In silico DNA methylation analysis identifies potential prognostic biomarkers in type 2 papillary renal cell carcinoma

Autor: Thai H. Ho, Man Yang, Dan Zhou, Ryan A. Hlady, Keith D. Robertson
Jazyk: angličtina
Rok vydání: 2019
Předmět:
0301 basic medicine
gene copy number
Cancer Research
DNA Copy Number Variations
Copy number analysis
Biology
lcsh:RC254-282
03 medical and health sciences
0302 clinical medicine
Biomarkers
Tumor
Humans
Radiology
Nuclear Medicine and imaging
Epigenetics
Copy-number variation
Carcinoma
Renal Cell
Epigenomics
Original Research
Neoplasm Staging
Papillary renal cell carcinomas
epigenetics
Sequence Analysis
RNA
Gene Expression Profiling
Receptor Protein-Tyrosine Kinases
biomarkers
Methylation
DNA Methylation
Prognosis
lcsh:Neoplasms. Tumors. Oncology. Including cancer and carcinogens
Survival Analysis
Kidney Neoplasms
3. Good health
Up-Regulation
Gene Expression Regulation
Neoplastic
030104 developmental biology
Oncology
030220 oncology & carcinogenesis
DNA methylation
Cancer cell
epigenomics
Cancer research
CpG Islands
Cancer Prevention
Cell Adhesion Molecules
Zdroj: Cancer Medicine, Vol 8, Iss 12, Pp 5760-5768 (2019)
Cancer Medicine
ISSN: 2045-7634
Popis: There are currently no effective treatments for advanced‐stage papillary renal cell carcinoma (PRCC). The goal of this study is to define potential DNA methylation‐based markers and treatment targets for advanced‐stage type 2 PRCC. Progressive DNA methylation changes and copy number variation (CNV) from localized to advanced‐stage type 2 PRCC are analyzed by using methylation data generated by TCGA's kidney renal papillary cell carcinoma (TCGA‐KIRP, 450k array) project. Survival analyses are performed for the identified biomarkers and genes with CNV. In addition, expression of the corresponding genes is investigated by RNA‐seq analysis. Progressive methylation changes in several CpGs from localized to advanced‐stage type 2 PRCC are observed. Four CpGs (cg00489401, cg27649239, cg20555674, and cg07196505) in particular are identified as markers for differentiating between localized and advanced‐stage type 2 PRCC. Copy number analysis reveals that copy gain of PTK7 mostly occurs in advanced‐stage type 2 PRCC. Both the four CpG methylation changes and PTK7 copy number gain are associated with patient survival. RNA‐seq analysis demonstrates that PTK7 copy gain leads to higher PTK7 expression relative to tumors without copy number gain. Moreover, PTK7 is significantly upregulated from localized to advanced‐stage type 2 PRCC and is linked to cancer cell invasion. In conclusion, DNA methylation markers that differentiate between localized and advanced‐stage type 2 PRCC may serve as useful markers for disease staging or outcome, while PTK7 copy gain represents a potential treatment target for advanced‐stage type 2 PRCC. Stepwise methylation changes and copy number gain also associate with disease stage in PRCC patients.
In the present study, we identified four DNA methylation markers that distinguished between localized and advanced‐stage type 2 papillary renal cell carcinoma (PRCC) with excellent sensitivity and specificity. Moreover, these four DNA methylation markers may be useful for predicting patient outcome since they were significantly associated with patient survival. Furthermore, copy number analysis revealed that gain of PTK7 occurred most frequently in advanced‐stage tumors, predicted poor survival, and was associated with upregulated PTK7 expression in advanced‐stage disease. This finding strongly suggests that PTK7 represents a potential therapeutic target in advanced‐stage type 2 PRCC.
Databáze: OpenAIRE
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