Clinical Significance of ADAMTS19, BMP7, SIM1, and SFRP1 Promoter Methylation in Renal Clear Cell Carcinoma

Raimonda Kubiliute; Algirdas Zalimas; Arnas Bakavicius; Albertas Ulys; Feliksas Jankevicius; Sonata Jarmalaite

doi:10.2147/OTT.S330341

Clinical Significance of ADAMTS19, BMP7, SIM1, and SFRP1 Promoter Methylation in Renal Clear Cell Carcinoma

Onco Targets Ther. 2021 Oct 5:14:4979-4990. doi: 10.2147/OTT.S330341. eCollection 2021.

Authors

Raimonda Kubiliute^{1

2}, Algirdas Zalimas^{1

2}, Arnas Bakavicius^{2

3

4}, Albertas Ulys², Feliksas Jankevicius^{3

4}, Sonata Jarmalaite^{1

2}

Affiliations

¹ Institute of Biosciences, Life Sciences Center, Vilnius University, Vilnius, Lithuania.
² National Cancer Institute, Vilnius, Lithuania.
³ Vilnius University Hospital Santaros Klinikos, Vilnius, Lithuania.
⁴ Institute of Clinical Medicine, Faculty of Medicine, Vilnius University, Vilnius, Lithuania.

Abstract

Background: Clear cell renal cell carcinoma (ccRCC) is the most common subtype of kidney tumors, accounting for the majority of deaths from genitourinary cancers. The currently used nomograms for predicting patient outcomes are based on clinical-pathological characteristics only; however, a significant number of ccRCC survivors with similar radiological and histological features still demonstrate a different clinical course of the disease. This study aimed at the identification of novel DNA methylation biomarkers for the monitoring of patients with ccRCC.

Methods: Gene expression profiling by SurePrint G3 Human GE 8×60K Microarrays was performed in 4 ccRCC tissues and adjacent non-cancerous renal tissue (NRT) samples. Four down-regulated genes were selected for further DNA methylation status analysis in 123 ccRCC and 45 NRT samples using methylation-specific PCR (MSP).

Results: DNA methylation changes of ADAMTS19, BMP7, SIM1, and SFRP1 were cancer-specific with significantly (P<0.050) higher methylation frequency (37%, 20%, 18%, and 42%, respectively) in tumor tissues. The methylated status of at least one gene was significantly related to various clinical-pathological parameters, including tumor size, Fuhrman and WHO/ISUP grades, intravascular invasion, and necrosis. Moreover, the methylated status of multimarker panel ADAMTS19, BMP7 & SFRP1 was predictive for poorer overall survival (HR, 4.11; 95% CI, 1.22-13.86).

Conclusion: In conclusion, DNA methylation of the three-gene panel consisting of ADAMTS19, BMP7 & SFRP1 supposedly predicts the outcome of patients diagnosed with ccRCC and possibly might be used to enrich the current prognostic tools.

Keywords: DNA methylation; clear cell renal cell carcinoma; prognostic biomarkers.

Grants and funding

This work was funded by the 2014–2020 European Union Structural Funds according to the activity “Intelligence. Joint science-business projects” grant No. J05-LVPA-K-04-0029. The study was also partially supported by the Research Council of Lithuania (RCL) grant No. S-MIP-17/54.