Case Report: Identification of a novel NTRK3-AJUBA fusion co-existing with ETV6-NTRK3 fusion in papillary thyroid carcinoma

by Selleckchem | Jul 08 2023

NTRK fusions are validated oncogenic drivers of various adult and pediatric tumor types, including thyroid cancer, and serve as a therapeutic target. Recently, tropomyosin receptor kinase (TRK) inhibitors, such as entrectinib and larotrectinib, display promising therapeutic efficacy in NTRK-positive solid tumors. Although some NTRK fusion partners have been identified in thyroid cancer, the spectrum of NTRK fusion is not fully characterized. In this study, a dual NTRK3 fusion was identified by targeted RNA-Seq in a 47-year-old female patient with papillary thyroid carcinoma. The patient harbors a novel in-frame fusion between NTRK3 exon 13 and AJUBA exon 2, co-existing with a known in-frame fusion between ETV6 exon 4 and NTRK3 exon 14. The dual NTRK3 fusion was validated by Sanger sequencing and fluorescence in situ hybridization (FISH) but lack TRK protein expression as defined by pan-TRK immunohistochemistry (IHC). We supposed the pan-TRK IHC result to be falsely negative. In conclusion, we present the first case of a novel NTRK3-AJUBA fusion co-existing with a known ETV6-NTRK3 fusion in thyroid cancer. These findings extend the spectrum of translocation partners in NTRK3 fusion, and the effect of dual NTRK3 fusion on TRK inhibitor therapy and prognosis needs long-term follow-up.

Comments:

The study you mentioned describes the identification of a dual NTRK3 fusion in a 47-year-old female patient with papillary thyroid carcinoma. NTRK fusions are genetic alterations in which the NTRK gene becomes fused with another gene, resulting in the production of abnormal TRK proteins. These fusions have been recognized as oncogenic drivers in various tumor types, including thyroid cancer, and can be targeted by TRK inhibitors such as entrectinib and larotrectinib.

In this case, the patient was found to have a novel in-frame fusion between NTRK3 exon 13 and AJUBA exon 2, along with a known in-frame fusion between ETV6 exon 4 and NTRK3 exon 14. The presence of these dual NTRK3 fusions was confirmed using targeted RNA sequencing, Sanger sequencing, and fluorescence in situ hybridization (FISH) techniques.

Interestingly, despite the detection of these NTRK3 fusions, the patient did not show TRK protein expression when assessed using pan-TRK immunohistochemistry (IHC). However, the researchers speculate that this negative result might be a false negative and suggest that further investigation is warranted.

The identification of this novel NTRK3-AJUBA fusion expands our understanding of the range of translocation partners involved in NTRK3 fusions in thyroid cancer. It highlights the importance of comprehensive molecular profiling techniques to uncover rare or complex fusion events. Additionally, the implications of having a dual NTRK3 fusion on the effectiveness of TRK inhibitor therapy and the patient's prognosis require long-term follow-up to assess their clinical significance.

Overall, this study underscores the significance of NTRK fusions as therapeutic targets in thyroid cancer and emphasizes the need for continued research to elucidate the clinical implications of different fusion variants.