Melanoregulin-Anaplastic Lymphoma Kinase (ALK), a Novel ALK Rearrangement That Responds to Crizotinib in Lung Adenocarcinoma
Authors: Leiming Wang, Shuyang Yao, Lianghong Teng, Weiwei Zhang, Li Chen
Journal: Journal of Thoracic Oncology (2020)

The rearrangement of anaplastic lymphoma kinase (ALK) is a distinct driver in NSCLC, which is found in 3% to 5% of patients with NSCLC.1Zhang M. Wang Q. Ding Y. et al.CUX1-ALK, a novel ALK rearrangement that responds to crizotinib in non-small cell lung cancer.J Thorac Oncol. 2018; 13: 1792-1797Abstract Full Text Full Text PDF PubMed Scopus (21) Google Scholar In NSCLC, many fusion partners of ALK have been reported, and the most common ALK rearrangement is echinoderm microtubule–associated protein like 4–ALK.2Hallberg B. Palmer R.H. The role of the ALK receptor in cancer biology.Ann Oncol. 2016; 27: iii4-iii15Abstract Full Text Full Text PDF PubMed Scopus (194) Google Scholar ALK rearrangements are correlated with response to ALK tyrosine kinase inhibitors (TKIs). Here, we report a novel melanoregulin (MREG)-ALK fusion, which is sensitive to crizotinib, in a patient with lung adenocarcinoma and brain metastasis. A 65-year-old nonsmoking Chinese woman was admitted to the local hospital with cough since 2 months. She had no fever, expectoration, or headache. Computed tomography scans of her chest reported an irregular nodular mass in the left main bronchial wall and the left lingual lobe, with a narrowing of the left lower lobe bronchi (Fig. 1A). Meanwhile, cranial computed tomography and magnetic resonance imaging revealed a space-occupying lesion in the frontal lobe, accompanied by bone destruction, which was considered a metastatic tumor (Fig. 1B). A biopsy through fiberoptic bronchoscopy was performed, and pathologic analysis reported a poorly differentiated lung adenocarcinoma with mucin production in cytoplasm (Fig. 1C and D). Formalin-fixed, paraffin-embedded specimens from bronchoscopy biopsy were sent for genomic testing by next-generation sequencing. Results revealed that MREG promoter was fused to ALK exon 20, leading to a novel MREG-ALK fusion gene with a mutant allele frequency of 13.09% (Fig. 2A and B). At the same time, immunohistochemistry was performed with the Ventana D5F3 (Roche), revealing the diffuse expression of ALK in the cytoplasm of tumor cells (Fig. 2C). Break-apart fluorescent in situ hybridization probe (Vysis FISH, Abbott) reported a separation of ALK (Fig. 2D). The patient received an ALK TKI crizotinib orally at a dose of 250 mg (twice daily) after our pathologic diagnosis. The tumor size decreased both in the lung and in the brain with an impressive symptomatic improvement after 3 months of therapy (Fig. 1E and F).Figure 2Identification of a novel MREG-ALK fusion by next-generation sequencing. (A) Sequencing reads of ALK and MREG were reported by the Integrative Genomics Viewer. (B) Schematic structure of the genomic DNA sequence revealed fusion points for the MREG-ALK fusion gene. (C) Ventana ALK (D5F3) IHC assay revealed diffuse expression of ALK in the cytoplasm of tumor cells; original magnification, ×400. (D) Break-apart FISH probe in the tumor sample revealed split red-green or single red dots, indicating ALK fusion. ALK, anaplastic lymphoma kinase; FSH, fluorescent in situ hybridization; IHC, immunohistochemistry; MREG, melanoregulin.View Large Image Figure ViewerDownload Hi-res image Download (PPT) Multiple ALK fusion partners have been reported in NSCLC, and break points vary across patients even with the same partner gene. These make it complicated when treatment and prognosis are concerned because responses to ALK TKIs are heterogeneous for different ALK fusion variants.3Sabir S.R. Yeoh S. Jackson G. Bayliss R. EML4-ALK variants: biological and molecular properties, and the implications for patients.Cancers (Basel). 2017; 9: 118Crossref Scopus (110) Google Scholar,4Yoshida T. Oya Y. Tanaka K. et al.Differential crizotinib response duration among ALK fusion variants in ALK-positive non-small-cell lung cancer.J Clin Oncol. 2016; 34: 3383-3389Crossref PubMed Scopus (211) Google Scholar To our knowledge, MREG has not been previously reported as a fusion partner of ALK. MREG, the product of the Mregdsu located at 2q35, has been shown to act as a factor in organelle biogenesis, maintain melanosome size and distribution, drive melanosome transfer from melanocytes to keratinocytes, regulate membrane fusion, and suppress the invasion and proliferation of thyroid cancer cells.5Meng X. Dong Y. Yu X. et al.MREG suppresses thyroid cancer cell invasion and proliferation by inhibiting Akt-mTOR signaling.Biochem Biophys Res Commun. 2017; 491: 72-78Crossref PubMed Scopus (14) Google Scholar In our present case, the break points of this fusion were located in the promoter of MREG and exon 20 of ALK. We speculate that the fusion of the MREG promoter activates the expression of ALK as indicated in other ALK fusion events. Moreover, the patient harboring MREG-ALK fusion reported a response to the ALK inhibitor crizotinib. To our knowledge, this is the first case to present a patient with lung adenocarcinoma harboring a new fusion of ALK rearrangement (MREG-ALK) showing response to crizotinib. Our finding expands the spectrum of ALK fusion variants that should be added to the list of ALK fusion genes. This project was supported by the Beijing Excellent Talents Training Project, China (No. 201600026833ZK07) and Beijing Higher Education Young Elite Teacher Project, China (No. CIT&TCD201904091) to Dr. Wang. The authors thank Dr. Chenguang Shi from Peking Union Medical College Hospital and Zhe Zhang from Vcanclinic (Tianjin) Genetic technology Co. Ltd. for their excellent work in technology support.