Gene Expression Analysis of Aggressive Clinical T1 Stage Clear Cell Renal Cell Carcinoma for Identifying Potential Diagnostic and Prognostic Biomarkers

Abstract

The molecular characteristics of early-stage clear cell renal cell carcinomas (ccRCCs) measuring ≤7 cm associated with poor clinical outcomes remain poorly understood. Here, we sought to validate genes associated with ccRCC progression and identify candidate genes to predict ccRCC aggressiveness. From among 1069 nephrectomies performed on patients, RNA sequencing was performed for 12 ccRCC patients with aggressive characteristics and matched pairs of 12 ccRCC patients without aggressive characteristics. Using a prospective cohort (ClinicalTrials.gov Identifier: NCT03694912), the expression levels of nine genes (PBRM1, BAP1, SETD2, KDM5C, FOXC2, CLIP4, AQP1, DDX11, and BAIAP2L1) were measured by reverse-transcription polymerase chain reaction from frozen tissues, and their relation to Fuhrman grade was investigated in 70 patients with small ccRCC (≤4 cm). In total, 251 genes were differentially expressed and presented fold changes with p-values < 0.05; moreover, 10 genes with the greatest upregulation or downregulation in aggressive ccRCC remained significant even after adjustment. We validated previously identified genes that were associated with ccRCC progression and identified new candidate genes that reflected the aggressiveness of ccRCC. Our study provides new insight into the tumor biology of ccRCC and will help stratify patients with early-stage ccRCC by molecular subtyping.

Prediction of High-Grade Clear Cell Renal Cell Carcinoma Based on Plasma mRNA Profiles in Patients with Localized Pathologic T1N0M0 Stage Disease

“…Our previous studies have demonstrated that forkhead box protein C2 (FOXC2) and cytoskeleton-associated, protein-glycine (CAP-Gly)-rich, domain-containing linker protein family member 4 (CLIP4) mutations were associated with early-stage ccRCC, and a synchronous metastasis [10] and validation study confirmed that PBRM1, BAP1, and FOXC2 were shown to be significantly associated with aggressive early-stage ccRCC through target sequencing and immunohistochemistry [5]. In our latest study, we have identified new candidate genes (AQP1, DDX11, BAIAP2L1, and TMEM38B) by RNA sequencing of formalin-fixed, paraffin-embedded tissues and validating in frozen tissues [11].…”

“…We analyzed the expression of six genes (PBRM1, BAP1, SETD2, KDM5C, FOXC2, and CLIP4) reportedly associated with ccRCC, and four genes (AQP1, DDX11, BAIAP2L1, and TMEM38B) from our previous RNA-seq analysis of aggressive ccRCC at the clinical T1 stage [11].…”

Association between visceral adiposity and DDX11 as a predictor of aggressiveness of small clear-cell renal-cell carcinoma: a prospective clinical trial

“…Diameters of the primary tumors were obtained via CT imaging. We assessed the expression levels of six genes (PBRM1, BAP1, SETD2, KDM5C, FOXC2, and CLIP4) reportedly associated with ccRCC, and four genes (AQP1, DDX11, BAIAP2L1, and TMEM38B) examined in our previous study involving RNA-seq analysis of aggressive ccRCC in clinical T1 stage [16,17].…”

“…Previously, we found that several potential prognostic biomarkers are considerably up-or downregulated in ccRCC, and can be used to identify the aggressive clinical T1-stage [16,17]. In this study, we aimed to determine the association between visceral adiposity and the mRNA expression of potential biomarkers using frozen tumor tissues and preoperative plasma of patients with small ccRCC.…”

T1 Stage Clear Cell Renal Cell Carcinoma: A CT-Based Radiomics Nomogram to Estimate the Risk of Recurrence and Metastasis

“…Tumor-node-metastasis stage and pathological grade are generally adopted to estimate the risk of tumor recurrence in patients with ccRCC after surgical operation. Nevertheless, distinct outcomes are demonstrated in patients with equivalent tumor-node-metastasis stage and pathological grade ( 5 – 8 ).…”