SMPD3‐ALK: A novel ALK fusion gene in lung adenocarcinoma

Abstract

Anaplastic lymphoma kinase (ALK) is one of the most important driver genes and therapeutic targets in patients with non-small-cell lung cancer (NSCLC), who tend to be young and either light smokers or nonsmokers. Next-generation sequencing (NGS) technology, which is widely used in clinical practice, allows clinicians to identify both the 50 partner and 30 kinase involved in ALK fusions. Various ALK fusion partners have been identified in NSCLC, which are associated with the response to ALK tyrosine kinase inhibitors. Here, we report a case of lung adenocarcinoma harboring a novel SMPD3-ALK fusion gene. A 56-year-old nonsmoking Chinese male was admitted to our hospital with cough. A chest computed tomography (CT) scan revealed a 4.4 × 3.3 cm mass in the right hilum, with mediastinal lymph node metastasis (Figure 1(A)). Stage IIIA lung adenocarcinoma was confirmed based on CT-guided lung puncture pathology (Figure 1(B)). To determine potential therapeutic regimens, the tumor sample was sent for NGS analysis using a DNA panel of 450 cancer-related genes. Informed consent was obtained from the patient. SMPD3-ALK, a fusion generated from the fusion of exon 1 of SMPD3 and Exons 20–29 of ALK (Figure 1 (C),(D)), was identified, and verified by FISH assay (Figure 1(E)). COSMIC fusion databases (https://cancer.sanger.ac.uk/cosmic/fusion) and Quiver fusion databases (http://quiver.archerdx.com/) confirmed that the SMPD3-ALK fusion identified in this case is a novel fusion. Sphingomyelin phosphodiesterase 3 (SMPD3), an enzyme encoded by SMPD3 in humans, is involved in the pathway sphingolipid metabolism. It also may has cellular response to tumor necrosis factor (GO:0071356). A genome-wide study has shown that SMPD3 is a potential repressor of hepatocellular carcinoma, playing an important role in tumor formation. Here, the breakpoints of SMPD3-ALK fusion were located in the Intron 1 of SMPD3 and the Intron 19 of ALK that preserves the intact kinase domain of the ALK and may lead to the activation of ALK kinase. Similarly, EML4-ALK fusion with similar breakpoints occurring in the Intron 19 of ALK activates the downstream RAS/MAPK, PI3K/Akt, and JAK signaling pathways. Here, the activation of ALK was confirmed by immunohistochemistry (Figure 1(F)). To date, crizotinib, ceritinib, alectinib, and brigatinib have been approved for the treatment of ALK fusion NSCLC. It has been shown that sequential use of ALK inhibitors may clinically benefit patients showing progress on an initial ALK inhibitor. Therefore, the use of ALK inhibitors in the later stages of treatment might be effective in our patient, who underwent surgical resection and received adjuvant chemotherapy post-operatively and no recurrence has been observed so far. However, future studies comparing the efficacy of ALK inhibitors against different variants of NSCLC are warranted. In conclusion, we present the first report of SMPD3-ALK fusion, which will expand the spectrum of known ALK fusion variants. By broadening the understanding of ALK fusions, our case study will help clinicians improve the precision of patient care.