MicroRNA profiles by deep sequencing (miRNA-seq) of human clear cell renal cell carcinoma (ccRCC) samples from patients treated with tyrosine kinase inhibitors (TKIs). Homo sapiens

The majority of metastatic clear cell renal cell carcinoma (ccRCC) patients are treated with tyrosine kinase inhibitors (TKIs) in first line, however, a fraction are refractory to these drugs. MicroRNAs (miRNA) are regulatory molecules that have proven to be accurate biomarkers in cancer. Here we identified miRNA predictive of progressive disease under TKI treatment. Whole miRNA expression was quantified by deep-sequencing in a discovery set of 74 metastatic ccRCC cases uniformly treated with TKIs. Twenty nine miRNAs were found to be differentially expressed in the tumors of patients who progressed under TKI therapy. Among six miRNAs selected for validation, an over-expression of miR-1307-3p, miR-155-5p, miR-221-3p, miR-425-5p and miR-222-3p was confirmed in patients with progressive disease as best response. A 2 miRNA-based classifier could discriminate individuals with progressive disease upon TKI treatment with a better predictive value than clinicopathological risk factors commonly used. miRNAs significantly associated with progression-free survival and overall survival were identified, and 7 miRNAs were found to overlap as predictive for early progressive disease, PFS and OS. Overall design: Deep-sequencing in a discovery set of metastatic ccRCC cases uniformly treated with TKIs. In the tumor bank of the University Hospitals Leuven (Belgium), we searched for metastatic ccRCC patients treated with sunitinib, sorafenib or pazopanib as first-line anti-VEGFR-TKIs with available archived formalin-fixed paraffin embedded (FFPE) primary tumors and nephrectomy as first therapeutic intervention. Previous immunotherapy or chemotherapy was allowed, but previous exposure to other targeted therapies was an exclusion criterion. miRNA NGS was performed in 81 cases identified, but subsequently 5 cases were excluded because no CT scan evaluating anti-VEGFR-TKI response was available (they all had less than 1 month TKI treatment), 1 case was a misclassified papillary RCC and 1 patient developed a secondary tumor potentially affecting TKI response. Therefore, 74 ccRCCs were included in the analysis.