Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance).
Small Cell Lung Cancer Exhibits Frequent Inactivating Mutations in the Histone Methyltransferase KMT2D/MLL2: CALGB 151111 (Alliance).
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DOI：
10.1016/j.jtho.2016.12.011
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发表时间：
2017-04
期刊：
影响因子：
--
通讯作者：
MacPherson D
中科院分区：
文献类型：
--
作者：
Augert A;Zhang Q;Bates B;Cui M;Wang X;Wildey G;Dowlati A;MacPherson D
小细胞肺癌是一种致命性神经内分泌肿瘤，极易发生转移。由于目前还没有获得批准的靶向治疗方法，因此迫切需要了解促进小细胞肺癌的突变基因。小细胞肺癌很少被切除，这限制了可用于体细胞突变基因组分析的样本数量。为了确定人类小细胞肺癌潜在的驱动突变，我们对18个原代小细胞肺癌和7个细胞系的全部外显子进行了测序，并与匹配的正常对照进行了比较。我们通过对40个原代SCLC和48个细胞系的一组基因进行重新测序，扩展了这些数据。我们报告了赖氨酸甲基转移酶2D基因(KMT2D)(也称为MLL2)的频繁突变，它是转录增强功能的关键调节因子。KMT2D在8%的SCLC肿瘤和17%的SCLC细胞系中显示截短无义/移码/剪接点突变。我们发现，人小细胞肺癌细胞系中KMT2D突变与赖氨酸甲基转移酶2D蛋白水平降低和组蛋白H3赖氨酸4单甲基化减少有关，组蛋白H3赖氨酸4是与转录增强子相关的标志。我们还发现了与转录增强子调控相关的其他基因的突变，包括CREB结合蛋白基因(CREBBP)、E1a结合蛋白p300基因(EP300)和染色域解旋酶DNA结合蛋白7基因(CHD7)，我们还报告了其他染色质重塑基因的突变，如Polybromo 1基因(PBRM1)。这些数据表明KMT2D是小细胞肺癌的主要突变基因之一，它们表明转录增强子控制的扰动可能是导致小细胞肺癌的原因之一。
SCLC is a lethal neuroendocrine tumor type that is highly prone to metastasis. There is an urgency to understand the mutated genes that promote SCLC, as there are no approved targeted therapies yet available. SCLC is rarely resected, limiting the number of samples available for genomic analyses of somatic mutations. To identify potential driver mutations in human SCLC we sequenced the whole exomes of 18 primary SCLCs and seven cell lines along with matched normal controls. We extended these data by resequencing a panel of genes across 40 primary SCLCs and 48 cell lines. We report frequent mutations in the lysine methyltransferase 2D gene (KMT2D) (also known as MLL2), a key regulator of transcriptional enhancer function. KMT2D exhibited truncating nonsense/frameshift/splice site mutations in 8% of SCLC tumors and 17% of SCLC cell lines. We found that KMT2D mutation in human SCLC cell lines was associated with reduced lysine methyltransferase 2D protein levels and reduced monomethylation of histone H3 lysine 4, a mark associated with transcriptional enhancers. We also found mutations in other genes associated with transcriptional enhancer control, including CREB binding protein gene (CREBBP), E1A binding protein p300 gene (EP300), and chromodomain helicase DNA binding protein 7 gene (CHD7), and we report mutations in additional chromatin remodeling genes such as polybromo 1 gene (PBRM1). These data indicate that KMT2D is one of the major mutated genes in SCLC, and they point to perturbation of transcriptional enhancer control as potentially contributing to SCLC.
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82.9
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