Multiplatform-based molecular subtypes of non-small-cell lung cancer.
Multiplatform-based molecular subtypes of non-small-cell lung cancer.
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DOI：
10.1038/onc.2016.303
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发表时间：
2017-03
期刊：
影响因子：
8
通讯作者：
Creighton CJ
中科院分区：
文献类型：
--
作者：
Chen F;Zhang Y;Parra E;Rodriguez J;Behrens C;Akbani R;Lu Y;Kurie JM;Gibbons DL;Mills GB;Wistuba II;Creighton CJ
非小细胞肺癌（NSCLC）表现出显着的分子多样性。随着癌症基因组图谱 (TCGA) 的完成，我们有机会对整个 TCGA NSCLC 队列进行系统分析，包括不同疾病子集之间的比较和对比。在多维和全面的分子特征（包括 DNA 甲基化和拷贝、RNA 和蛋白质表达）的基础上，使用“簇中簇”分析方法对 1023 例 NSCLC 病例进行分类，其中 519 例来自 TCGA 腺癌 (AD) 项目，504 例来自 TCGA 鳞状细胞 (SQCC) 项目。 TCGA NSCLC 子集的模式在独立的外部数据库中进行了检查，包括 PROSPECT（胸部癌症评估中的耐药模式和致癌信号通路分析）NSCLC 数据集。已鉴定出 9 种 NSCLC 基因组亚型，其中 3 种属于 SQCC，6 种属于 AD。 SQCC 亚型与 SOX2 或 p63 的转录靶标相关。一种主要的 AD 亚型（其中大部分为 SQCC）与神经内分泌肿瘤具有相同的分子特征。两种 AD 亚型表现出 CpG 岛甲基化表型 (CIMP)。三种 AD 亚型显示出高 p38 和 mTOR 通路激活。与低分化相关的AD亚型预后相对较差。 SQCC 亚型和两种 AD 亚型表达癌睾丸抗原基因，而三种 AD 亚型表达多种免疫检查点基因，包括 PDL1 和 PDL2，与更大的免疫细胞浸润模式相对应。使用免疫组织化学在 PROSPECT 队列中证实了几种免疫相关标记物（包括 PD1、PDL1、CD3 和 CD8）的亚型关联。 NSCLC 分子亚型具有治疗意义，并支持基于分子特征的个性化 NSCLC 管理方法。
Non-Small Cell Lung Cancer (NSCLC) demonstrates remarkable molecular diversity. With the completion of The Cancer Genome Atlas (TCGA), there is opportunity for systematic analyses of the entire TCGA NSCLC cohort, including comparisons and contrasts between different disease subsets. On the basis of multidimensional and comprehensive molecular characterization (including DNA methylation and copy, and RNA and protein expression), 1023 NSCLC cases—519 from TCGA adenocarcinoma (AD) project and 504 from TCGA squamous cell (SQCC) project—were classified using a “cluster-of-clusters” analytic approach. Patterns from TCGA NSCLC subsets were examined in independent external databases, including the PROSPECT (Profiling of Resistance patterns and Oncogenic Signaling Pathways in Evaluation of Cancers of the Thorax) NSCLC dataset. Nine genomic subtypes of NSCLC were identified, three within SQCC and six within AD. SQCC subtypes were associated with transcriptional targets of SOX2 or p63. One predominately AD subtype (with a large proportion of SQCC) shared molecular features with neuroendocrine tumors. Two AD subtypes manifested a CpG island methylator phenotype (CIMP). Three AD subtypes showed high p38 and mTOR pathway activation. AD subtypes associated with low differentiation showed relatively worse prognosis. SQCC subtypes and two of the AD subtypes expressed cancer-testis antigen genes, while three AD subtypes expressed several immune checkpoint genes including PDL1 and PDL2, corresponding with patterns of greater immune cell infiltration. Subtype associations for several immune-related markers—including PD1, PDL1, CD3, and CD8—were confirmed in the PROSPECT cohort using immunohistochemistry. NSCLC molecular subtypes have therapeutic implications and lend support to a personalized approach to NSCLC management based on molecular characterization.