A lepidic gene signature predicts patient prognosis and sensitivity to immunotherapy in lung adenocarcinoma.
A lepidic gene signature predicts patient prognosis and sensitivity to immunotherapy in lung adenocarcinoma.
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DOI：
10.1186/s13073-021-01010-w
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发表时间：
2022-01-12
期刊：
影响因子：
12.3
通讯作者：
Cheng C
中科院分区：
文献类型：
--
作者：
Nguyen TT;Lee HS;Burt BM;Wu J;Zhang J;Amos CI;Cheng C
肺腺癌是最常见的肺癌类型，具有高度的形态异质性，由多种组织学亚型的肿瘤细胞组成。据报道，免疫细胞浸润显著影响肺腺癌患者的临床结局。然而，目前尚不清楚组织学亚型是否可以反映肿瘤免疫微环境，以及组织学亚型是否可以应用于当前标准治疗的治疗分层。我们使用组织学亚型特异性基因表达数据集推断免疫细胞浸润水平。从不同组织学亚型之间的差异基因表达分析，我们开发了两个基因签名，以计算确定肺腺癌样本中的鳞片和固体成分的相对丰度（分别表示为L-评分和S-评分）。这些特征使我们能够使用先前发表的数据集研究肺腺癌的组织学组成和临床结果之间的关系。我们发现组织学亚型之间存在显着的免疫学差异。差异基因表达分析显示，根据基因表达模式可以区分出麻风型和实体型，而其他亚型的基因表达模式相似。我们的研究结果表明，较高的L评分与生存期延长相关，较高的S评分与生存期缩短相关。L评分和S评分也与全局基因组特征相关，例如肿瘤突变负荷和驱动基因组事件。有趣的是，我们观察到EGFR基因扩增的肺腺癌样本中L评分显著降低，S评分显著增加，但EGFR基因突变的样本中没有。在肺癌细胞系中，我们观察到L评分与细胞对许多靶向药物（包括EGFR抑制剂）的敏感性之间存在显著相关性。此外，L评分较高的肺癌患者更有可能从免疫检查点阻断治疗中受益。我们的研究结果为评估肺腺癌的组织学组成提供了进一步的见解。已建立的特征反映了肺腺癌中的麻风和实体亚型与预后、基因组特征以及对靶向治疗和免疫治疗的反应相关。因此，这些特征表明在预测患者生存和治疗反应方面具有潜在的临床转化。此外，我们的框架可以应用于具有异质组织学亚型的其他类型的癌症。在线版本包含补充材料，可通过10.1186/s13073-021-01010-w获得。
Lung adenocarcinoma, the most common type of lung cancer, has a high level of morphologic heterogeneity and is composed of tumor cells of multiple histological subtypes. It has been reported that immune cell infiltration significantly impacts clinical outcomes of patients with lung adenocarcinoma. However, it is unclear whether histologic subtyping can reflect the tumor immune microenvironment, and whether histologic subtyping can be applied for therapeutic stratification of the current standard of care. We inferred immune cell infiltration levels using a histological subtype-specific gene expression dataset. From differential gene expression analysis between different histological subtypes, we developed two gene signatures to computationally determine the relative abundance of lepidic and solid components (denoted as the L-score and S-score, respectively) in lung adenocarcinoma samples. These signatures enabled us to investigate the relationship between histological composition and clinical outcomes in lung adenocarcinoma using previously published datasets. We found dramatic immunological differences among histological subtypes. Differential gene expression analysis showed that the lepidic and solid subtypes could be differentiated based on their gene expression patterns while the other subtypes shared similar gene expression patterns. Our results indicated that higher L-scores were associated with prolonged survival, and higher S-scores were associated with shortened survival. L-scores and S-scores were also correlated with global genomic features such as tumor mutation burdens and driver genomic events. Interestingly, we observed significantly decreased L-scores and increased S-scores in lung adenocarcinoma samples with EGFR gene amplification but not in samples with EGFR gene mutations. In lung cancer cell lines, we observed significant correlations between L-scores and cell sensitivity to a number of targeted drugs including EGFR inhibitors. Moreover, lung cancer patients with higher L-scores were more likely to benefit from immune checkpoint blockade therapy. Our findings provided further insights into evaluating histology composition in lung adenocarcinoma. The established signatures reflected that lepidic and solid subtypes in lung adenocarcinoma would be associated with prognosis, genomic features, and responses to targeted therapy and immunotherapy. The signatures therefore suggested potential clinical translation in predicting patient survival and treatment responses. In addition, our framework can be applied to other types of cancer with heterogeneous histological subtypes. The online version contains supplementary material available at 10.1186/s13073-021-01010-w.
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影响因子：
5.6
作者：
Hao Q;Cho WC
通讯作者：
Cho WC
实现癌症基因组数据的共同愿景。
DOI：
10.1056/nejmp1607591
发表时间：
2016-09-22
期刊：
The New England journal of medicine
影响因子：
--
作者：
Grossman RL;Heath AP;Ferretti V;Varmus HE;Lowy DR;Kibbe WA;Staudt LM
通讯作者：
Staudt LM
影响因子：
--
作者：
Chen H;Li Y;Long Y;Tang E;Wang R;Huang K;Xie C;Chen G
通讯作者：
Chen G
影响因子：
82.9
作者：
Binnewies M;Roberts EW;Kersten K;Chan V;Fearon DF;Merad M;Coussens LM;Gabrilovich DI;Ostrand-Rosenberg S;Hedrick CC;Vonderheide RH;Pittet MJ;Jain RK;Zou W;Howcroft TK;Woodhouse EC;Weinberg RA;Krummel MF
通讯作者：
Krummel MF
影响因子：
7.2
作者：
Huang, Qingyuan;Zhang, Hua;Stebbing, Justin
通讯作者：
Stebbing, Justin