ALG8-RET: A novel RET rearrangement in a patient with malignant melanoma of the palatal mucosal
To the editor,
Malignant melanomas (MM) is a type of cancer that develops from the pigment-containing cells known as melanocytes [1]. Malignant melanomas of the oral cavity (OMM) is extremely rare, accounting for 0.2–8.0% of all MM [2]. Despite several breakthroughs in treatment of melanoma in recently years, the 5-year survival rate is still poor and new therapies are urgently needed in clinical practice. The rearranged during transfection proto-oncogene (RET) rearrangement is best investigated and characterized in non-small cell lung cancer (NSCLC), but occurs rarely (less than 1%) in MM cases [3]. Herein, we report a novel RET rearrangement (ALG8-RET) in a patient with malignant melanoma of the palatal mucosal (see Fig. 1).
A 28-year-old male patient was admitted to the hospital complaining for a painful black lump on palate of mouth cavity with rupture bleeding. Computed tomography (CT) detected swollen lymph nodes in bilateral neck, which were considered as a possible metastasis. Then, the patient underwent cryotherapy for the primary foci and pathologic diagnosis revealed palatal mucosal malignant melanoma. Bilateral submandibular gland resection and neck lymph node dissection were performed subsequently. Immunohistochemistry staining of lymph nodes showed Melan-A (+), Tyro (+), HMB45 (+), S100 (+), SOX-10 (+) and Ki67 (40–50%+), and cervical lymph node metastasis was confirmed. One cycle of adjuvant anti-angiogenesis therapy (endostatin, day 1–7, 30 mg) combined with chemotherapy (Vincristine, day 4, 3 mg plus Nedaplatin, day 4, 110 mg plus DTIC, day 4–7, 400 mg) was administered. Unfortunately, there was no remission on the disease.
To seek for precision therapy, the formalin-fixed and paraffin-embedded specimens were subjected to next-generation sequencing (NGS) analysis via DNA-based hybrid capture. A novel ALG8-RET fusion was detected (4.09% abundance) and tumor mutation burden was 10.29 Muts/Mb. In addition, several other mutations, such as ARID1A, STAT4 and FGA were also observed. Considering the high TMB value, toripalimab plus anlotinib was immediately administered, and the disease was evaluated as stable disease within 6 months. https://doi.org/10.1016/j.oraloncology.2020.104973 Received 31 July 2020; Accepted 7 August 2020 1368-8375/ © 2020 Published by Elsevier Ltd.
Accompanied by the widespread application of the NGS analysis, various novel mutation variants have been identified in MM. Herein, a novel ALG8-RET fusion was firstly detected in MM. This fusion was generated by the fusion of exons 1 of ALG8 to exons 4–20 of RET, retaining the complete kinase domain of RET. In this setting, we considered ALG8 would form homodimer and activate RET, raising the intracellular downstream RAS/MAPK signaling associated with cellular proliferation and migration, which lead to the excessive activation of RET kinase in the OMM cells.
Although surgery is the most effective treatment for MM, wide resection with a surgical margin of 20–50 mm is not always doable for an OMM [4]. So far, treatments for OMM are still limited, chemotherapy and radiotherapy play only adjuvant roles. The 5-year survival rate of OMM is poor, ranging from 5.2% to 20%, indicating that precision targeted treatment is desperately desired and clinically valuable [4]. Fortunately, the FDA has granted an accelerated approval to selpercatinib (LOXO-292) for the treatment of patients with RET-alteration- positive NSCLC [5]. Meanwhile, the closely-watched umbrella trials, which seek to streamline the investigation of genotype-based treatments and triaging patients to genotype-matched therapeutic agents, clearly confirm substantial efficacy, with OR rates over 60% in some enrolled cohorts [6]. Thus, we speculated that the OMM patient with this novel ALG8-RET fusion might benefit from the recently approved RET-specific inhibitor after the failure of immunotherapy.
To the best of our knowledge, this is the first report of a novel RET arrangement in a patient with OMM. Our case report expands the spectrum of RET arrangement types and may therefore provide specific and promising RET-TKI target variant for clinical treatment after the failure of standard treatments. Declaration of Competing Interest
References
[1] Tucker MA. Melanoma epidemiology. Hematol Oncol Clin North Am 2009;23(383–95):vii. https://doi.org/10.1016/j.hoc.2009.03.010. Dongliang Weia Shanghai Ninth People’s Hospital, Shanghai JiaoTong University School of a, Dongsheng Chenb, Lijian Lib, Jing Tianb, Guoxin Rena,
[2] Regezi JA, Sciubba J. Oral Pathology. 2nd ed. PA: WB Saunders; 1993. p. 165–71. Medicine, Shanghai 210000, China
[3] Ferrara R, Auger N, Auclin E, Besse B. Clinical and Translational Implications of RET Rearrangements in Non-Small Cell Lung Cancer. J Thoracic Oncol 2018;13:27–45. https://doi.org/10.1016/j.jtho.2017.10.021. Development, Jiangsu Simcere Diagnostics Co., Ltd, Nanjing 210002, China b The State Key Laboratory of Translational Medicine and Innovative Drug
[4] Dimitrakopoulos I, Lazaridis N, Skordalaki A. Primary malignant melanoma of the oral cavity. Report of an unusual case. Aust Dent J 1998;43:379–81.