The molecular prognostic markers of metastasis are important for personalized approaches to clear cell renal cell carcinoma (ccRCC) treatment but markers for practical use are still missing. To address this gap we studied the expression of ten genes—CA9, NDUFA4L2, VWF, IGFBP3, BHLHE41, EGLN3, SAA1, CSF1R, C1QA, and FN1—through RT-PCR, in 56 ccRCC patients without metastases and with metastases. All of these, excluding CSF1R, showed differential and increased (besides SAA1) expression in non-metastasis tumors. The gene expression levels in metastasis tumors were decreased, besides CSF1R, FN1 (not changed), and SAA1 (increased). There were significant associations of the differentially expressed genes with ccRCC metastasis by ROC analysis and the Fisher exact test. The association of the NDUFA4L2, VWF, EGLN3, SAA1, and C1QA expression with ccRCC metastasis is shown for the first time. The CA9, NDUFA4L2, BHLHE4, and EGLN3 were distinguished as the strongest candidates for ccRCC metastasis biomarkers. We used an approach that presupposed that the metastasis marker was the expression levels of any three genes from the selected panel and received sensitivity (88%) and specificity (73%) levels with a relative risk of RR > 3. In conclusion, a panel of selected genes—the candidates in biomarkers of ccRCC metastasis—was created for the first time. The results might shed some light on the ccRCC metastasis processes.
The main mechanisms of pathogenesis of clear cell renal cell carcinoma (CCRCC) are realized through the PI3K-AKT-mTOR and Ras-RAF-ERK signaling pathways. Targeted therapy is directed primarily at the genes and their encoded products that are components of these pathways. The levels of expression and coexpression of target genes were determined, and the difference in the functioning of the genes of one of the two major signaling pathways in tumors of CCRCC patients with different life duration (more and less than 3.5 years) and the relationship of the VEGFA gene expression level with the life duration was revealed.
The VHL gene is often inactivated in sporadic clear cell renal cancer (CCRC) due to somatic mutations, and its germline mutations cause hereditary CCRC: von Hippel-Lindau syndrome. Localization of mutations in VHL, identification of new mutations, and their influence on CCRC progression and sensi tivity to targeted therapy are topical problems in modern oncogenetics. In the current work, we identified and characterized mutations in 248 primary CCRCs using SSCP analysis and sequencing. Somatic mutations were detected in 37.5% of samples, with 72% of mutations identified for the first time. New missense muta tions were analyzed by alignment programs and three dimensional structure modeling. Mutation frequency was compared in different groups of patients with respect to stage, grade, and metastases. It was demonstrated that 39.1% of samples of stage I harbored somatic mutations; however, no association with progression or metastases was found. We also investigated localization of mutations in the VHL coding part and positions of missense mutations and inframe deletions/insertions, focusing on VHL critical sequences. The VHL muta tion analysis performed in this study expands the opportunities of laboratory diagnostics of familial and spo radic CCRC.
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