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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.

SUBMITTER: Park JS

PROVIDER: S-EPMC7017065 | biostudies-literature | 2020 Jan

REPOSITORIES: biostudies-literature

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

Park Jee Soo JS Pierorazio Phillip M PM Lee Ji Hyun JH Lee Hyo Jung HJ Lim Young Soun YS Jang Won Sik WS Kim Jongchan J Lee Seung Hwan SH Rha Koon Ho KH Cho Nam Hoon NH Ham Won Sik WS

Cancers 20200116 1

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 characte ...[more]

PMID: 31963294

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Project description:Clear cell renal cell carcinoma (ccRCC) is the most common lethal subtype of renal cancer, and changes in tumor metabolism play a key role in its development. Solute carriers (SLCs) are important in the transport of small molecules in humans, and defects in SLC transporters can lead to serious diseases. The expression patterns and prognostic values of SLC family transporters in the development of ccRCC are still unclear. The current study analyzed the expression levels of SLC family members and their correlation with prognosis in ccRCC patients with data from Oncomine, Gene Expression Profiling Interactive Analysis (GEPIA), The Cancer Genome Atlas (TCGA), cBioPortal, the Human Protein Atlas (HPA), the International Cancer Genome Consortium (ICGC), and the Gene Expression Omnibus (GEO). We found that the mRNA expression levels of SLC22A6, SLC22A7, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 were significantly lower in ccRCC tissues than in normal tissues and the protein expression levels of SLC22A6, SLC22A7, SLC22A13, and SLC34A1 were also significantly lower. Except for SLC22A7, the expression levels of SLC22A6, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 were correlated with the clinical stage of ccRCC patients. The lower the expression levels of SLC22A6, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 were, the later the clinical stage of ccRCC patients was. Further experiments revealed that the expression levels of SLC22A6, SLC22A7, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 were significantly associated with overall survival (OS) and disease-free survival (DFS) in ccRCC patients. High SLC22A6, SLC22A7, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 expression predicted improved OS and DFS. Finally, GSE53757 and ICGC were used to revalidate the differential expression and clinical prognostic value. This study suggests that SLC22A6, SLC22A7, SLC22A13, SLC25A4, SLC34A1, and SLC44A4 may be potential targets for the clinical diagnosis, prognosis, and treatment of ccRCC patients.

Project description:PurposeClear cell renal cell carcinoma (ccRCC) is the most common pathology type in kidney cancer. However, the prognosis of advanced ccRCC is unsatisfactory. Thus, early diagnosis becomes one of the most important research priorities of ccRCC. However, currently available studies about ccRCC lack urine-related further studies. In this study, we applied proteomics to search urinary biomarkers to assist early diagnosis of ccRCC. In addition, we constructed a prognostic model to assist judge patients' prognosis.Materials and methodsUrine which was used to perform 4D label-free quantitative proteomics was collected from 12 ccRCC patients and 11 non-tumor patients with no urinary system diseases. The urine of 12 patients with ccRCC confirmed by pathological examination after surgery was collected before operatoin. Bioinformatics analysis was used to describe the urinary proteomics landscape of these patients with ccRCC. The top ten proteins with the highest expression content were selected as the basis for subsequent validation. Urine from 46 ccRCC patients and 45 control patients were collected to use for verification by enzyme linked immunosorbent assay (ELISA). In order to assess the prognostic value of urine proteomics, a prognostic model was constructed by COX regression analysis on the intersection of RNA-sequencing data in The Cancer Genome Atlas (TCGA) database and our urine proteomic data.Results133 proteins differentially expressed in the urinary samples were found and 85 proteins (Fold Change, FC>1.5) were identified up-regulated while 48 down-regulated (FC<0.5). Top 10 proteins including S100A14, PKHD1L1, FABP4, ITIH2, C3, C8G, C2, ATF6, ANGPTL6, F13B were performed ELISA to verify. The results showed that PKHD1L1, ANGPTL6, FABP4 and C3 were statistically significant (P<0.05). We performed multivariate logistic regression analysis and plotted a nomogram. Receiver operating characteristic (ROC) curve indicted that the diagnostic efficiency of combined indicators is satisfactory (Aare under curve, AUC=0.835). Furthermore, the prognostic value of the urine proteomics was explored through the intersection between urine proteomics and TCGA RNA-seq data. Thus, COX regression analysis showed that VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 were statistically significant (P<0.05).ConclusionOur study indicated that the application of urine proteomics to explore diagnostic biomarkers and to construct prognostic models of renal clear cell carcinoma is of certain clinical value. PKHD1L1, ANGPTL6, FABP4 and C3 can assist to diagnose ccRCC. The prognostic model constituted of VSIG4, HLA-DRA, SERPINF1, and IGLV2-23 can significantly predict the prognosis of ccRCC patients, but this still needs more clinical trials to verify.

Dataset Information

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

Publications

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

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