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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing
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Detection of Targetable Alterations in Non-small Cell Lung Cancer using Next-generation Sequencing

Published on: October 10, 2025

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Clinicopathological and genomic comparisons between different histologic components in combined small cell lung

Mong-Wei Lin1, Kang-Yi Su2, Te-Jen Su3

  • 1Department of Surgery, National Taiwan University Hospital and National Taiwan University College of Medicine, Taipei, Taiwan.

Lung Cancer (Amsterdam, Netherlands)
|November 16, 2018
PubMed
Abstract

Insights

Small cell lung cancer (SCLC) transformation in lung adenocarcinoma, often linked to EGFR tyrosine kinase inhibitor (TKI) resistance, may involve ASCL1 and PI3K/AKT1 pathway activation. Inactivation of TP53/RB1 is a potential early event in SCLC/NSCLC development.

Area of Science:

  • Oncology
  • Molecular Biology
  • Genetics

Background:

  • Histologic transformation from adenocarcinoma to small cell lung cancer (SCLC) is a known resistance mechanism to epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs).
  • De novo combined SCLC/non-small cell lung cancer (NSCLC) cases have been reported, but their genetic profiles and clinical features remain unclear.

Purpose of the Study:

  • To investigate the mutational status and clinicopathological features of de novo combined SCLC/NSCLC.
  • To compare the genetic backgrounds of de novo combined SCLC/NSCLC with lung adenocarcinoma that transformed to SCLC after TKI treatment.

Main Methods:

  • Immunohistochemistry was used to assess markers (TTF-1, p40, synaptophysin, chromogranin A, p53, Rb, ASCL1) in distinct histologic components.
  • Next-generation sequencing (Oncomine Focus Assay and Comprehensive Assay) was performed on macroscopically dissected tumor components for mutational analysis.

Main Results:

  • High consistency in EGFR/TP53/RB1 mutations and p53/Rb expression was observed between distinct histologic components in both de novo and transformed SCLC/NSCLC.
  • Activating mutations in the PI3K/AKT1 signaling pathway were frequent in the SCLC component.
  • Nuclear ASCL1 expression was predominantly found in SCLC, but not in adenocarcinoma.

Conclusions:

  • Inactivation of TP53/RB1 function may be an early event in the development of synchronous and metachronous SCLC/NSCLC.
  • The SCLC component might originate from the NSCLC component, potentially involving activation of ASCL1 and PI3K/AKT1 signaling pathways.
Keywords:
Lung adenocarcinomaMutation analysisNext-generation sequencingSmall cell lung cancerSmall cell transformation

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