164基因型分布存在显著差异，（P = 0.000002），GC杂合子状态与获得PTC的风险增加相关（比值比= 1.62，P = 0.000007），两种纯合子状态均具有保护作用，CC基因型的优势比= 0.42（P = 0.003），GG基因型的优势比= 0.69（P = 0.0006）。此外，4.7%的肿瘤发生了SNP序列的体细胞突变。因此，我们的数据表明，一个共同的多态性在前miR-146 a影响miR的表达，有助于遗传易感性PTC，并通过体细胞突变在肿瘤发生中发挥作用。初步证据表明，这些作用是通过靶基因介导的，其表达受SNP状态的影响。
Although papillary thyroid carcinoma (PTC) displays strong heritability, no predisposing germ-line mutations have been found. We show that a common G/C polymorphism (rs2910164) within the pre-miR-146a sequence reduced the amount of pre- and mature miR-146a from the C allele 1.9- and 1.8-fold, respectively, compared with the G allele. This is matched by a similar decrease in the amount of each pre-miR generated from the corresponding pri-miR-146a in an in vitro processing reaction. The C allele also interfered with the binding of a nuclear factor to pre-miR-146a. The reduction in miR-146a led to less efficient inhibition of target genes involved in the Toll-like receptor and cytokine signaling pathway (TRAF6, IRAK1), and PTC1 (also known as CCDC6 or 1-14), a gene frequently rearranged with RET proto-oncogene in PTC. In an association study of 608 PTC patients and 901 controls, we found marked differences in genotype distribution of rs2910164 (P = 0.000002), the GC heterozygous state being associated with an increased risk of acquiring PTC (odds ratio = 1.62, P = 0.000007), and both homozygous states protective with odds ratio = 0.42 for the CC genotype (P = 0.003) and odds ratio = 0.69 for the GG genotype (P = 0.0006). Moreover, 4.7% of tumors had undergone somatic mutations of the SNP sequence. Thus, our data suggest that a common polymorphism in pre-miR-146a affects the miR expression, contributes to the genetic predisposition to PTC, and plays a role in the tumorigenesis through somatic mutation. Preliminary evidence suggests that these effects are mediated through target genes whose expression is affected by the SNP status.