A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk.
A SNP in a let-7 microRNA complementary site in the KRAS 3' untranslated region increases non-small cell lung cancer risk.
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DOI：
10.1158/0008-5472.can-08-2129
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发表时间：
2008-10-15
期刊：
影响因子：
11.2
通讯作者：
Weidhaas JB
中科院分区：
文献类型：
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作者：
Chin LJ;Ratner E;Leng S;Zhai R;Nallur S;Babar I;Muller RU;Straka E;Su L;Burki EA;Crowell RE;Patel R;Kulkarni T;Homer R;Zelterman D;Kidd KK;Zhu Y;Christiani DC;Belinsky SA;Slack FJ;Weidhaas JB
肺癌是全球癌症死亡的主要原因，但对筛查有用的肺癌风险遗传标记却很少。Let-7家族的microRNAs(MiRNAs)是一种全球性的基因调控因子，通过与其靶信使RNAs(MRNAs)的3‘UTrs(非翻译区)结合，控制肺癌癌基因的表达。本研究的目的是确定能够改变let-7结合的单核苷酸多态(SNPs)，并评估其对靶基因调控和非小细胞肺癌(NSCLC)风险的影响。对74例非小细胞肺癌患者KRAS 3‘非编码区的let-7互补位点(LCSs)进行测序，以确定与NSCLC相关的突变和SNP。在2433人(代表46个人类群体)中，研究了位于LCS6的一个先前未识别的SNP的等位基因频率。该变异等位基因在非小细胞肺癌患者中的频率为18.1-20.3%，在世界人群中为5.8%。在两个独立的病例对照研究中，确定了SNP与非小细胞肺癌风险之间的关联。一项来自新墨西哥州的肺癌病例对照研究显示，吸烟40年的患者患非小细胞肺癌的风险增加2.3倍(C.I.=1.1-4.6，p=0.02)。这种联系在第二个独立的病例对照研究中得到了验证。在功能上，变异的等位基因导致KRAS在体外过度表达。在中度吸烟者中，KRAS miRNA互补位点的LCS6变异等位基因与NSCLC的风险显著相关，并代表了let-7 miRNAs在肺癌易感性中的新范例。
Lung cancer is the leading cause of cancer deaths worldwide, yet few genetic markers of lung cancer risk useful for screening exist. The let-7 family-of-microRNAs (miRNAs) are global genetic regulators important in controlling lung cancer oncogene expression by binding to the 3′UTRs (untranslated regions) of their target messenger RNAs (mRNAs). The purpose of this study was to identify single nucleotide polymorphisms (SNPs) that could modify let-7 binding and to assess the effect of such SNPs on target gene regulation and risk for non-small cell lung cancer (NSCLC). let-7 complementary sites (LCSs) were sequenced in the KRAS 3′UTR from 74 NSCLC cases to identify mutations and SNPs that correlated with NSCLC. The allele frequency of a previously un-identified SNP at LCS6 was characterized in 2433 people (representing 46 human populations). The frequency of the variant allele is 18.1–20.3% in NSCLC patients and 5.8% in world populations. The association between the SNP and the risk for NSCLC was defined in two independent case-control studies. A case-control study of lung cancer from New Mexico showed a 2.3-fold increased risk (C.I.= 1.1–4.6, p = 0.02) for NSCLC cancer in patients who smoked < 40 pack years. This association was validated in a second independent case-control study. Functionally, the variant allele results in KRAS over-expression in vitro. The LCS6 variant allele in a KRAS miRNA complementary site is significantly associated with increased risk for NSCLC among moderate smokers, and represents a new paradigm for let-7 miRNAs in lung cancer susceptibility.