The MKK7 p.Glu116Lys Rare Variant Serves as a Predictor for Lung Cancer Risk and Prognosis in Chinese.
The MKK7 p.Glu116Lys Rare Variant Serves as a Predictor for Lung Cancer Risk and Prognosis in Chinese.
复制标题
MKK7 p.Glu116Lys 罕见变异可作为中国人肺癌风险和预后的预测因子
DOI：
10.1371/journal.pgen.1005955
复制
发表时间：
2016-03
期刊：
影响因子：
4.5
通讯作者：
Lu J
中科院分区：
文献类型：
--
作者：
Qiu F;Yang L;Lu X;Chen J;Wu D;Wei Y;Nong Q;Zhang L;Fang W;Chen X;Ling X;Yang B;Zhang X;Zhou Y;Lu J
越来越多的证据表明，罕见的变异在人类疾病的易感性和进展中起着至关重要的作用，这为研究疾病病因学提供了新的见解。在本研究中，基于对5,016例肺癌患者和5,181名对照的三项独立的回顾性研究，我们分析了MKK7中五个罕见的基因多态(即p.Glu116Lys、p.Asn118Ser、p.Arg138Cys、p.Ala195Thr和p.Leu259Phe)与肺癌风险和预后的关系。为了破译MKK7罕见突变在肺癌中的确切机制，进一步进行了一系列生物学实验。我们发现MKK7p.Glu116Lys罕见多态与肺癌的风险、进展和预后显著相关。与Glu/Glu常见基因型相比，Lys/Glu/+Lys/Lys罕见变异对肺癌易感性有不良影响(优势比[OR]=3.29，95%可信区间[CI]=2.70~4.01)。这些罕见的变异加强了患者的临床进程，116Lys变异的患者在确诊时有显著更高的转移率和晚期的N，M期。此外，携带116Lys变异的患者的肿瘤预后也比携带Glu/Glu基因的患者差(风险比[HR]=1.53，95%CI=1.32~1.78)。功能实验进一步证实，MKK7 p.116Lys变异体改变了多种肿瘤相关基因的表达，从而在体内和体外影响肺癌细胞的增殖、肿瘤生长和转移。综上所述，我们的发现表明，MKK7p.Glu116Lys罕见多态通过调节一系列癌症相关基因的表达而对肺癌风险和预后产生有害影响。
Accumulated evidence indicates that rare variants exert a vital role on predisposition and progression of human diseases, which provides neoteric insights into disease etiology. In the current study, based on three independently retrospective studies of 5,016 lung cancer patients and 5,181 controls, we analyzed the associations between five rare polymorphisms (i.e., p.Glu116Lys, p.Asn118Ser, p.Arg138Cys, p.Ala195Thr and p.Leu259Phe) in MKK7 and lung cancer risk and prognosis. To decipher the precise mechanisms of MKK7 rare variants on lung cancer, a series of biological experiments was further performed. We found that the MKK7 p.Glu116Lys rare polymorphism was significantly associated with lung cancer risk, progression and prognosis. Compared with Glu/Glu common genotype, the 116Lys rare variants (Lys/Glu/+ Lys/Lys) presented an adverse effect on lung cancer susceptibility (odds ratio [OR] = 3.29, 95% confidence interval [CI] = 2.70–4.01). These rare variants strengthened patients’ clinical progression that patients with 116Lys variants had a significantly higher metastasis rate and advanced N, M stages at diagnosis. In addition, the patients with 116Lys variants also contributed to worse cancer prognosis than those carriers with Glu/Glu genotype (hazard ratio [HR] = 1.53, 95% CI = 1.32–1.78). Functional experiments further verified that the MKK7 p.116Lys variants altered the expression of several cancer-related genes and thus affected lung cancer cells proliferation, tumor growth and metastasis in vivo and in vitro. Taken together, our findings proposed that the MKK7 p.Glu116Lys rare polymorphism incurred a pernicious impact on lung cancer risk and prognosis through modulating expressions of a serial of cancer-related genes.