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Identification of NTRK gene fusions in lung adenocarcinomas in the Chinese population.

ABSTRACT: The molecular profile of neurotrophic tyrosine kinase receptor (NTRK) gene fusions in lung adenocarcinoma (LUAD) is not fully understood. Next-generation sequencing (NGS) and pan-tyrosine kinase receptor (TRK) immunohistochemistry (IHC) are powerful tools for NTRK fusion detection. In this study, a total of 4,619 LUAD formalin-fixed, paraffin-embedded tissues were collected from patients who underwent biopsy or resection at the Shanghai Chest Hospital during 2017-2019. All specimens were screened for NTRK1 rearrangements using DNA-based NGS. Thereafter, the cases with NTRK1 rearrangements and cases negative for common driver mutations were analyzed for NTRK1/2/3 fusions using total nucleic acid (TNA)-based NGS and pan-TRK IHC. Overall, four NTRK1/2 fusion events were identified, representing 0.087% of the original sample set. At the DNA level, seven NTRK1 rearrangements were identified, while only two TPM3-NTRK1 fusions were confirmed on TNA-based NGS as functional. In addition, two NTRK2 fusions (SQSTM1-NTRK2 and KIF5B-NTRK2) were identified by TNA-based NGS in 350 'pan-negative' cases. Two patients harboring NTRK1/2 fusions were diagnosed with invasive adenocarcinoma, while the other two were diagnosed with adenocarcinoma in situ and minimally invasive adenocarcinoma. All four samples with NTRK fusions were positive for the expression of pan-TRK. The two samples with NTRK2 fusions showed cytoplasmic staining alone, while the other two samples with NTRK1 fusions exhibited both cytoplasmic and membranous staining. In summary, functional NTRK fusions are found in early-stage LUAD; however, they are extremely rare. According to this study's results, they are independent oncogenic drivers, mutually exclusive with other driver mutations. We demonstrated that NTRK rearrangement analysis using a DNA-based approach should be verified with an RNA-based assay.

SUBMITTER: Zhao R

PROVIDER: S-EPMC8185368 | biostudies-literature |

REPOSITORIES: biostudies-literature

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Project description:A major breakthrough in the classification of soft tissue tumors has been the recent identification of NTRK-fusion related neoplasms which are amenable to highly effective targeted therapies. Despite these therapeutic opportunities, diagnostic challenges have emerged in recognizing tumors characterized by protein kinase fusions, as they are associated with a wide morphologic spectrum, variable risk of malignancy and a rather nonspecific immunoprofile. As such, NTRK-related fusions may occur in infantile fibrosarcoma, lipofibromatosis-like neural tumors (LPF-NTs), tumors resembling malignant peripheral nerve sheath tumors, etc. Triggered by an index case resembling LPF-NT but harboring RET gene rearrangement, we investigated our files for cases showing RET gene abnormalities to establish their clinicopathologic features. Tumors were tested with a combination of targeted RNA sequencing and fluorescence in situ hybridization methods. Six cases with RET gene rearrangements were identified, all except 1 occurred in children, including 4 infants. Their morphologic spectrum was quite diverse, but closely reproduced the phenotype of NTRK-fusion-positive tumors, including LPF-NTs (n=3), infantile fibrosarcoma-like tumor (n=2) and malignant peripheral nerve sheath tumor-like (n=1). Three cases showed coexpression of S100 and CD34, whereas the remaining 3 had a nonspecific immunoprofile. The tumors ranged morphologically and clinically from benign to highly malignant. None of the LPF-NT cases recurred, whereas 2 patients with malignant histology had a highly aggressive course with distant metastases to lung and other viscera. By targeted RNA sequencing these tumors harbored RET fusions with an identical break in exon 12, which retains the tyrosine kinase domain in the fusion oncoprotein and involving various gene partners (CLIP2, CCDC6, SPECC1L, MYH10, and NCOA4). Our results suggest that RET fusion-positive neoplasms share a similar phenotypic spectrum with the NTRK-positive tumors, displaying either fibroblastic or neural-like differentiation, and spanning a wide spectrum of clinical behavior. These findings open new avenues for targeted therapy with RET inhibitors currently available in clinical trials.

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Identification of NTRK gene fusions in lung adenocarcinomas in the Chinese population.

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