Journal
CANCERS
Volume 13, Issue 13, Pages -Publisher
MDPI
DOI: 10.3390/cancers13133376
Keywords
gene fusions; NTRK genes; next generation sequencing; gene panels; agnostic biomarker; precision medicine; colorectal carcinoma; lung adenocarcinomas; melanoma; immunohistochemistry
Categories
Funding
- MIUR-Dipartimenti di Eccellenza 2018-2022 [D15D18000410001]
- FONDAZIONE AIRC under 5 per Mille 2018 [21091]
- FPRC 5xMille Ministero Salute 2015-Progetto FUTURO
- Dipartimenti di Eccellenza 2018-2022 [D15D18000410001]
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The study demonstrates the enrichment of gene fusions in colorectal carcinomas, melanomas, and lung adenocarcinomas, confirming the feasibility of this approach in clinical practice. Detection of NTRK gene fusions was performed using different techniques, providing comparative data for effective detection.
Simple Summary The main aim of our study is to provide real-world data on the enrichment of gene fusions in patients affected by colorectal carcinomas, melanomas, and lung adenocarcinomas characterized by the absence of mutations in the main driver genes and in colorectal tumours with microsatellite instability, using a comprehensive method. By demonstrating this enrichment in a real-world cohort, we confirm the feasibility of this approach, suggesting a workflow applicable in diagnostic practice. A second aim points towards a thorough investigation of NTRK gene fusions detected in the study by applying different techniques. We therefore provide comparative data across in situ methods and in vitro nucleic acid-based assays to document effective NTRK gene fusion detection. Agnostic biomarkers such as gene fusions allow to address cancer patients to targeted therapies; however, the low prevalence of these alterations across common malignancies poses challenges and needs a feasible and sensitive diagnostic process. RNA-based targeted next generation sequencing was performed on 125 samples of patients affected either by colorectal carcinoma, melanoma, or lung adenocarcinoma lacking genetic alterations in canonical driver genes, or by a colorectal carcinoma with microsatellite instability. Gene fusion rates were compared with in silico data from MSKCC datasets. For NTRK gene fusion detection we also employed a multitarget qRT-PCR and pan-TRK immunohistochemistry. Gene fusions were detected in 7/55 microsatellite instable colorectal carcinomas (12.73%), and in 4/70 of the gene driver free population (5.71%: 3/28 melanomas, 10.7%, and 1/12 lung adenocarcinomas, 8.3%). Fusion rates were significantly higher compared with the microsatellite stable and gene driver positive MSKCC cohorts. Pan-TRK immunohistochemistry showed 100% sensitivity, 91.7% specificity, and the occurrence of heterogeneous and/or subtle staining patterns. The enrichment of gene fusions in this real-world cohort highlights the feasibility of a workflow applicable in clinical practice. The heterogeneous expression in NTRK fusion positive tumours unveils challenging patterns to recognize and raises questions on the effective translation of the chimeric protein.
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