Identification of a novel crizotinib-sensitive MET–ATXN7L1 gene fusion variant in lung adenocarcinoma by next generation sequencing
Authors: Y.C. Zhu, W.X. Wang, C.W. Xu, Q.X. Zhang, K.Q. Du, G. Chen, T.F. Lv, Y. Song
Journal: Annals of Oncology (2018)

The MET gene is located on chromosome 7q21-31 and encodes for a protein tyrosine kinase. The incidence of MET fusions in NSCLC are rare [1.Plenker D. Bertrand M. de Langen A.J. et al.Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients.Clin Cancer Res. 2018; 24: 1337-1343Crossref PubMed Scopus (49) Google Scholar]. Currently, a total of six MET fusion partner genes have been reported in NSCLC, including KIF5B−, STARD3NL−, HLA-DRB1−, UBE2H−, SLC1A2−, and PTPRZ1− [1.Plenker D. Bertrand M. de Langen A.J. et al.Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients.Clin Cancer Res. 2018; 24: 1337-1343Crossref PubMed Scopus (49) Google Scholar, 2.Davies K.D. Ng T.L. Estrada-Bernal A. et al.Dramatic response to crizotinib in a patient with lung cancer positive for an HLA-DRB1-MET gene fusion.JCO Precis Oncol. 2017; 2017: 1-6Google Scholar, 3.Cho J.H. Ku B.M. Sun J.M. et al.KIF5B-MET gene rearrangement with robust antitumor activity in response to crizotinib in lung adenocarcinoma.J Thorac Oncol. 2018; 13: e29-e31Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar, 4.Zhu Y. Wang W. Zhang Q. et al.MET-UBE2H fusion as a novel mechanism of acquired EGFR resistance in lung adenocarcinoma.J Thorac Oncol. 2018; 13: e202-e204Abstract Full Text Full Text PDF PubMed Scopus (16) Google Scholar]. Previous cases have shown the efficacy of crizotinib in NSCLC patients with MET fusions [1.Plenker D. Bertrand M. de Langen A.J. et al.Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients.Clin Cancer Res. 2018; 24: 1337-1343Crossref PubMed Scopus (49) Google Scholar, 3.Cho J.H. Ku B.M. Sun J.M. et al.KIF5B-MET gene rearrangement with robust antitumor activity in response to crizotinib in lung adenocarcinoma.J Thorac Oncol. 2018; 13: e29-e31Abstract Full Text Full Text PDF PubMed Scopus (23) Google Scholar]. Herein we report a novel fusion partner for MET fused to ATXN7L1 and had significant clinical sensitivity to crizotinib. A 56-year-old female (never-smoker) presented to our hospital with a 1-month history of a cough. A computed tomography (CT) scan and magnetic resonance imaging revealed the disease was T4N3M1 stage IV. A bronchoscopic biopsy and Immunohistochemistry analysis showed adenocarcinoma cells. ALK protein expression was negative (Ventana Medical Systems, Roche, Inc., USA). The patient was wild-type for sensitive epidermal growth factor receptor variants by ARMS detection (AmoyDx, Xiamen, China). The tumor tissue was further subjected to NGS (3D Medicines, Shanghai, China), which showed MET–ATXN7L1 fusion (Figure 1). The genes co-altered with MET fusion were not concurrent with other known drivers. The patient then received two cycles of TP chemotherapy [paclitaxel (135 mg/m2 days 1 and 8; carboplatin AUC = 5 day 1)] in January 2017. Unfortunately, the disease progressed in March 2017. Therefore, the patient underwent crizotinib treatment (250 mg/b.i.d. orally) in March 2017. After 1 month, chest CT scan images demonstrated a partial response to crizotinib according to RECIST 1.1 Unfortunately, after 4 months (in July 2017), the disease progressed. The patient was then switched to another chemotherapy regimen. The overall survival was 15 months. This is the first report of an MET–ATXN7L1 fusion case with lung adenocarcinoma who responded to crizotinib treatment. Considering this rare condition and with the potential good response to targeted therapy, clinicians should be aware of the existence of MET fusions in patients with NSCLC. Plenker et al. [1.Plenker D. Bertrand M. de Langen A.J. et al.Structural alterations of MET trigger response to MET kinase inhibition in lung adenocarcinoma patients.Clin Cancer Res. 2018; 24: 1337-1343Crossref PubMed Scopus (49) Google Scholar] reported that the incidence of MET fusions in lung adenocarcinoma was 0.5% (2/337). ATXN7L1- represents a novel fusion partner for MET. MET fusion-driven activation of MET is most likely due to constitutive dimerization and is likely to be an actionable target for drug-induced inhibition, which is similar to other fusions in lung cancer, such as fusions involving ALK, ROS1, and RET [5.Stransky N. Cerami E. Schalm S. et al.The landscape of kinase fusions in cancer.Nat Commun. 2014; 5: 4846Crossref PubMed Scopus (640) Google Scholar]. Testing for gene fusions in tumors can help establish a diagnosis and guide targeted therapy decisions. The fusion genes need more accurate detection methods, such as RNA sequencing (RNA-Seq) or NGS technologies. NGS could analyze simultaneously multiple biomarkers and further improving NGS technology should give rise to powerful tools and reliable approaches for detecting gene fusions in tumors. MET gene fusion is relatively rare and may be a promising molecular target for individualized diagnosis and treatment of lung adenocarcinoma. We summarized case reports involving MET fusions in NSCLC (Supplementary Table S1, available at Annals of Oncology online). Continued efforts to explore driver gene alterations are warranted. This work was supported by the Science and Technology Planning Project of Zhejiang Province (2015C33194) and the National Clinical Key Specialty Construction Program (2013) the Medical Scientific Research Foundation of Zhejiang Province (2019RC027).