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Updated: Jan 26, 2026
Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
Published on: October 10, 2025
The Landscape of Actionable Molecular Alterations in Immunomarker-Defined Large-Cell Carcinoma of the Lung
Anthony W Chan1, Shuk L Chau1, Joanna H Tong1
1Department of Anatomical and Cellular Pathology, State Key Laboratory of Translational Oncology, the Chinese University of Hong Kong, Hong Kong, China; Li Ka-Shing Institute of Health Sciences, Sir Y.K. Pao Cancer Center, the Chinese University of Hong Kong, Hong Kong, China; Institute of Digestive Disease, State Key Laboratory of Digestive Disease, the Chinese University of Hong Kong, Hong Kong, China.
Introduction:
Patients with pulmonary large-cell carcinoma (LCC) have poor prognosis and limited treatment options. The identification of clinically actionable molecular alterations helps to guide personalized cancer treatment decisions.
Patients And Methods:
A consecutive cohort of 789 resected NSCLC cases were reviewed. Fifty-nine NSCLC cases lacking morphologic differentiation, accounting for 7.5% of all resected NSCLCs, were identified and further characterized by immunohistochemistry according to the 2015 WHO lung tumor classification. Molecular alterations were investigated by multiple technologies including target capture sequencing, immunohistochemistry, and fluorescence in situ hybridizations.
Results:
Of 59 NSCLC cases lacking morphologic differentiation, 20 (33.9%) were reclassified as adenocarcinoma (LCC-AD), 14 (23.7%) as squamous cell carcinoma (LCC-SqCC), and 25 (42.4%) as LCC-Null. Approximately 92% of LCC-Null, 95% of LCC-AD, and 86% of LCC-SqCC harbored clinically relevant alterations. Alterations characteristic of adenocarcinoma (EGFR, KRAS, ALK receptor tyrosine kinase [ALK], ROS1, and serine/threonine kinase 11 [STK11]) were detected in the LCC-AD subgroup but not in LCC-SqCC, whereas squamous-lineage alterations (phosphatidylinositol-4,5-biphosphate 3-kinase catalytic subunit alpha [PIK3CA], SRY-box 2 [SOX2], fibroblast growth factor receptor 1 [FGFR1], and AKT1) were detected in the LCC-SqCC subgroup but not in the LCC-AD group. Although some LCC-Null tumors displayed a genetic profile similar to either adenocarcinoma or squamous-cell carcinoma, more than half of the LCC-Null group were completely devoid of recognizable lineage-specific genetic profiles. High programmed death ligand 1 expression and high frequency of cell cycle regulatory gene alterations were found in the LCC-Null group offering alternative options of targeted therapy.
Conclusions:
This comprehensive molecular study provided further insight into the genetic architecture of LCC. The presence of clinically actionable alterations in a majority of the tumors allowed personalized treatment to emerge.
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