MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking.
MAP2K1 (MEK1) Mutations Define a Distinct Subset of Lung Adenocarcinoma Associated with Smoking.
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DOI：
10.1158/1078-0432.ccr-14-2124
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发表时间：
2015-04-15
期刊：
影响因子：
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通讯作者：
Ladanyi M
中科院分区：
文献类型：
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作者：
Arcila ME;Drilon A;Sylvester BE;Lovly CM;Borsu L;Reva B;Kris MG;Solit DB;Ladanyi M
影响MAPK/ERK通路的遗传改变在肺腺癌（LAD）中很常见。信号通路的早期步骤最常受到EGFR、KRAS和BRAF突变的影响，占所有改变的70%以上。位于BRAF下游的MEK1的体细胞突变是罕见的，并且作为一个独特的分子亚群仍然定义不清。通过对大量LAD队列进行靶向筛选，同时询问MEK1、EGFR、KRAS、BRAF、ERBB2/HER2、NRAS、PIK3CA和AKT的复发突变，确定了含有MEK1突变的肿瘤。通过搜索可公开获得的癌症基因组数据集确定了其他病例。突变与患者特征和治疗结果相关。总生存率与分期匹配的KRAS和EGFR突变肺腺癌患者进行比较。我们在6024例LAD中发现36例MEK1突变病例（0.6%,95% CI 0.42至0.85）。大多数患者为吸烟者（97%,n=35/36）。这与年龄、性别、种族或阶段无关。最常见的突变是K57N(64%, 23/36)，其次是Q56P(19%, 7/36)，这些突变在靶组中与其他驱动突变相互排斥。G:C、bb0、T:A的基因转位居多（89%,31/35），与吸烟相关的DNA损伤一致。在激酶结构域中发现了其他不太常见的体细胞突变，所有这些突变都被预测为基于计算机三维建模的单一相互作用区域。MEK1突变定义了对MEK抑制剂具有潜在敏感性的肺癌的一个独特亚群（约1%）。突变主要是变异，与吸烟密切相关。
Genetic alterations affecting the MAPK/ERK pathway are common in lung adenocarcinoma (LAD). Early steps of the signaling pathway are most often affected with EGFR, KRAS and BRAF mutations encompassing over 70% of all alterations. Somatic mutations in MEK1, located downstream of BRAF, are rare and remain poorly defined as a distinct molecular subset. Tumors harboring MEK1 mutations were identified through targeted screening of a large LAD cohort concurrently interrogated for recurrent mutations in MEK1, EGFR, KRAS, BRAF, ERBB2/HER2, NRAS, PIK3CA, and AKT. Additional cases were identified through a search of publically available cancer genomic datasets. Mutations were correlated with patient characteristics and treatment outcomes. Overall survival was compared to stage-matched patients with KRAS and EGFR mutant lung adenocarcinomas. We identified 36 MEK1 mutated cases among 6024 LAD (0.6%, 95% CI 0.42 to 0.85). The majority of patients were smokers (97%, n=35/36). There was no association with age, sex, race, or stage. The most common mutations were K57N (64%, 23/36) followed by Q56P (19%, 7/36), all mutually exclusive with other driver mutations in the targeted panel. Transversions G:C > T:A were predominant (89%, 31/35), in keeping with smoking-associated DNA damage. Additional less common somatic mutations were identified in the kinase domain, all of which are predicted to converge into a single interaction area based on in-silico 3D modeling. MEK1 mutations define a distinct subset of lung cancers (∼1%) with potential sensitivity to MEK inhibitors. Mutations are predominantly transversions, in keeping with a strong association with smoking.