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Open AccessArticle

Targeted Gene Next-Generation Sequencing Panel in Patients with Advanced Lung Adenocarcinoma: Paving the Way for Clinical Implementation

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Pulmonology Department, Centro Hospitalar Universitário de São João, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
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Faculty of Medicine, University of Porto, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
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Institute of Molecular Pathology and Immunology of the University of Porto (IPATIMUP), 4200-135 Porto, Portugal
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Institute for Research and Innovation in Health (i3S), University of Porto, Rua Alfredo Allen, 4200-135 Porto, Portugal
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Pathology Department, Centro Hospitalar Universitário de São João, Alameda Prof. Hernani Monteiro, 4200-319 Porto, Portugal
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Escola Superior de Saúde (ESS), Instituto Politecnico do Porto (IPP), Rua Dr António Bernardino de Almeida, 4200-072 Porto, Portugal
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Author to whom correspondence should be addressed.
Cancers 2019, 11(9), 1229; https://doi.org/10.3390/cancers11091229
Received: 16 July 2019 / Revised: 4 August 2019 / Accepted: 15 August 2019 / Published: 22 August 2019
(This article belongs to the Special Issue Molecular Profiling of Lung Cancer)
Identification of targetable molecular changes is essential for selecting appropriate treatment in patients with advanced lung adenocarcinoma. Methods: In this study, a Sanger sequencing plus Fluorescence In Situ Hybridization (FISH) sequential approach was compared with a Next-Generation Sequencing (NGS)-based approach for the detection of actionable genomic mutations in an experimental cohort (EC) of 117 patients with advanced lung adenocarcinoma. Its applicability was assessed in small biopsies and cytology specimens previously tested for epidermal growth factor receptor (EGFR) and anaplastic lymphoma kinase (ALK) mutational status, comparing the molecular changes identified and the impact on clinical outcomes. Subsequently, an NGS-based approach was applied and tested in an implementation cohort (IC) in clinical practice. Using Sanger and FISH, patients were classified as EGFR-mutated (n = 22, 18.8%), ALK-mutated (n = 9, 7.7%), and unclassifiable (UC) (n = 86, 73.5%). Retesting the EC with NGS led to the identification of at least one gene variant in 56 (47.9%) patients, totaling 68 variants among all samples. Still, in the EC, combining NGS plus FISH for ALK, patients were classified as 23 (19.7%) EGFR; 20 (17.1%) KRAS; five (4.3%) B-Raf proto-oncogene (BRAF); one (0.9%) Erb-B2 Receptor Tyrosine Kinase 2 (ERBB2); one (0.9%) STK11; one (0.9%) TP53, and nine (7.7%) ALK mutated. Only 57 (48.7%) remained genomically UC, reducing the UC rate by 24.8%. Fourteen (12.0%) patients presented synchronous alterations. Concordance between NGS and Sanger for EGFR status was very high (κ = 0.972; 99.1%). In the IC, a combined DNA and RNA NGS panel was used in 123 patients. Genomic variants were found in 79 (64.2%). In addition, eight (6.3%) EML4-ALK, four (3.1%), KIF5B-RET, four (3.1%) CD74-ROS1, one (0.8%) TPM3-NTRK translocations and three (2.4%) exon 14 skipping MET Proto-Oncogene (MET) mutations were detected, and 36% were treatable alterations. Conclusions: This study supports the use of NGS as the first-line test for genomic profiling of patients with advanced lung adenocarcinoma. View Full-Text
Keywords: lung cancer; targeted therapy; next-generation sequencing; molecular profiling lung cancer; targeted therapy; next-generation sequencing; molecular profiling
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Fernandes, M.G.O.; Jacob, M.; Martins, N.; Moura, C.S.; Guimarães, S.; Reis, J.P.; Justino, A.; Pina, M.J.; Cirnes, L.; Sousa, C.; Pinto, J.; Marques, J.A.; Machado, J.C.; Hespanhol, V.; Costa, J.L. Targeted Gene Next-Generation Sequencing Panel in Patients with Advanced Lung Adenocarcinoma: Paving the Way for Clinical Implementation. Cancers 2019, 11, 1229.

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