A Novel Intergenic Region between CENPA and DPYSL5-ALK Exon 20 Fusion Variant Responding to Crizotinib Treatment in a Patient with Lung Adenocarcinoma

Abstract

ALK receptor tyrosine kinase gene (ALK) fusion, one of the driver gene alterations leading to the development of lung cancer, occurs in 5% of NSCLC in China.1Iwama E. Goto Y. Murakami H. et al.Alectinib for patients with ALK rearrangement-positive non-small cell lung cancer and a poor performance status (Lung Oncology Group in Kyushu 1401).J Thorac Oncol. 2017; 12: 1161-1166Abstract Full Text Full Text PDF PubMed Scopus (32) Google Scholar In addition to echinoderm microtubule associated protein like 4 gene (EML4)-ALK, which is the most common type of ALK fusion, various fusion partner genes have been identified in recent years.2Ou S.H. Klempner S.J. Greenbowe J.R. et al.Identification of a novel HIP1-ALK fusion variant in non-small-cell lung cancer (NSCLC) and discovery of ALK I1171 (I1171N/S) mutations in two ALK rearranged NSCLC patients with resistance to alectinib.J Thorac Oncol. 2014; 9: 1821-1825Abstract Full Text Full Text PDF PubMed Scopus (78) Google Scholar, 3Takeuchi K. Choi Y.L. Togashi Y. et al.KIF5B-ALK, a novel fusion oncokinase identified by an immunohistochemistry-based diagnostic system for ALK-positive lung cancer.Clin Cancer Res. 2009; 15: 3143-3149Crossref PubMed Scopus (630) Google Scholar Herein, we report a novel intergenic region between centromere protein A gene (CENPA) and dihydropyridiminase like 5 (DPYSL5)-ALK fusion in a patient with lung adenocarcinoma. A 60-year-old man was admitted to the hospital with a complaint of persistent stimulating dry cough. A chest computed tomography (CT) scan revealed the existence of a space-occupying lesion in the inferior lobe of his left lung; the lesion was accompanied by segmental atelectasis. Meanwhile, another space-occupying lesion was found in the patient's right adrenal gland. Computed tomography–guided lung puncture was performed in the left lung, resulting in a pathological diagnosis of lung adenocarcinoma. The biopsy specimen was then subjected to next-generation sequencing analysis, and a novel intergenic region between CENPA and DPYSL5-ALK fusion was identified (Fig.1). Breakpoints were located in the intergenic region between the CENPA and DPYSL5 genes and intron 19 of the ALK gene, and this new fusion included the complete ALK kinase domain. Fluorescence in situ hybridization (FISH) and immunohistochemistry (IHC) were then performed, and ALK-positive NSCLC was confirmed (Fig. 2). Crizotinib (250 mg orally twice daily) was immediately administrated; the patient achieved a partial response in the left lung and right adrenal lesions after 2 months of treatment (Fig. 3).Figure 3Tumor response of the patient’s left lung and right adrenal lesions during crizotinib treatment. (A) Tumor lesion in the left lung before crizotinib treatment. (B) The tumor lesion in the left lung decreased significantly according to chest computed tomography scan evaluation after 2 months of crizotinib treatment. (C) Tumor lesion of the right adrenal before crizotinib treatment. (D) Chest and abdomen computed tomography examination indicated that the tumor lesion of the right adrenal decreased significantly after 2 months of crizotinib treatment.View Large Image Figure ViewerDownload Hi-res image Download (PPT) As far as we know, this is the first report of breakpoints coexisting simultaneously in the intergenic region between CENPA and DPYSL5 gene and intron 19 of the ALK gene, as well as a novel ALK rearrangement. To guide ALK inhibitor therapy in patients with NSCLC, the FISH and IHC methods were used to identify ALK fusion status. However, previous studies showed that tumor response to an ALK inhibitor is heterogeneous in patients with ALK-positive NSCLC. One of the explanations for this confusing phenomenon is that different ALK fusion variants might bring disparate clinical outcomes.4Lin J.J. Shaw A.T. Differential sensitivity to crizotinib: does EML4-ALK fusion variant matter?.J Clin Oncol. 2016; 34: 3363-3365Crossref PubMed Scopus (22) Google Scholar, 5Yoshida 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, the shortcoming of traditional FISH and IHC was that the precise ALK fusion variants could not be identified, and the application of next-generation sequencing might be used as an optional and supplementary method. Because this patient received a remarkable tumor response after crizotinib therapy, our case report has expanded the spectrum of ALK fusion and provided useful information for precise ALK inhibitor administration in the future.