Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
Integrative Genomic Characterization Identifies Molecular Subtypes of Lung Carcinoids
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DOI：
10.1158/0008-5472.can-19-0214
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发表时间：
2019-09-01
期刊：
影响因子：
11.2
通讯作者：
Chan, Chang S.
中科院分区：
文献类型：
--
作者：
Laddha, Saurabh V.;da Silva, Edaise M.;Chan, Chang S.
肺类癌是一种罕见的生长缓慢的原发性肺神经内分泌肿瘤。我们对宏观解剖的LC进行靶向外显子组测序、mRNA测序和DNA甲基化阵列分析。复发突变富集了参与共价组蛋白修饰/染色质重塑（34.5%; MEN 1、ARID 1A、KMT 2C和KMT 2A）以及DNA修复（17.2%）途径的基因。基因表达和DNA甲基化谱的无监督聚类和主成分分析显示了三个具有不同临床特征的分子亚型（LC 1，LC 2，LC 3）。发现MEN 1基因突变仅在LC 2亚型中富集。LC 1和LC 3亚型分别主要见于外周肺和支气管内肺。LC 3亚型的诊断年龄小于LC 1和LC 2亚型。两种生物标志物ASCL 1和S100的IHC染色充分分层了三种亚型。这三种亚型的LC分子分类可能有助于了解其分子机制，提高诊断和临床management.Significance：肺类癌的综合基因组分析确定了三个新的分子亚型具有不同的临床特征，并提供了深入了解其独特的分子特征的肿瘤发生，诊断和预后。
Lung carcinoids (LC) are rare and slow growing primary lung neuroendocrine tumors. We performed targeted exome sequencing, mRNA sequencing, and DNA methylation array analysis on macro-dissected LCs. Recurrent mutations were enriched for genes involved in covalent histone modification/chromatin remodeling (34.5%; MEN1, ARID1A, KMT2C, and KMT2A) as well as DNA repair (17.2%) pathways. Unsupervised clustering and principle component analysis on gene expression and DNA methylation profiles showed three robust molecular subtypes (LC1, LC2, LC3) with distinct clinical features. MEN1 gene mutations were found to be exclusively enriched in the LC2 subtype. LC1 and LC3 subtypes were predominately found at peripheral and endobronchial lung, respectively. The LC3 subtype was diagnosed at a younger age than LC1 and LC2 subtypes. IHC staining of two biomarkers, ASCL1 and S100, sufficiently stratified the three subtypes. This molecular classification of LCs into three subtypes may facilitate understanding of their molecular mechanisms and improve diagnosis and clinical management.Significance: Integrative genomic analysis of lung carcinoids identifies three novel molecular subtypes with distinct clinical features and provides insight into their distinctive molecular signatures of tumorigenesis, diagnosis, and prognosis.