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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 KRAS-mutated 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. doi: 10.5858/arpa.2017-0495-OA, Several therapeutic agents have been approved by the US Food and Drug Administration in the United States for targeted therapy of metastatic non-small cell lung cancers (NSCLCs). (1) These include [...]