Related Experiment Video
Updated: Sep 20, 2025
Author Spotlight: Advancements in Molecular Biomarker Testing for Non-Squamous Non-Small Cell Lung Cancer
Published on: September 8, 2023
Genomic and Transcriptomic Analysis of Neuroendocrine Transformation in ALK-Rearranged Lung Adenocarcinoma After
Jie Huang1, Shi-Ling Zhang1,2, Chaozheng Zhou3,4
1Guangdong Lung Cancer Institute, Guangdong Provincial People's Hospital, Guangdong Academy of Medical Sciences, Guangzhou, People's Republic of China.
Introduction:
Neuroendocrine (NE) transformation has been reported in patients with ALK-rearranged NSCLC after ALK inhibition, but unlike EGFR-mutant NSCLC, the exact mechanism of NE transformation in ALK-rearranged NSCLC is poorly studied.
Methods:
We collected the matched pre- and post-transformation samples from a patient with ALK-rearranged lung adenocarcinoma (LUAD) and performed targeted panel sequencing, whole exome sequencing, and bulk RNA sequencing.
Results:
Multiple mutations were shared between the pretransformation and post-transformation samples. Neither RB1 nor TP53 mutation was detected, but CDKN2A deletion and CDK4 amplification were found instead. Mismatch repair-associated mutational signature was significantly enriched after transformation. Genes associated with Notch signaling and PI3K/AKT pathway were significantly up-regulated, whereas genes related to lymphocyte activation and NF-kB signaling were down-regulated. Signatures relating to homologous recombination, mismatch repair, and Notch signaling pathways were enriched, which were further validated in The Cancer Genome Atlas cohorts. Macrophages M2 were found to have prominently higher abundance in the tumor immune microenvironment after NE transformation.
Conclusions:
The mechanism of NE transformation in ALK-rearranged LUAD may be different from that in EGFR-mutant LUAD.
Insights
Neuroendocrine transformation in ALK-rearranged lung cancer involves unique genetic alterations and pathway changes. This study reveals distinct mechanisms compared to EGFR-mutant lung cancer.
Area of Science:
- Oncology
- Molecular Biology
- Genomics
Background:
- Neuroendocrine (NE) transformation occurs in ALK-rearranged non-small cell lung cancer (NSCLC) post-ALK inhibition.
- The precise mechanisms driving NE transformation in ALK-rearranged NSCLC remain largely unelucidated, unlike in EGFR-mutant NSCLC.
Purpose of the Study:
- To investigate the molecular mechanisms underlying NE transformation in ALK-rearranged lung adenocarcinoma (LUAD).
- To compare the transformation mechanisms between ALK-rearranged and EGFR-mutant LUAD.
Main Methods:
- Collected matched pre- and post-transformation tumor samples from a patient with ALK-rearranged LUAD.
- Performed targeted panel sequencing, whole exome sequencing, and bulk RNA sequencing.
- Validated findings in The Cancer Genome Atlas (TCGA) cohorts.
Main Results:
- Identified shared mutations and specific alterations including CDKN2A deletion and CDK4 amplification.
- Observed enrichment of mismatch repair-associated mutational signatures and upregulation of Notch signaling and PI3K/AKT pathways.
- Detected increased M2 macrophage abundance in the tumor immune microenvironment post-transformation.
Conclusions:
- The mechanism of NE transformation in ALK-rearranged LUAD appears distinct from that observed in EGFR-mutant LUAD.
- Genetic alterations, pathway dysregulation, and immune microenvironment changes contribute to NE transformation in ALK-rearranged LUAD.
More Related Videos
09:49Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
09:38Establishing Dual Resistance to EGFR-TKI and MET-TKI in Lung Adenocarcinoma Cells In Vitro with a 2-step Dose-escalation Procedure
Published on: August 11, 2017