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Published on: July 5, 2019
Assessing targetable NTRK1/2/3 fusions in mesenchymal tumors via whole-exome RNA sequencing
H Vanacker1, M Brahmi1, D Pissaloux1
1Unicancer Centre Léon Bérard, Lyon France; Centre de Recherche en Cancérologie de Lyon, INSERM U1052 - CNRS UMR5286, Lyon France; Université de Lyon, Université Claude Bernard Lyon 1, Lyon, France; French Sarcoma Group, France.
Background:
Neurotrophic receptor tyrosine kinase (NTRK) 1/2/3 fusions, though rare, are highly sought in cancer diagnostics due to tyrosine kinase inhibitors' histology-agnostic approval based on significant efficacy across tumor types. In mesenchymal tumors, these fusions are identified in five typical NTRK-rearranged mesenchymal tumors (NMT): infantile fibrosarcomas, lipofibromatosis-like neural tumors, NTRK-rearranged spindle cell neoplasms, and minority subsets of ALK-negative inflammatory myofibroblastic tumors and quadruple wild-type gastrointestinal stromal tumors. However, their occurrence in other subtypes and actionability remain uncertain.
Methods:
This retrospective study included adult and pediatric patients with mesenchymal FFPE (formalin-fixed, paraffin-embedded) tumor samples collected between January 2016 and March 2023. Eligible samples underwent whole-exome RNA sequencing (WERS) for mesenchymal tumor diagnosis or theranostic assessment. Results were reviewed by a multidisciplinary molecular board to assess technical, biological, and clinical relevance.
Results:
Among 3015 samples, primarily malignant, intermediate, and benign mesenchymal tumors, 111 (3.68%) harbored at least one bioinformatically detected NTRK fusion. Forty-three were biologically irrelevant due to absent kinase domains (group 1), and 11 were technical false positives (group 2). Of the 57 robustly identified cases (1.8%), 54 were typical NMT subtypes with canonical gene partners (group 3). Group 4 included three rare fusions in genetically complex sarcomas: MDM2/CDK4-amplified liposarcoma, MDM2/CDK4-amplified intimal sarcoma, and uterine leiomyosarcoma. These cases featured novel fusion partners, higher fusion counts, and comparable single nucleotide variants (SNVs) to group 3.
Conclusion:
WERS reliably identifies actionable NTRK fusions, predominantly in five NMT subtypes, whereas NTRK fusions were rare and extremely rare in other sarcomas where their targetability remains unclear. Routine NTRK screening should prioritize tumors suspected of being NMT rather than being broadly applied.
Insights
Neurotrophic receptor tyrosine kinase (NTRK) fusions are actionable targets in specific mesenchymal tumors. Whole-exome RNA sequencing reliably detects these fusions, primarily in typical NTRK-rearranged mesenchymal tumors (NMT).
Area of Science:
- Oncology
- Molecular Diagnostics
- Genomics
Background:
- Neurotrophic receptor tyrosine kinase (NTRK) 1/2/3 fusions are rare but significant in cancer diagnostics due to targeted therapy efficacy.
- These fusions are found in specific mesenchymal tumors, including infantile fibrosarcomas and lipofibromatosis-like neural tumors.
- The presence and actionability of NTRK fusions in other sarcoma subtypes require further investigation.
Purpose of the Study:
- To evaluate the utility of whole-exome RNA sequencing (WERS) for detecting NTRK fusions in mesenchymal tumors.
- To identify the prevalence and subtypes of mesenchymal tumors harboring NTRK fusions.
- To assess the clinical relevance and targetability of detected NTRK fusions.
Main Methods:
- Retrospective analysis of 3015 mesenchymal tumor samples (FFPE) from adult and pediatric patients (Jan 2016 - Mar 2023).
- Whole-exome RNA sequencing (WERS) was performed for diagnosis and theranostic assessment.
- Results were reviewed by a multidisciplinary molecular board for technical, biological, and clinical relevance.
Main Results:
- 111 (3.68%) samples showed bioinformatically detected NTRK fusions; 57 (1.8%) were robustly identified after excluding false positives and irrelevant cases.
- 54 of the 57 relevant cases were typical NTRK-rearranged mesenchymal tumor (NMT) subtypes.
- Three rare NTRK fusions were found in genetically complex sarcomas (liposarcoma, intimal sarcoma, uterine leiomyosarcoma) with novel partners.
Conclusions:
- Whole-exome RNA sequencing (WERS) is a reliable method for detecting actionable NTRK fusions in mesenchymal tumors.
- NTRK fusions are predominantly found in specific NMT subtypes, with rare occurrences in other sarcomas.
- Routine NTRK screening should focus on suspected NMT cases rather than broad application across all sarcomas.
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