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Updated: Jan 9, 2026
Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
Comprehensive Genomic Profiling of Small-Cell Lung Cancer Reveals Frequent Potentially Targetable Alterations
Dániel Schmalz1, Zoltán Krabóth2, Veronika Czoma2
1Center of Omics, János Szentágothai Research Center, University of Pécs, Ifjúság Street 20, 7624 Pécs, Hungary.
Abstract:
Small-cell lung carcinoma (SCLC) remains one of the most aggressive lung cancers and continues to pose a major challenge for precision oncology. Despite its morphological uniformity, SCLC exhibits marked molecular heterogeneity with recurrent, potentially targetable genomic alterations. Comprehensive profiling is often hindered by limited tissue availability and the need for rapid therapeutic intervention. We performed genomic profiling of 55 primary and metastatic SCLC samples using a 324-gene hybrid-capture next-generation sequencing panel. Consistent with prior reports, nearly all tumors exhibited biallelic TP53 and RB1 inactivation. Recurrent alterations involved the PI3K/Akt/mTOR pathway (62%), chromatin regulators (42%), and NOTCH signaling genes (15%). PTEN mutations were enriched in brain metastases. Frequent copy-number gains affected SOX2, NKX2-1, MYC-family genes, and CCNE1. Two novel recurrent amplifications of potential clinical significance were identified: TYRO3 (33%) and SDHA (13%). TYRO3, a TAM family receptor tyrosine kinase, and SDHA, a mitochondrial enzyme involved in succinate metabolism, may contribute to tumor progression and represent emerging therapeutic vulnerabilities. These findings underscore the genomic diversity of SCLC and highlight the potential utility of broad next-generation sequencing in uncovering new molecular targets for precision therapy.
Insights
Genomic profiling of small-cell lung cancer (SCLC) reveals significant molecular diversity. Novel therapeutic targets, including TYRO3 and SDHA, were identified, offering new avenues for precision oncology.
Area of Science:
- Oncology
- Genomics
- Molecular Biology
Background:
- Small-cell lung cancer (SCLC) is an aggressive malignancy with limited precision oncology options.
- Despite uniform morphology, SCLC displays significant molecular heterogeneity and actionable genomic alterations.
- Tissue limitations and rapid progression necessitate efficient molecular profiling.
Purpose of the Study:
- To comprehensively characterize the genomic landscape of SCLC.
- To identify novel, potentially targetable genomic alterations in SCLC.
- To explore the utility of next-generation sequencing for SCLC precision therapy.
Main Methods:
- Genomic profiling of 55 primary and metastatic SCLC samples.
- Utilized a 324-gene hybrid-capture next-generation sequencing panel.
- Analyzed recurrent alterations, copy-number variations, and novel amplifications.
Main Results:
- Confirmed frequent biallelic TP53 and RB1 inactivation.
- Identified recurrent alterations in PI3K/Akt/mTOR (62%), chromatin regulators (42%), and NOTCH (15%).
- Discovered novel amplifications in TYRO3 (33%) and SDHA (13%), with PTEN mutations enriched in brain metastases.
Conclusions:
- SCLC exhibits substantial genomic diversity, challenging traditional classification.
- TYRO3 and SDHA represent emerging therapeutic vulnerabilities in SCLC.
- Broad genomic profiling is crucial for uncovering SCLC molecular targets and advancing precision therapy.
