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Abstract
Purpose: The purpose of this study was to identify aberrant long non-coding RNAs (lncRNAs) and explore the predictive value of lncRNA expression patterns on the risk of brain metastases (BMs) in patients with limited-stage small-cell lung cancer (SCLC).Patients and Methods: We executed an array of lncRNA and mRNA chip assays to examine the expression in peripheral blood mononuclear cells obtained from SCLC patients with BMs and compared the expression patterns against those from patients without BMs to identify lncRNAs associated with BMs. Validation was performed against clinical data to further confirm the relationship between lncRNAs and BM. Kaplan–Meier analysis was applied to estimate the cumulative incidence of BMs, and differences between the groups were analyzed using the log-rank test.Results: The expression of 67 lncRNAs (27 upregulated and 40 downregulated) and 47 mRNAs (20 upregulated and 27 downregulated) was significantly different between the BM and non-BM groups (fold change ≥ 2.0, p-value ≤ 0.05), based on the lncRNA and mRNA chip assays. Four lncRNAs were verified by quantitative real-time polymerase chain reaction (qRT-PCR) to confirm the accuracy of the microarray data, and the results of 11 patient pairs (11 patients with BM and 11 patients without BM) revealed that low LncRNA XR_429159.1 expression was a high-risk factor for BM. Further clinical data showed that the incidence of BM among 25 patients with low-level LncRNA XR_429159.1 expression was 31% at 1 year, compared with 14.3% among the 18 patients with high-level LncRNA XR_429159.1 expression (p = 0.035).Conclusion: Our present study identified the low-level expression of lncRNA XR_429159.1 as a high-risk factor among BM in patients with limited-stage SCLC. LncRNA XR_429159.1 is a critical molecule that regulates SCLC metastasis, involved in the neuroepithelial transforming gene 1 (NET1) pathway, and serum levels of this lncRNA are significantly associated with the risk of BM.
Highlights
The brain is the most common distant metastasis site for patients with small-cell lung cancer (SCLC), and brain metastasis (BM) is an unfavorable prognosis factor, regardless of the disease stage at presentation
The positive role played by prophylactic cranial irradiation (PCI) in patients with SCLC was established by a meta-analysis in 1999, and PCI has become part of the standard treatment modality used in patients with limited-stage SCLC who respond well to initial treatment
The correlation between long noncoding RNAs (lncRNAs) XR_429159.1 expression and BM was further explored in 11 patient pairs, in which limited-stage SCLC patients were matched with extensivestage SCLC patients with BM
Summary
The brain is the most common distant metastasis site for patients with small-cell lung cancer (SCLC), and brain metastasis (BM) is an unfavorable prognosis factor, regardless of the disease stage at presentation. The positive role played by prophylactic cranial irradiation (PCI) in patients with SCLC was established by a meta-analysis in 1999, and PCI has become part of the standard treatment modality used in patients with limited-stage SCLC who respond well to initial treatment. The role played by PCI has recently been challenged in patients with stage I limited- and extensive-stage SCLC, with fewer survival benefits observed following PCI based on follow-up magnetic resonance imaging study [4,5,6,7]. Our retrospective study revealed that patients with completely resected p-stage II–III SCLC and lymphovascular invasion were at the highest risk for BM, whereas the incidence of BM among patients with p-stage I SCLC was
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