Abstract
Syndrome of inappropriate antidiuresis (SIAD) in cancer is the main cause of hyponatremia and is associated with poorer survival, hospitalization and health costs in lung cancer (LC) patients (pts). Micro-RNAs (miRNAs) represent promising biomarkers with therapeutic potential. Our retrospective study aims to assess a miRNA signature to discriminate hyponatremia and predict clinical outcome in LC pts. We performed a miRNA sequencing in 20 FFPE tumor samples of 10 eunatremic and 10 hyponatremia-developing LC pts through Illumina NextSeq500 sequencer. Pts’ records were reviewed to assess outcome measures. The differential miRNA expression profile was analyzed between the two groups. miRNAs with |log2(fold change)|>0.58 and p<0.05 were considered statistically significant and correlated with survival outcomes, relapse-free survival (RFS), progression-free survival (PFS) and overall survival (OS), using three Cox multivariate regression models. 12 miRNAs were differentially expressed at diagnosis between hypo- and eunatremic pts at univariate analysis (p<0.05). At multivariate analysis, miR-147b-3p (median expression 10.8 vs 92.6, p=0.025), miR-147b-5p (2.6 vs 15.9, p=0.002), miR-937-3p (3.4 vs 14.6, p=0.039) and miR-146a-5p (6106.6 vs 16601.4, p=0.035) were significantly downregulated in hypo- vs eunatremic pts. Similarly, miR-539-3p (3.4 vs 14.9, p=0.083) and miR-625-3p (97.8 vs 308.9, p=0.061) showed a trend towards significance for downregulation. Contrarily, miR-190a-5p (304.2 vs 179.5, p=0.006) and miR-32-3p (7 vs 3, p=0.017) were upregulated in the hyponatremic vs control group. Looking at survival outcomes, the upregulation of miR-937-3p (p=0.042), miR-190a-5p (p=0.001) and miR-9-3p (p=0.035) was associated with worse OS, while the upregulation of miR-32-3p was associated with improved OS (p=0.010) and RFS (p=0.064). Our results reveal new insights into the role of vasopressin pathways in LC. These miRNAs appear as valuable early predictors of hyponatremia and their expression is associated with a significant impact on pts’ survival. Further investigations, including our prospective study, are warranted to provide advances in SIAD management.
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