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Updated: Oct 14, 2025
Oncogenic Gene Fusion Detection Using Anchored Multiplex Polymerase Chain Reaction Followed by Next Generation Sequencing
Published on: July 5, 2019
The Pan-Tumor Landscape of Targetable Kinase Fusions in Circulating Tumor DNA
Purpose:
Oncogenic kinase fusions are targetable with approved and investigational therapies and can also mediate acquired resistance (AR) to targeted therapy. We aimed to understand the clinical validity of liquid biopsy comprehensive genomic profiling (CGP) to detect kinase fusions pan tumor.
Experimental Design:
CGP was performed on plasma and tissue samples during clinical care. All exons plus selected introns of 16 kinases involved in oncogenic fusions (ALK, BRAF, EGFR, ERBB2, FGFR1/2/3, MET, NTRK1/2/3, PDGFRA/B, RAF1, RET, and ROS1) were sequenced to capture fusions, including well-characterized and novel breakpoints. Plasma circulating tumor DNA (ctDNA) fraction was estimated to inform sensitivity.
Results:
Of 36,916 plasma cases, 32,492 (88%) had detectable ctDNA. Kinase fusions were detected in 1.8% of ctDNA-positive cases (571/32,492) and were most prevalent in patients with cholangiocarcinoma (4.2%), bladder cancer (3.6%), and non-small cell lung cancer (NSCLC; 3.1%). Of the 63 paired patient samples that had tissue and ctDNA specimens collected within 1 year and with estimated plasma ctDNA fraction >1%, fusions were detected in 47 of 51 (92%) liquid specimens with a fusion in the tissue sample. In 32 patients with fusions detected in liquid but not in tissue, 21 (66%) had evidence of putative acquired resistance.
Conclusions:
Targetable kinase fusions are identified in ctDNA across cancer types. In pairs with tissue-identified fusions, fusion detection in ctDNA is reliable with elevated ctDNA fraction. These data support the validity of CGP to enable ctDNA-based fusion detection for informing clinical care in patients with advanced cancer.
Insights
Comprehensive genomic profiling (CGP) of liquid biopsies effectively detects targetable kinase fusions in advanced cancers. This approach is clinically valid for identifying fusions in circulating tumor DNA (ctDNA) to guide treatment decisions.
Area of Science:
- Oncology
- Genomics
- Molecular Diagnostics
Background:
- Oncogenic kinase fusions are crucial drivers in various cancers.
- These fusions can be targeted by therapies but also lead to acquired resistance.
- Liquid biopsy offers a non-invasive method for comprehensive genomic profiling (CGP).
Purpose of the Study:
- To assess the clinical validity of liquid biopsy CGP for detecting kinase fusions across diverse tumor types.
- To evaluate the utility of circulating tumor DNA (ctDNA) fraction in predicting fusion detection sensitivity.
Main Methods:
- CGP was performed on plasma and tissue samples.
- Sequencing targeted 16 kinases known for oncogenic fusions.
- Analysis included ctDNA fraction estimation to determine assay sensitivity.
Main Results:
- Kinase fusions were detected in 1.8% of ctDNA-positive plasma samples across 36,916 cases.
- Prevalence was highest in cholangiocarcinoma (4.2%), bladder cancer (3.6%), and NSCLC (3.1%).
- In paired samples, 92% of tissue-identified fusions were detected in ctDNA with >1% ctDNA fraction. 66% of liquid-detected, tissue-undetected fusions suggested acquired resistance.
Conclusions:
- Targetable kinase fusions are detectable in ctDNA across multiple cancer types.
- ctDNA-based fusion detection is reliable, especially with higher ctDNA fractions.
- CGP of liquid biopsies is clinically valid for identifying fusions in advanced cancers, informing clinical care.
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