A Novel Intergenic Region Between KLHL31 and LRRC1-ALK Exon 20 Fusion Variant in Advanced Lung Adenocarcinoma and its Remarkable Response to ALK Inhibitor

Whereas very few genomic rearrangements have been found to contribute in smoking-associated mutations in lung adenocarcinoma, they frequently serve as the driver events for lung adenocarcinoma in nonsmoking patients. These frequent genetic alterations give rise to some oncogenes, such as point mutations in EGFR and gene fusions associated with ALK, ROS1, and RET.1Herbst R. Morgensztern D. Boshoff C. The biology and management of non-small cell lung cancer.Nature. 2018; 553: 446-454Crossref PubMed Scopus (1333) Google Scholar Among them, ALK gene fusions occur in as many as 5% of patients with NSCLC in the People’s Republic of China, and ALK inhibitors targeting therapy with ALK gene mutations have revolutionized anticancer treatments in the advanced stages. Here, we report a novel intergenic region between KLHL31 and LRRC1-ALK fusion variant in a patient with lung adenocarcinoma and its remarkable response to ensartinib. A 50-year old Chinese nonsmoking man had repeated productive cough for more than 6 months and was admitted to the hospital for a lung mass seen in chest computed tomography scan. Further enhanced computed tomography scans revealed a space-occupying lesion in the middle lobe of the right lung, multiple lymph nodes in the mediastinum and right lung, and multiple cysts in the liver and kidney. Magnetic resonance imaging of the spine and pelvis revealed tumor metastasis of the S1 vertebra, potential hemangioma in the thoracic vertebra, and right pleural effusion. The patient underwent a bronchoscopic biopsy and pathologic results further revealed stage IV lung adenocarcinoma. Next-generation sequencing on cell-free DNA was performed and revealed a specific intergenic region between the KLHL31 and LRRC1 gene on 6p12.1 and also the common ALK intron 19 (Fig. 1A and B), which included the complete kinase domain of ALK protein. Immunohistochemistry results further confirmed a positive ALK protein expression (Fig. 1C). After treatment with two cycles of chemotherapy using pemetrexed combined with nedaplatin, the patient was given ALK inhibitor ensartinib (225 mg orally once daily) in August 2020. Afterward, he achieved a partial response in the right lung and lymph nodes in the mediastinum soon after 1-month treatment, which lasted until present (Fig. 1D). He was also treated with radiotherapy plus zoledronic acid for bone metastases. As a therapeutic response to ALK inhibitors in ALK-positive patients is heterogeneous,2Zhou F. Zhou C. Treatment algorithm for advanced ALK-rearranged NSCLC: a marathon rather than a sprint.J Thorac Oncol. 2020; 15: 485-488Abstract Full Text Full Text PDF PubMed Scopus (3) Google Scholar it is crucial to understand the comprehensive genomic information of ALK fusion besides protein expression with other fluorescence or immunohistochemistry approaches.3Lin C. Shi X. Yang S. et al.Comparison of ALK detection by FISH, IHC and NGS to predict benefit from crizotinib in advanced non-small-cell lung cancer.Lung Cancer. 2019; 131: 62-68Abstract Full Text Full Text PDF PubMed Scopus (42) Google Scholar To date, several different fusion partners beyond EML4-ALK fusions have been identified using next-generation sequencing techniques in recent years.4Hou X. Xu H. Chen L. SRBD1-ALK, a novel ALK fusion gene identified in an adenocarcinoma patient by next-generation sequencing.J Thorac Oncol. 2019; 14: e72-e73Abstract Full Text Full Text PDF PubMed Scopus (8) Google Scholar,5Qin B.D. Jiao X.D. Liu K. Wu Y. Zang Y.S. Identification of a novel EML4-ALK, BCL11A-ALK double-fusion variant in lung adenocarcinoma using next-generation sequencing and response to crizotinib.J Thorac Oncol. 2019; 14: e115-e117Abstract Full Text Full Text PDF PubMed Scopus (9) Google Scholar This may provide supplementary data for identifying precise ALK fusion variants to guide targeted therapy with ALK inhibitors in patients with NSCLC. In our patient, ALK protein was positively expressed in tumor cells. The patient continued with ensartinib treatment and responded well till the cutoff date. We speculated that this might be owing to a gene expression regulator or strong promoter in this novel fusion variant, and we are aiming to clarify the potential mechanism through in vitro models. In summary, our present case exhibited a novel intergenic region between the KLHL31 and LRRC1-ALK exon 20 fusion variant in a Chinese patient with advanced lung adenocarcinoma, which enriches the mutational spectrum of ALK fusion and serves as an indicator of an effective response to ALK inhibitors in NSCLC. The authors thank the Foundation for Fostering Key Talents from Middle-aged and Young Medical Personnel in Wuhan (2016), the Chinese Society of Clinical Oncology Cancer Research Fund (No. Y-2019Genecast-061 and No. Y-sy2018-018), and the 2019 Wu Jieping Medical Fundation-Xinda Cancer Research Fund (through Dr. Meng) for supporting this study.