肺腺癌脑转移下一代外显子组测序检测到的基因突变谱。

Spectrum of gene mutations detected by next generation exome sequencing in brain metastases of lung adenocarcinoma.

机构信息

Department of Medicine I, Medical University of Vienna, Austria; Comprehensive Cancer Center, Central Nervous System Unit (CCC-CNS), Medical University of Vienna, Austria.

Institute of Neurology, Medical University of Vienna, Austria; Comprehensive Cancer Center, Central Nervous System Unit (CCC-CNS), Medical University of Vienna, Austria.

出版信息

Eur J Cancer. 2015 Sep;51(13):1803-11. doi: 10.1016/j.ejca.2015.06.107. Epub 2015 Jul 8.

DOI:10.1016/j.ejca.2015.06.107

PMID:26164066

Abstract

BACKGROUND

Brain metastases (BM) are a life-threatening complication. We aimed to analyse gene mutations in lung adenocarcinoma BM.

METHODS

We performed next generation sequencing (NGS) of a pre-defined set of 48 cancer-related genes in a cohort of 76 neurosurgical lung adenocarcinoma BM specimens using a cancer specific gene panel on the MiSeq platform (Illumina, San Diego, CA). NGS results were statistically correlated to patient characteristics. Data on ALK, ROS1, MET and FGFR1 gene status assessed by FISH were available from previous studies in the majority of patients.

RESULTS

Twenty-nine (60.4%) of the 48 investigated cancer-related genes were mutated in at least one BM sample and 64 (84.2%) of the 76 BM samples carried at least one mutated gene. The number of mutated genes per sample ranged from 0 to 9 (median 2). The most commonly mutated genes were TP53, KRAS and CDKN2A, which were affected in 35/76 (46.1%), 29/76 (38.2%) and 17/76 (22.4%) samples, respectively. Other potentially druggable alterations included EGFR mutations (3/76, 3.9% of samples), PIK3CA mutation (2/76, 2.6%), BRAF mutation (1/76, 1.3%) and SMO mutation (1/76, 1.3%). Presence of KRAS mutations was associated with positive smoking history (p=0.015, Chi square test) and presence of EGFR mutation correlated with unfavourable overall survival time from BM diagnosis (p=0.019, log rank test).

CONCLUSIONS

Deleterious gene mutations, some of them with potential therapeutic implications, are found in a high fraction of lung adenocarcinoma BM.

摘要

背景

脑转移（BM）是一种危及生命的并发症。我们旨在分析肺腺癌 BM 中的基因突变。

方法

我们使用 MiSeq 平台（Illumina，圣地亚哥，CA）上的癌症特异性基因面板，对 76 例神经外科肺腺癌 BM 标本进行了预先确定的 48 个癌症相关基因的下一代测序（NGS）。NGS 结果与患者特征进行了统计学相关性分析。大多数患者的 FISH 检测到 ALK、ROS1、MET 和 FGFR1 基因状态的数据可从以前的研究中获得。

结果

在所研究的 48 个癌症相关基因中，至少有一个 BM 样本发生了 29 个（60.4%）突变，76 个 BM 样本中至少有一个发生了突变基因 64 个（84.2%）。每个样本的突变基因数量从 0 到 9 不等（中位数为 2）。最常见的突变基因是 TP53、KRAS 和 CDKN2A，分别影响 35/76（46.1%）、29/76（38.2%）和 17/76（22.4%）的样本。其他潜在可用药的改变包括 EGFR 突变（3/76，3.9%的样本）、PIK3CA 突变（2/76，2.6%）、BRAF 突变（1/76，1.3%）和 SMO 突变（1/76，1.3%）。KRAS 突变的存在与阳性吸烟史相关（p=0.015，卡方检验），EGFR 突变的存在与 BM 诊断后总生存时间不利相关（p=0.019，对数秩检验）。