J Korean Med Sci.  2019 May;34(19):e144. 10.3346/jkms.2019.34.e144.

Methylation Signature for Prediction of Progression Free Survival in Surgically Treated Clear Cell Renal Cell Carcinoma

Affiliations
  • 1Department of Urology, Chungbuk National University Hospital, Chungbuk National University College of Medicine, Cheongju, Korea. urokyj@cbnu.ac.kr
  • 2Astellas Pharma Korea, Inc., Seoul, Korea.
  • 3Clinical Genomics Analysis Branch, National Cancer Center, Goyang, Korea.
  • 4Medical Research Institute, School of Medicine, Chungbuk National University, Cheongju, Korea.
  • 5Department of Computer Science, Chungbuk National University, Cheongju, Korea.

Abstract

BACKGROUND
Little is known about epigenetic silencing of genes by promoter hypermethylation in renal cell carcinoma (RCC). The aim of this study was to identify prognostic methylation markers in surgically treated clear cell RCC (ccRCC).
METHODS
Methylation patterns were assayed using the Infinium HumanMethylation450 BeadChip array on pairs of ccRCC and normal tissue from 12 patients. Using quantitative PSQ analysis, tumor-specific hypermethylated genes were validated in 25 independent cohorts and their clinical relevance was also verified in 152 independent cohorts.
RESULTS
Using genome-wide methylation array, Zinc finger protein 278 (ZNF278), Family with sequence similarity 155 member A (FAM155A) and Dipeptidyl peptidase 6 (DPP6) were selected for tumor-specific hypermethylated genes in primary ccRCC. The promoter methylation of these genes occurred more frequently in ccRCC than normal kidney in independent validation cohort. The hypermethylation of three genes were associated with advanced tumor stage and high grade tumor in ccRCC. During median follow-up of 39.2 (interquartile range, 15.4-79.1) months, 22 (14.5%) patients experienced distant metastasis. Multivariate analysis identified the methylation status of these three genes, either alone, or in a combined risk score as an independent predictor of distant metastasis.
CONCLUSION
The promoter methylation of ZNF278, FAM155A and DPP6 genes are associated with aggressive tumor phenotype and early development of distant metastasis in patients with surgically treated ccRCC. These potential methylation markers, either alone, or in combination, could provide novel targets for development of individualized therapeutic and prevention regimens.

Keyword

Renal Cell Carcinoma; Methylation; Progression

MeSH Terms

Carcinoma, Renal Cell*
Cohort Studies
Disease-Free Survival*
Epigenomics
Follow-Up Studies
Humans
Kidney
Methylation*
Multivariate Analysis
Neoplasm Metastasis
Phenotype
Zinc Fingers
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