Clinical Validation of Coexisting Activating Mutations Within EGFR, Mitogen-Activated Protein Kinase, and Phosphatidylinositol 3-Kinase Pathways in Lung Cancers
Clinical Validation of Coexisting Activating Mutations Within EGFR, Mitogen-Activated Protein Kinase, and Phosphatidylinositol 3-Kinase Pathways in Lung Cancers
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DOI：
10.5858/arpa.2017-0495-oa
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发表时间：
2019-02-01
影响因子：
4.6
通讯作者：
Lin, Ming-Tseh
中科院分区：
文献类型：
--
作者：
De Marchi, Federico;Haley, Lisa;Lin, Ming-Tseh
背景。相同信号转导通路内的突变是冗余的，因此大多数是相互排斥的。然而，实验室错误可能会引入意想不到的共存突变。验证表皮生长因子受体（EGFR）、促分裂原活化蛋白激酶和磷脂酰肌醇3-激酶通路内的共存突变。在这项针对临床诊断环境中下一代测序的质量评估的回顾性研究中，在1208例非小细胞肺癌患者中检查了EGFR、KRAS、NRAS、BRAF、AKT 1和PIK 3CA基因内的共存突变。EGFR突变不与BRAF突变共存，既不是激酶激活突变也不是激酶受损突变。BRAF、EGFR和KRA-S突变肺癌中PIK 3CA突变的发生率较低但相似（3.3%-5.1%），在1208例肺癌中的1例（0.08%）或226例EGFR突变肺癌中的1例（0.4%）中检测到KRAS和EGFR突变共存的罕见发生率。在4例AKT 1 p.E17K突变肺癌中的3例中观察到BRAF p.V600E突变共存。使用另一种检测方法，对从具有相同或不同组织形态学的亚区中重新分离的DNA进行突变谱分析，证实了共存突变可能存在于相同（全或亚克隆）群体或不同群体中，并澄清了最初在标本中报告的所谓共存激活KRAS和BRAF突变确实存在于同一区块中提交的单独肺结节中。结果支持EGFR和BRAF突变是肺癌的早期驱动突变。官方组织制定标准操作程序的指导方针是必要的，以验证意外的共存突变，如果有临床指征，以确定它们在相同或不同的肿瘤群体中的存在。
Context.-Mutations within the same signature transduction pathway are redundant and, therefore, most are mutually exclusive. Laboratory errors, however, may introduce unexpected coexisting mutations.Objective.-To validate coexisting mutations within epidermal growth factor receptor (EGFR), mitogen-activated protein kinase, and phosphatidylinositol 3-kinase pathways.Design.-In this retrospective study for quality assessment of next-generation sequencing in a clinical diagnostics setting, coexisting mutations within EGFR, KRAS, NRAS, BRAF, AKT1, and PIK3CA genes were examined in 1208 non-small cell lung cancers.Results.-EGFR mutations did not coexist with BRAF mutations, neither kinase-activated nor kinase-impaired mutations. There was a low but similar incidence (3.3%5.1%) of PIK3CA mutations in BRAF-, EGFR-, and KRA-Smutated lung cancers and a rare incidence of coexisting KRAS and EGFR mutations detected in 1 of 1208 lung cancers (0.08%) or 1 of 226 EGFR-mutated lung cancers 0.4%). Coexisting BRAF p.V600E mutation was observed in 3 of 4 AKT1 p.E17K-mutated lung cancers. Mutational profiling of DNA reisolated from subareas with the same or different histomorphology, using an alternative assay, confirmed that coexisting mutations might present within the same (whole or subclonal) population or different populations and clarified that the so-called coexisting activating KRAS and BRAF mutations originally reported in a specimen were indeed present in separate lung nodules submitted in the same block.Conclusions.-The results supported that EGFR and BRAF mutations are early driver mutations in lung cancers. Guidelines from official organizations to establish standard operating procedures are warranted to validate unexpected coexisting mutations and, if clinically indicated, to determine their presence in the same or different tumor populations.