RASAL2-RET: a novel RET rearrangement in a patient with high-grade sarcoma of the chest
Authors: Y. Zhou, C. Qi, M.Z. Xiao, S.L. Cai, B.J. Chen
Journal: Annals of Oncology (2020)

RET rearrangements occur in 1%–2% of non-small-cell lung cancer (NSCLC) cases.1Mulligan L.M. RET revisited: expanding the oncogenic portfolio.Nat Rev Cancer. 2014; 14: 173-186Crossref PubMed Scopus (345) Google Scholar Herein, a novel RET rearrangement (RASAL2-RET) was first detected in a patient with high-grade sarcoma of the chest. A 22-year-old woman was admitted to the hospital for intermittent fever with cough. Chest computed tomography revealed a space-occupying lesion in the right lung. After the exclusion of any contraindications, surgeries for mediastinal tumor resection, inferior lobe resection of the right lung, and thoracic lymph node dissection were performed. Postoperative pathological findings of the right lung and mediastinal tumors led to the diagnosis of a high-grade sarcoma of the chest. Next-generation sequencing (NGS) analysis based on a pan-cancer 437-gene panel of the lung tumor tissues revealed the presence of a novel RET rearrangement (RASAL2-RET; Figure 1). Mutation profiling of this patient is summarized in Table 1. The fusion of RASAL2-RET included exons 1–18 of RASAL2 and exons 12–20 of RET. This new type of RET arrangement retained the complete kinase structure of the RET protein, which might lead to the abnormal activation of RET kinase in the tumor cells. Fluorescence in situ hybridization confirmed RET arrangement (Figure 2).Table 1Next-generation sequencing findings of the high-grade sarcoma of the chest tumor tissue sampleGeneMutation styleFrequency (%) or copy numberFGFR1Amplification6CDKN2ADeletion0RETRASAL2-RETN/ACDKN2BDeletion0ADGRA2Amplification6ZNF703Amplification6TP53p.V147Gfs*2 Exon541.26% Open table in a new tab Figure 2FISH findings of the primary lung tumor tissue sample.Show full captionThe green spots (probe 5′ RET) and the red spots (probe 3′ RET) are split, revealing a rearrangement of the RET gene. Split signal was observed with a frequency of 54% in FISH image.View Large Image Figure ViewerDownload (PPT) The green spots (probe 5′ RET) and the red spots (probe 3′ RET) are split, revealing a rearrangement of the RET gene. Split signal was observed with a frequency of 54% in FISH image. The RET signaling pathway could be activated by the binding of its ligands to receptors, yielding a RET dimer, thereby activating the intracellular downstream RAS/MAPK signaling pathway to promote cell proliferation and survival. However, the activation of the above-mentioned cellular pathway could be triggered irrespective of the existing ligands when RET fuses with its partner genes.2Ferrara R. Auger N. Auclin E. Besse B. Clinical and translational implications of RET rearrangements in non-small cell lung cancer.J Thorac Oncol. 2018; 13: 27-45Abstract Full Text Full Text PDF PubMed Scopus (129) Google Scholar Due to the widespread use of the NGS method in clinical practice, various fusion patterns have been identified, including the kinesin family member 5B gene (KIF5B), a coiled-coil domain containing six genes (CCDC6), and others.3Bronte G. Ulivi P. Verlicchi A. et al.Targeting RET-rearranged non-small-cell lung cancer: future prospects.Lung Cancer (Auckl). 2019; 10: 27-36PubMed Google Scholar Some patients with RET-rearranged NSCLC could have tumor response after the use of RET tyrosine kinase inhibitors (TKIs) such as cabozantinib4Drilon A. Rekhtman N. Arcila M. et al.Cabozantinib in patients with advanced RET-rearranged non-small-cell lung cancer: an open-label, single-centre, phase 2, single-arm trial.Lancet Oncol. 2016; 17: 1653-1660Abstract Full Text Full Text PDF PubMed Scopus (322) Google Scholar and vandetanib.5Lee S.H. Lee J.K. Ahn M.J. et al.Vandetanib in pretreated patients with advanced non-small cell lung cancer-harboring RET rearrangement: a phase II clinical trial.Ann Oncol. 2017; 28: 292-297Abstract Full Text Full Text PDF PubMed Scopus (163) Google Scholar Patients with high-grade sarcoma of the chest are usually not sensitive to chemotherapy or radiation, and new treatments are urgently needed to improve prognosis. To date, several RET inhibitors (e.g. LOXO-292 and BLU-667) have shown improved clinical outcomes because of increased potency and less off-target toxicity in RET-rearranged NSCLC6Oxnard G. Subbiah V. Park K. et al.OA12.07 Clinical activity of LOXO-292, a highly selective RET inhibitor, in patients with RET fusion+ non-small cell lung cancer.J Thorac Oncol. 2018; 13: S349-S350Abstract Full Text Full Text PDF Google Scholar,7Subbiah V. Taylor M. Lin J. et al.Abstract CT043: highly potent and selective RET inhibitor, BLU-667, achieves proof of concept in a phase I study of advanced, RET-altered solid tumors.Cancer Res. 2018; 78: CT043Google Scholar and patients may potentially benefit from RET inhibitors in the future. To the best of our knowledge, this is the first report of a novel RET arrangement in a patient with high-grade sarcoma of the chest. Our case report expands the spectrum of RET arrangement types and may, therefore, provide promising RET-TKI drugs after the failure of standard treatments. None declared.