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The Urinary Peptidome Identifies Prognostic Biomarkers for Small Renal Masses

ABSTRACT: Purpose: Renal cell carcinoma (RCC) is often diagnosed incidentally as an early-stage small renal mass (SRM; pT1a, ≤ 4 cm). Increasing concerns surrounding the overtreatment of patients with benign or clinically indolent tumors has led to a shift in current treatment recommendations, especially for elderly and infirm patients. There are currently no available biomarkers to accurately stratify patients according to risk. Therefore, we set out to identify early biomarkers of RCC progression. Experimental Design: We employed label-free LC-MS/MS and targeted parallel-reaction monitoring (PRM) to identify early, non-invasive diagnostic and prognostic biomarkers for early-stage RCC-SRMs. In total, we evaluated 115 urine samples, including 33 renal oncocytoma (≤ 4 cm) cases, 30 progressive and 26 non-progressive clear cell RCC-SRM (ccRCC-SRM) cases, in addition to 26 healthy controls. Results: We identified nine endogenous peptides which displayed significantly elevated expression in ccRCC-SRMs relative to healthy controls. Peptides NVINGGSHAGNKLAMQEF, VNVDEVGGEALGRL, and VVAGVANALAHKYH showed significantly elevated expression in ccRCC-SRMs relative to renal oncocytoma. Additionally, peptides SHTSDSDVPSGVTEVVVKL and IVDNNILFLGKVNRP displayed significantly elevated expression in progressive relative to non-progressive ccRCC-SRMs. Peptide SHTSDSDVPSGVTEVVVKL showed the most significant discriminatory ability (AUC: 0.76, 95% CI: 0.62 to 0.90, p = 0.0027). Patients with elevated SHTSDSDVPSGVTEVVVKL expression had significantly shorter overall survival (HR: 4.13, 95% CI: 1.09 to 15.65, p = 0.024) compared to patients with lower expression. Conclusions: Our in-depth peptidomic analysis identified novel biomarkers for early-stage RCC-SRMs. Characterization of urinary peptides may provide insight into early RCC progression and could potentially help assign patients to appropriate management programs.

INSTRUMENT(S): Q Exactive

ORGANISM(S): Homo Sapiens (human)

TISSUE(S): Urine

DISEASE(S): Renal Clear Cell Carcinoma

SUBMITTER: Ashley Di Meo

LAB HEAD: Eleftherios P. Diamandis

PROVIDER: PXD013111 | Pride | 2019-08-08

REPOSITORIES: Pride

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Project description:Renal cell carcinoma (RCC) is the most common neoplasm of the adult kidney. Currently, there are no biomarkers for the diagnostic, prognostic, or predictive applications in RCC. MicroRNAs (miRNAs) are short non protein-coding RNAs that negatively regulate gene expression and have been shown to be involved in cancer. We analyzed a total of 70 matched pairs of clear cell RCC (ccRCC) and normal kidney tissues from the same patients by microarray analysis and validated our results by quantitative real time PCR. We identified 166 miRNAs significantly dysregulated in ccRCC. MiR-122, miR-155 and miR-210 had the highest fold changes of overexpression while miR-200c, miR-335, and miR-218 were the most downregulated. We performed extensive bioinformatics analysis including a combinatorial analysis of previously reported miRNAs dysregulated in RCC and extensive target prediction analysis. Many miRNAs were predicted to target a number of genes involved in RCC pathogenesis. Our results showed that miRNA dysregulation in RCC can be attributed in part, to chromosomal aberrations, the co-regulation of miRNA clusters, and co-expression with host genes. We also correlated miRNA expression with clinical characteristics and found miR-155 expression was correlated with ccRCC tumor size. In conclusion, our analysis showed that a number of miRNAs are dysregulated in ccRCC and may contribute to kidney cancer pathogenesis by targeting more than one key molecule. We identified mechanisms that may contribute to miRNA dysregulation in ccRCC. Dysregulated miRNAs represent potential biomarkers for kidney cancer. We preformed a miRNA microarray on 20 pairs of matched primary clear cell renal cell carcinoma (ccRCC) and normal kidney tissue from the same patient (St. Michael's Hospital, Toronto, Canada). One matched pair was used per array for a total of 20 arrays. Microarray results were validated by quantitative real time PCR using an independent set of 50 matched pairs of ccRCC and normal kidney tissue from the same patient.

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The Urinary Peptidome Identifies Prognostic Biomarkers for Small Renal Masses

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