AGAP2-AS1 as prognostic biomarker in low-risk clear cell renal cell carcinoma patients with progressing disease

Purpose: Clear cell renal cell carcinoma (ccRCC) is the most common renal cancer. Thirty percent of patients with localized ccRCC develop metastases during follow-up. Although current scoring methods correctly identify patients at low progression risk, a small subgroup still experiences metastatization. We therefore aimed to identify ccRCC progression biomarkers in “low-risk” patients, potentially eligible for adjuvant treatments. Methods: We performed next-generation sequencing of RNA from formalin-fixed samples obtained at initial surgery from 8 “low-risk” patients with progressing tumours and 16 patients with similar Leibovich score, tumour stage and size, creatinine levels and surgical treatment, not progressing to recurrence with metastasis. Key results were confirmed with qPCR, immunohistochemistry and in external data. Results: Principal component analysis indicates that systematic transcriptomic differences are detectable at the time of initial surgery. 1167 genes, related to cancer and immune-related pathways, were differentially expressed between progressors and non-progressors. Search for a classifier revealed that overexpression of AGAP2-AS1, an antisense long non-coding RNA, alone, correctly classified 23 of 24 samples without requiring larger gene panels. AGAP2-AS1 gene overexpression was confirmed by qPCR (p <0.05) and correlated with shorter progression-free survival (p: <0.0005). Immunohistochemistry confirmed upregulation at the protein level of AGAP2. Conclusion: AGAP2-AS1 may represent a novel biomarker identifying high risk patients currently classified as “low risk” at the time of surgery. Next-generation sequencing of RNA from formalin-fixed samples obtained at initial surgery from 8 “low-risk” patients with progressing tumours and 16 patients with similar Leibovich score, tumour stage and size, creatinine levels and surgical treatment, not progressing to recurrence with metastasis. Key results were confirmed with qPCR, immunohistochemistry and in external data. *** Raw data is to be made available through dbGaP (controlled access) due to patient privacy concerns****