A novel NECTIN4-NTRK1 fusion identified in a lung squamous cell carcinoma patient with MSI-H

Abstract

Microsatellite instability (MSI), one of the types of human cancers genomic instability, is due to DNA slippage in the process of DNA replication, resulting in the repeating units insert or missing. High MSI (MSI-H) always caused by DNA mismatch repair deficiency (dMMR) and dMMR can occur sporadically due to methylation of MLH1 promoter or genetically in Lynch syndrome (LS) with germline mutations in MMR genes. MSI-H is most common in colorectal and endometrial cancers, but rare in lung cancer (Li et al. 2020). MSI can be tested via PCR or next-generation sequencing (Bonneville et al. 2020). Neurotrophic receptor tyrosine kinase (NTRK) is a receptor tyrosine kinase, including NTRK1, NTRK2 and NTRK3. NTRK fusions are identified as oncogenes in various cancer types (Solomon et al. 2020). A multitude of NTRK1 fusion partner genes have been described, such as CD74, MPRIP and NFASC (Cocco et al. 2018). Herein, we first identified a novel NECTIN4NTRK1 fusion and MSI-H in a patient with lung squamous cell carcinoma. A 64-year-old male with a history of smoking was admitted to hospital in July 2020 with pulmonary shadow found in the examination for 21 days. The patient cough with small amount white phlegm and night exacerbation. Positron-emission tomography/computed tomography (PET/ CT) imaging in the whole body was performed and showed a 20 mm × 19 mm soft-tissue density nodule in the lateral middle lobe of the right lung with spotted calcification lesions insight and increased radioactive uptake with SUVmax 5.7 (Fig. 1a). A slightly larger lymph node was found in the rearward of mediastinal anterior tracheal vena cava with a short diameter of 8 mm, low density necrosis, increased radioactive uptake with SUVmax 4.4 (Fig. 1b). After the elimination of surgical contraindications, videoassisted thoracoscopic surgery (VATS) including right lung midsection resection, systemic lymph node dissection, and pleural adhesion lysis were performed under general anesthesia on July 28, 2020. Postoperative pathology revealed moderately differentiated squamous cell carcinoma of the middle lobe of the right lung. Next-generation sequencing (NGS) 539-gene panel (Simceredx) profiling was performed using postoperative tissue. The result showed that tumor mutation burden (TMB) was 93.38Muts/Mb belonged to TMB-H; MSI status was MSI-H; and found a total of 164 mutations including novel NECTIN4 (Exon 1–9)-NTRK1 (Exon 9–17) fusion (Fig. 2a). Pathogenicity or suspected pathogenic variation of LS-related genes was not found. Immunohistochemistry (IHC) and fluorescence in situ hybridization (FISH) were performed to verify NTRK1 fusion and the results were both positive (Fig. 2b). PD-L1 expression was detected using 22C3 and the result was positive (TPS 1%). The NECTIN4-NTRK1 fusion in our case comprised exons 1–9 of NECTIN4 and exons 9–17 of NTRK1 (Fig. 2a). The complete kinase domain of NTRK1 gene was retained. The partner gene NECTIN4, one of the nectin cell adhesion molecule (NECTIN) family, was a Ca2+-independent immunoglobulin-like molecules. NECTIN4 was over-expression in cancer tissues and NECTIN4 was reported as a cancer-specific TIGIT ligand (Reches et al. 2020). NECTIN4 gene retained a coiled-coil domain in the fusion, which can activate the downstream TRK * Yongjie Wang [email protected]