Identification of a novel gene signature of lung adenocarcinoma based on epidermal growth factor receptor-tyrosine kinase inhibitor resistance.
Identification of a novel gene signature of lung adenocarcinoma based on epidermal growth factor receptor-tyrosine kinase inhibitor resistance.
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DOI：
10.3389/fonc.2022.1008283
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发表时间：
2022
影响因子：
4.7
通讯作者：
Jin, Yang
中科院分区：
文献类型：
--
作者：
Zhou, E.;Wu, Feng;Guo, Mengfei;Yin, Zhengrong;Li, Yumei;Li, Minglei;Xia, Hui;Deng, Jingjing;Yang, Guanghai;Jin, Yang
关键词：
针对表皮生长因子受体(EGFR)突变的酪氨酸激酶抑制剂(TKIs)通常用于EGFR阳性肺癌患者。然而，对EGFR-TKI(主要是吉非替尼和厄洛替尼)的耐药性目前是一个严重的问题。有限的研究集中在肺腺癌(LUAD)中的EGFR-TKI耐药相关基因信号(ERS)。通过对三个基因表达总集的差异分析，获得了吉非替尼和厄洛替尼抗性相关基因。这些基因在来自癌症基因组图谱(TCGA)的LUAD患者中进行了进一步的研究。TCGA-LUAD队列中的患者被分为两组：一组接受培训，另一组进行测试。训练队列用于构建ERS，测试队列用于测试ERS。GO和KEGG分析探讨了高危和低危人群之间丰富的通路。各种软件，主要是CiberSort和ssGSEA，被用于免疫渗透图谱。此外，还进行了体细胞突变和药敏分析。构建了基于5个基因(FGD3、PCDH7、DEPDC1B、SATB2和S100P)的ERS，并使用TCGA-LUAD队列进行了验证，导致LUAD患者明显分为高危和低危两组。多变量COX分析证实ERS对LUAD有独立的预后价值。途径浓缩分析表明，两个风险组之间存在差异的基因大多与免疫系统有关。进一步的免疫浸润结果显示，高危患者的免疫浸润评分较低，各种白细胞与ERS显著相关。重要的是，高危人群的样本显示PD-1、PD-L1和CTLA-4水平较低，这些都是免疫治疗反应的重要生物标志物。高风险组的患者也有更多的基因突变变化，对多西他赛和索拉非尼等化疗药物更敏感。ERS在GSE30219、GSE11969和GSE72094中也得到了验证，对LUAD患者具有良好的预后价值。在这项研究中建立的ERS能够预测LUAD患者的不良预后，并具有预测药物反应的巨大潜力。
Tyrosine kinase inhibitors (TKIs) that target epidermal growth factor receptor (EGFR) mutations are commonly administered to EGFR-positive lung cancer patients. However, resistance to EGFR-TKIs (mostly gefitinib and erlotinib) is presently a significant problem. Limited studies have focused on an EGFR-TKI resistance-related gene signature (ERS) in lung adenocarcinoma (LUAD). Gefitinib and erlotinib resistance-related genes were obtained through the differential analyses of three Gene Expression Omnibus datasets. These genes were investigated further in LUAD patients from The Cancer Genome Atlas (TCGA). Patients in the TCGA-LUAD cohort were split into two groups: one for training and one for testing. The training cohort was used to build the ERS, and the testing cohort was used to test it. GO and KEGG analyses were explored for the enriched pathways between the high-risk and low-risk groups. Various software, mainly CIBERSORT and ssGSEA, were used for immune infiltration profiles. Somatic mutation and drug sensitivity analyses were also explored. An ERS based on five genes (FGD3, PCDH7, DEPDC1B, SATB2, and S100P) was constructed and validated using the TCGA-LUAD cohort, resulting in the significant stratification of LUAD patients into high-risk and low-risk groups. Multivariable Cox analyses confirmed that ERS had an independent prognostic value in LUAD. The pathway enrichment analyses showed that most of the genes that were different between the two risk groups were related to the immune system. Further immune infiltration results revealed that a lower immune infiltration score was observed in high-risk patients, and that various leukocytes were significantly related to the ERS. Importantly, samples from the high-risk group showed lower levels of PD-1, PD-L1, and CTLA-4, which are important biomarkers for immunotherapy responses. Patients in the high-risk group also had more gene mutation changes and were more sensitive to chemotherapy drugs like docetaxel and sorafenib. The ERS was also validated in the GSE30219, GSE11969 and GSE72094, and showed a favorable prognostic value for LUAD patients. The ERS established during this study was able to predict a poor prognosis for LUAD patients and had great potential for predicting drug responses.
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影响因子：
5.2
作者：
Susini T;Saccardin G;Renda I;Giani M;Tartarotti E;Nori J;Vanzi E;Pasqualini E;Bianchi S
通讯作者：
Bianchi S
影响因子：
51.1
作者：
Park, Keunchil;Tan, Eng-Huat;Paz-Ares, Luis
通讯作者：
Paz-Ares, Luis
影响因子：
5.2
作者：
Wu, Shang-Gin;Chang, Tzu-Hua;Shih, Jin-Yuan
通讯作者：
Shih, Jin-Yuan
影响因子：
158.5
作者：
Soria, J. -C.;Ohe, Y.;Nguyen, Nhung
通讯作者：
Nguyen, Nhung
高水平的 DEPDC1B 预测前列腺癌患者的生化无复发生存期较短
影响因子：
2.9
作者：
Bai, Shoumin;Chen, Ting;Huang, Hai
通讯作者：
Huang, Hai