Nuclear Pore Glycoprotein 62 Genetic Variant rs9523 is Associated with Clinical Outcomes of Epidermal Growth Factor Receptor Tyrosine Kinase Inhibitors in Lung Adenocarcinoma Patients.

INTRODUCTION

Epidermal growth factor receptor (EGFR) tyrosine kinase inhibitors (TKIs) have represented the prototype of targeted therapy in NSCLC. Patients with EGFR-mutant lung adenocarcinoma extract an extraordinary clinical benefit from EGFR-TKIs. However, the extent and duration of these responses are heterogeneous, suggesting the existence of genetic modifiers affecting an individual's response to TKIs. We investigated whether genetic variants in miRNA binding sites are associated with the clinical outcome of EGFR-TKIs in lung adenocarcinoma patients.

METHODS

One hundred SNPs at miRNA binding sites in cancer-related genes were selected for the analysis using the crosslinking, ligation and sequencing of hybrids (CLASH) and CancerGenes database. qRT-PCR and luciferase assays were conducted to evaluate the functional relevance of the SNPs.

RESULTS

rs9523A>G were significantly associated with worse response to EGFR-TKIs, overall survival (OS), and progression-free survival (PFS). The other three SNPs ( rs2074216G>A, rs11541557G>T, and rs2261988C>A) were significantly associated with worse OS and PFS. The rs9523A>G was significantly associated with decreased expression in tumor tissues. In addition, a significantly decreased luciferase activity was noted in rs9523 G allele compared to A allele.

CONCLUSION

Genetic variants in miRNA binding sites, especially rs9523A>G, may be useful in predicting the clinical outcomes of EGFR-mutant lung adenocarcinoma patients treated with EGFR-TKIs.