PMID- 37927472 OWN - NLM STAT- PubMed-not-MEDLINE LR - 20231107 IS - 2234-943X (Print) IS - 2234-943X (Electronic) IS - 2234-943X (Linking) VI - 13 DP - 2023 TI - Comprehensive NGS profiling to enable detection of ALK gene rearrangements and MET amplifications in non-small cell lung cancer. PG - 1225646 LID - 10.3389/fonc.2023.1225646 [doi] LID - 1225646 AB - INTRODUCTION: Next-generation sequencing (NGS) is currently widely used for biomarker studies and molecular profiling to identify concurrent alterations that can lead to the better characterization of a tumor's molecular landscape. However, further evaluation of technical aspects related to the detection of gene rearrangements and copy number alterations is warranted. METHODS: There were 12 ALK rearrangement-positive tumor specimens from patients with non-small cell lung cancer (NSCLC) previously detected via fluorescence in situ hybridization (FISH), immunohistochemistry (IHC), and an RNA-based NGS assay, and 26 MET high gene copy number (GCN) cases detected by FISH, selected for this retrospective study. All 38 pre-characterized cases were reassessed utilizing the PGDx elio tissue complete assay, a 505 gene targeted NGS panel, to evaluate concordance with these conventional diagnostic techniques. RESULTS: The detection of ALK rearrangements using the DNA-based NGS assay demonstrated excellent sensitivity with the added benefit of characterizing gene fusion partners and genomic breakpoints. MET copy number alterations were also detected; however, some discordances were observed likely attributed to differences in algorithm, reporting thresholds and gene copy number state. TMB was also assessed by the assay and correlated to the presence of NSCLC driver alterations and was found to be significantly lower in cases with NGS-confirmed canonical driver mutations compared with those without (p=0.0019). DISCUSSION: Overall, this study validates NGS as an accurate approach for detecting structural variants while also highlighting the need for further optimization to enable harmonization across methodologies for amplifications. CI - Copyright (c) 2023 Clave, Jackson, Salido, Kames, Gerding, Verner, Kong, Weingartner, Gibert, Hardy-Werbin, Rocha, Riera, Torres, Hernandez, Cerqueira, Nichol, Simmons, Taus, Pijuan, Bellosillo and Arriola. FAU - Clave, Sergi AU - Clave S AD - Pathology Department, Hospital del Mar, Barcelona, Spain. AD - Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. FAU - Jackson, Jennifer B AU - Jackson JB AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Salido, Marta AU - Salido M AD - Pathology Department, Hospital del Mar, Barcelona, Spain. AD - Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. FAU - Kames, Jacob AU - Kames J AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Gerding, Kelly M R AU - Gerding KMR AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Verner, Ellen L AU - Verner EL AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Kong, Eric F AU - Kong EF AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Weingartner, Elizabeth AU - Weingartner E AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Gibert, Joan AU - Gibert J AD - Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. FAU - Hardy-Werbin, Max AU - Hardy-Werbin M AD - Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. AD - Medical Oncology Department, Hospital del Mar, Barcelona, Spain. FAU - Rocha, Pedro AU - Rocha P AD - Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. AD - Medical Oncology Department, Hospital del Mar, Barcelona, Spain. FAU - Riera, Xenia AU - Riera X AD - Pathology Department, Hospital del Mar, Barcelona, Spain. AD - Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. FAU - Torres, Erica AU - Torres E AD - Pathology Department, Hospital del Mar, Barcelona, Spain. FAU - Hernandez, James AU - Hernandez J AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Cerqueira, Gustavo AU - Cerqueira G AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Nichol, Donna AU - Nichol D AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Simmons, John AU - Simmons J AD - Personal Genome Diagnostics (PGDx/Labcorp), Baltimore, MD, United States. FAU - Taus, Alvaro AU - Taus A AD - Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. AD - Medical Oncology Department, Hospital del Mar, Barcelona, Spain. FAU - Pijuan, Lara AU - Pijuan L AD - Pathology Department, Hospital del Mar, Barcelona, Spain. FAU - Bellosillo, Beatriz AU - Bellosillo B AD - Pathology Department, Hospital del Mar, Barcelona, Spain. AD - Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. FAU - Arriola, Edurne AU - Arriola E AD - Cancer Research Program, Hospital del Mar Medical Research Institute, Barcelona, Spain. AD - Centro de Investigacion Biomedica en Red de Cancer (CIBERONC), Madrid, Spain. AD - Medical Oncology Department, Hospital del Mar, Barcelona, Spain. LA - eng PT - Journal Article DEP - 20231020 PL - Switzerland TA - Front Oncol JT - Frontiers in oncology JID - 101568867 PMC - PMC10623306 OTO - NOTNLM OT - ALK rearrangement OT - MET amplification OT - biomarkers OT - fluorescence in situ hybridization (FISH) OT - molecular testing OT - next generation sequencing (NGS) OT - non-small cell lung cancer (NSCLC) COIS- Authors JJ, JK, KG, EV, EK, EW, JH, GC, DN, and JS were or are currently employed by Personal Genome Diagnostics (PGDx/Labcorp). The authors declare that the research was conducted in the absence of any commercial or financial relationships that could be construed as a potential conflict of interest. EDAT- 2023/11/06 06:42 MHDA- 2023/11/06 06:43 PMCR- 2023/01/01 CRDT- 2023/11/06 04:19 PHST- 2023/05/19 00:00 [received] PHST- 2023/08/28 00:00 [accepted] PHST- 2023/11/06 06:43 [medline] PHST- 2023/11/06 06:42 [pubmed] PHST- 2023/11/06 04:19 [entrez] PHST- 2023/01/01 00:00 [pmc-release] AID - 10.3389/fonc.2023.1225646 [doi] PST - epublish SO - Front Oncol. 2023 Oct 20;13:1225646. doi: 10.3389/fonc.2023.1225646. eCollection 2023.