Development and validation of a five-gene model to predict postoperative brain metastasis in operable lung adenocarcinoma
Development and validation of a five-gene model to predict postoperative brain metastasis in operable lung adenocarcinoma
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开发和验证五基因模型来预测可手术肺腺癌术后脑转移。
DOI：
10.1002/ijc.32981
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发表时间：
2020-04-02
影响因子：
6.4
通讯作者：
Chen, Haiquan
中科院分区：
文献类型：
--
作者：
Fu, Fangqiu;Zhang, Yang;Chen, Haiquan
非小细胞肺癌胸外远处转移最常见的部位之一是脑。我们的研究旨在发现与可手术肺腺癌（LUAD）术后脑转移相关的基因。对 7 名脑转移患者和 45 名未复发患者的原发性 LUAD 标本进行了 RNA 测序。对 272 个手术切除的 LUAD 标本进行了差异表达基因的免疫组织化学 (IHC) 分析。采用LASSO Cox回归筛选与脑转移相关的基因并构建脑转移评分（BMS）。 GSE31210和GSE50081用作模型的验证数据集。对 TCGA 数据库中按脑转移风险分层的患者进行基因集富集分析。通过初步筛选，选择 8 个基因（CDK1、KPNA2、KIF11、ASPM、CEP55、HJURP、TYMS 和 TTK）进行 IHC 分析。基于五个基因（TYMS、CDK1、HJURP、CEP55 和 KIF11）蛋白表达水平的 BMS 高度预测我们队列中的脑转移（12 个月 AUC：0.791、36 个月 AUC：0.766、60 个月 AUC：0.812）。 BMS对GSE31210和GSE50081总生存率的验证也显示出优异的预测价值（GSE31210，12个月AUC：0.682，36个月AUC：0.713，60个月AUC：0.762；GSE50081，12个月AUC：0.706，36个月AUC： 0.700，60 个月 AUC：0.724）。进一步的分析表明，高 BMS 与细胞周期和 DNA 修复途径相关。五基因预测模型对于预测术后脑转移和根治性切除后 LUAD 患者的个体化管理具有潜在的临床实用性。
One of the most common sites of extra-thoracic distant metastasis of nonsmall-cell lung cancer is the brain. Our study was performed to discover genes associated with postoperative brain metastasis in operable lung adenocarcinoma (LUAD). RNA seq was performed in specimens of primary LUAD from seven patients with brain metastases and 45 patients without recurrence. Immunohistochemical (IHC) assays of the differentially expressed genes were conducted in 272 surgical-resected LUAD specimens. LASSO Cox regression was used to filter genes related to brain metastasis and construct brain metastasis score (BMS). GSE31210 and GSE50081 were used as validation datasets of the model. Gene Set Enrichment Analysis was performed in patients stratified by risk of brain metastasis in the TCGA database. Through the initial screening, eight genes (CDK1, KPNA2, KIF11, ASPM, CEP55, HJURP, TYMS and TTK) were selected for IHC analyses. The BMS based on protein expression levels of five genes (TYMS, CDK1, HJURP, CEP55 and KIF11) was highly predictive of brain metastasis in our cohort (12-month AUC: 0.791, 36-month AUC: 0.766, 60-month AUC: 0.812). The validation of BMS on overall survival of GSE31210 and GSE50081 also showed excellent predictive value (GSE31210, 12-month AUC: 0.682, 36-month AUC: 0.713, 60-month AUC: 0.762; GSE50081, 12-month AUC: 0.706, 36-month AUC: 0.700, 60-month AUC: 0.724). Further analyses showed high BMS was associated with pathways of cell cycle and DNA repair. A five-gene predictive model exhibits potential clinical utility for the prediction of postoperative brain metastasis and the individual management of patients with LUAD after radical resection.