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Abstract
Clear-cell renal cell carcinoma (ccRCC) is a common aggressive urinary malignant tumor that cannot be easily diagnosed at an early stage. The DNA methylation occurs within promoter before precancerous lesion plays a pivotal role that could help us in diagnosing and understanding ccRCC. In this study, based on a whole-genome promoter DNA methylation profiling, we used shrunken centroids classifier method to identify a CpG-based biomarker that is capable of differentiating between ccRCC tumor and adjacent tissues. The biomarker was validated in 19 ccRCCs and three public datasets. We found that both CYP4B1 and RAB25 are downregulated with promoter hypermethylation and CA9 is upregulated with promoter hypomethylation, and we validated their mRNA differential expressions in 19 ccRCCs and 10 GEO datasets. We further confirmed that hypermethylated RAB25 is inversely correlated with its mRNA level. Log-rank test showed that ccRCC patients with low levels of CA9 promoter methylation had a higher survival rate. This reveals clinically a potential biomarker for use in early detection for ccRCC, and provides a better understanding of carcinogenesis.
Highlights
Renal cell carcinoma (RCC) has the highest mortality rate among urinary malignant tumors, and it represents 2–3% of human malignant neoplasms[1,2]
From our The Cancer Genome Atlas data (TCGA) data analysis, we found that in Clear-cell renal cell carcinoma (ccRCC) samples, RAB25 (Delta Beta = 0.202, Methylation FDR = 1.080E-56, mRNA FDR = 1.180E-38, log[2] FC = −3.505) and CYP4B1 (Delta Beta = 0.314, Methylation FDR = 1.600E-48, mRNA FDR = 4.070E-05, log[2] FC = −1.836) are both downregulated with promoter hypermethylations and CA9 is upregulated with promoter hypomethylation (Delta Beta = 0.220, Methylation FDR = 6.790E-61, mRNA FDR = 2.350E-211, log[2] FC = 5.836)
We found that RAB25 was downregulated (P = 0.400E-3) and CA9 was upregulated (P = 1.600E-2) in ccRCC tissues, but no differential expression was detected in CYP4B1 (P = 0.856) (Fig. 3A)
Summary
Renal cell carcinoma (RCC) has the highest mortality rate among urinary malignant tumors, and it represents 2–3% of human malignant neoplasms[1,2]. One third of RCC cases are asymptomatic at early stages and are already metastatic when diagnosed, which leads to a 95% mortality rate[3] Conventional diagnostic methods such as imaging studies and ultrasound or computed tomography-guided biopsies have a limited reliability in distinguishing RCC in early stages[4], there is a strong need to identify ccRCC biomarkers for early tumorigenesis. DNA methylation alters biological functions through regulating the stabilization of genomic sequences or the expressions of genes[10]. It can restrain transcription factor bindings, alter chromatin structures, and prevent transcription factors to access gene promoters[11]. Our results provide new information about aberrant DNA methylation within the promoters of ccRCC and suggest a potential diagnostic biomarker for the disease
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