{"status":"ok","message-type":"work","message-version":"1.0.0","message":{"indexed":{"date-parts":[[2026,3,26]],"date-time":"2026-03-26T14:17:29Z","timestamp":1774534649291,"version":"3.50.1"},"reference-count":95,"publisher":"MDPI AG","issue":"7","license":[{"start":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T00:00:00Z","timestamp":1774310400000},"content-version":"vor","delay-in-days":0,"URL":"https:\/\/creativecommons.org\/licenses\/by\/4.0\/"}],"funder":[{"name":"Institute of Tuberculosis and Lung Diseases in Warsaw, Poland","award":["3.3\/2022"],"award-info":[{"award-number":["3.3\/2022"]}]},{"name":"Institute of Tuberculosis and Lung Diseases in Warsaw, Poland","award":["3.11\/2023"],"award-info":[{"award-number":["3.11\/2023"]}]},{"name":"Institute of Tuberculosis and Lung Diseases in Warsaw, Poland","award":["3.13\/2025"],"award-info":[{"award-number":["3.13\/2025"]}]}],"content-domain":{"domain":[],"crossmark-restriction":false},"short-container-title":["IJMS"],"abstract":"<jats:p>Pulmonary large-cell neuroendocrine carcinoma (LCNEC) is a rare lung malignancy characterized by an aggressive clinical course and an unfavorable prognosis. Next-generation sequencing (NGS) has revealed that LCNECs exhibit molecular features resembling either small-cell lung carcinoma (SCLC-like LCNEC) or non-small cell lung carcinoma (NSCLC-like LCNEC). This study aimed to characterize the incidence of actionable gene variants in a retrospective cohort of LCNEC patients using a targeted NGS approach. Microscopic diagnosis was established according to the 2021 World Health Organization (WHO) classification using a standard immunohistochemical (IHC) panel. In total, 216 LCNEC tumor samples were analyzed for molecular variants in 17 genes using the RNA-based Archer FusionPlex Lung NGS assay (Integrated DNA Technologies, USA) and the MiSeq platform (Illumina, USA)\u2014an algorithm utilized for routine NSCLC diagnosis. Overall, 46 variants were identified in 46\/216 (21.3%) tumor samples, with 28\/216 (13%) LCNECs harboring at least one actionable molecular variant potentially targetable by registered or investigational agents. KRAS variants (5%; including G12C at 2%) and PIK3CA variants (5%) were the most prevalent, followed by RET single-nucleotide variants (3%), uncommon EGFR variants (1%), and BRAF class II and III variants (&lt;1%). Notably, no classical EGFR exon 18\u201321 mutations nor ALK, FGFR1\/2\/3, or ROS1 alterations (mutations or fusions) were detected, despite the technical capability of the assay to identify such variants. A novel in-frame gene fusion (TMEM79::NTRK1) was identified in a single tumor sample (0.5%). Our results confirm that LCNECs harbor potentially targetable alterations in KRAS, PIK3CA, RET, BRAF, and NTRK1, albeit at lower frequencies than those typically observed in NSCLC.<\/jats:p>","DOI":"10.3390\/ijms27072939","type":"journal-article","created":{"date-parts":[[2026,3,24]],"date-time":"2026-03-24T12:58:59Z","timestamp":1774357139000},"page":"2939","update-policy":"https:\/\/doi.org\/10.3390\/mdpi_crossmark_policy","source":"Crossref","is-referenced-by-count":0,"title":["Identification of Actionable Gene Variants in Pulmonary Large-Cell Neuroendocrine Carcinoma: A Real-World Analysis of a Polish Cohort"],"prefix":"10.3390","volume":"27","author":[{"ORCID":"https:\/\/orcid.org\/0000-0002-8920-6931","authenticated-orcid":false,"given":"Adam","family":"Szpechcinski","sequence":"first","affiliation":[{"name":"Department of Genetics and Clinical Immunology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-4475-9003","authenticated-orcid":false,"given":"Magdalena","family":"Pelc","sequence":"additional","affiliation":[{"name":"Department of Genetics and Clinical Immunology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0002-2645-8779","authenticated-orcid":false,"given":"Urszula","family":"Lechowicz","sequence":"additional","affiliation":[{"name":"Department of Genetics and Clinical Immunology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Malgorzata","family":"Szolkowska","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1706-8290","authenticated-orcid":false,"given":"Joanna","family":"Moes-Sosnowska","sequence":"additional","affiliation":[{"name":"Department of Genetics and Clinical Immunology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Piotr","family":"Rudzinski","sequence":"additional","affiliation":[{"name":"Clinical Department of Thoracic Surgery, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Emil","family":"Wojda","sequence":"additional","affiliation":[{"name":"Clinical Department of Thoracic Tumors, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Paulina","family":"Skronska","sequence":"additional","affiliation":[{"name":"Department of Genetics and Clinical Immunology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-0405-9299","authenticated-orcid":false,"given":"Elzbieta","family":"Podgorska","sequence":"additional","affiliation":[{"name":"Department of Genetics and Clinical Immunology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Krystyna","family":"Maszkowska-Kopij","sequence":"additional","affiliation":[{"name":"Outpatient Clinic, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-2737-1808","authenticated-orcid":false,"given":"Mateusz","family":"Polaczek","sequence":"additional","affiliation":[{"name":"Clinical Department of Thoracic Tumors, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Tadeusz","family":"Orlowski","sequence":"additional","affiliation":[{"name":"Clinical Department of Thoracic Surgery, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"given":"Renata","family":"Langfort","sequence":"additional","affiliation":[{"name":"Department of Pathology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]},{"ORCID":"https:\/\/orcid.org\/0000-0003-1743-2961","authenticated-orcid":false,"given":"Joanna","family":"Chorostowska-Wynimko","sequence":"additional","affiliation":[{"name":"Department of Genetics and Clinical Immunology, The Institute of Tuberculosis and Lung Diseases, 01-138 Warsaw, Poland"}],"role":[{"role":"author","vocabulary":"crossref"}]}],"member":"1968","published-online":{"date-parts":[[2026,3,24]]},"reference":[{"key":"ref_1","doi-asserted-by":"crossref","first-page":"469","DOI":"10.1016\/j.thorsurg.2021.05.005","article-title":"Neuroendocrine Tumors of the Lung","volume":"31","author":"Randhawa","year":"2021","journal-title":"Thorac. 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