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Updated: Oct 19, 2025
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
Comprehensive Molecular Analysis of Inflammatory Myofibroblastic Tumors Reveals Diverse Genomic Landscape and
Che-Jui Lee1, Patrick Schöffski1,2, Elodie Modave3,4
1Department of Oncology, Laboratory of Experimental Oncology, KU Leuven, Leuven, Belgium.
Purpose:
The European Organization for Research and Treatment of Cancer (EORTC) clinical phase II trial 90101 "CREATE" showed high antitumor activity of crizotinib, an inhibitor of anaplastic lymphoma kinase (ALK)/ROS1, in patients with advanced inflammatory myofibroblastic tumor (IMFT). However, recent findings suggested that other molecular targets in addition to ALK/ROS1 might also contribute to the sensitivity of this kinase inhibitor. We therefore performed an in-depth molecular characterization of archival IMFT tissue, collected from patients enrolled in this trial, with the aim to identify other molecular alterations that could play a role in the response to crizotinib.
Experimental Design:
Twenty-four archival IMFT samples were used for histopathological assessment and DNA/RNA evaluation to identify gene fusions, copy-number alterations (CNA), and mutations in the tumor tissue. Results were correlated with clinical parameters to assess a potential association between molecular findings and clinical outcomes.
Results:
We found 12 ALK fusions with 11 different partners in ALK-positive IMFT cases by Archer analysis whereas we did not identify any ROS1-rearranged tumor. One ALK-negative patient responding to crizotinib was found to have an ETV6-NTRK fusion in the tumor specimen. The CNA profile and mutational landscape of IMFT revealed extensive molecular heterogeneity. Loss of chromosome 19 (25% of cases) and PIK3CA mutations (9% of cases) were associated with shorter progression-free survival in patients receiving crizotinib.
Conclusions:
We identified multiple genetic alterations in archival IMFT material and provide further insight into the molecular profile of this ultra-rare, heterogeneous malignancy, which may potentially translate into novel treatment approaches for this orphan disease.
Insights
This study investigated molecular alterations in inflammatory myofibroblastic tumor (IMFT) and found ALK fusions and ETV6-NTRK fusions in patients responding to crizotinib. Genetic changes like chromosome 19 loss and PIK3CA mutations were linked to poorer outcomes.
Area of Science:
- Oncology
- Molecular Biology
- Genetics
Background:
- Crizotinib, an anaplastic lymphoma kinase (ALK)/ROS1 inhibitor, shows antitumor activity in advanced inflammatory myofibroblastic tumor (IMFT).
- Emerging evidence suggests molecular targets beyond ALK/ROS1 may influence crizotinib sensitivity in IMFT.
- Understanding IMFT's molecular landscape is crucial for developing targeted therapies.
Purpose of the Study:
- To conduct an in-depth molecular characterization of archival IMFT tissue from patients treated in a clinical trial.
- To identify genetic alterations beyond ALK/ROS1 that may contribute to crizotinib response in IMFT.
- To correlate molecular findings with clinical outcomes in IMFT patients.
Main Methods:
- Histopathological assessment of 24 archival IMFT samples.
- DNA/RNA evaluation for gene fusions, copy-number alterations (CNA), and mutations.
- Correlation of molecular findings with clinical parameters and patient outcomes.
Main Results:
- Identified 12 ALK fusions with diverse partners; no ROS1 rearrangements were found.
- One ALK-negative patient exhibited an ETV6-NTRK fusion and responded to crizotinib.
- Extensive molecular heterogeneity observed, with chromosome 19 loss and PIK3CA mutations associated with shorter progression-free survival.
Conclusions:
- Multiple genetic alterations identified in IMFT, revealing significant molecular heterogeneity.
- Provides deeper insight into the molecular profile of this rare malignancy.
- Findings may inform novel therapeutic strategies for IMFT as an orphan disease.
