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

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 clinicalpathological 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 cancerspecific 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,). 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.

High BMP7 expression is associated with poor prognosis in ovarian cancer

“…37 Kubiliute et al reported that the DNA methylated status of the three gene panel of ADAMTS19, BMP7 and SFRP1 was predictive of a poorer overall survival in clear cell renal carcinoma. 38 The relationship between BMP7 expression and overall survival in the current study suggests that BMP7 expression could potentially be used as a prognostic tool in ovarian cancer patients.…”

Preservation of circadian rhythm in hepatocellular cancer

“…These functions are associated with cellular and neoplastic growth, and interestingly, the peak expression times for these genes are different in healthy livers and tumors, as shown in Figure 5 D . Another notable difference is a set of cancer-associated genes that are significantly rhythmic in tumor ( 31 , 32 , 33 , 34 , 35 , 36 , 37 ) only; examples of these are shown in Figure 5 E . For this class of genes rhythmic in tumor only, we were interested to see if protein expression was rhythmic in tumor only.…”

“…Of the genes, “rhythmic in tumor only” were 95 genes classified as “multicellular organism development” or “cell differentiation.” These included genes associated with carcinogenesis such as Aurkb, Wnk2, Wnt11, Wnt7b, Notch3, Sim 1, and Sim2 ( Figs. 5 E and S2 ) ( 31 , 32 , 33 , 34 , 35 , 36 , 37 ). Importantly, the “rhythmic in tumor only” proliferation genes exhibited peak expression times (ZT0 to ZT8) that differed from the peak expression times of “rhythmic in liver only” nucleic acid metabolism genes (predawn and predusk, Fig.…”