GATA5 CpG island hypermethylation is an independent predictor for poor clinical outcome in renal cell carcinoma

Abstract

Transcriptional inactivation and CpG island (CGI) methylation of GATA transcription factor family members GATA3 and GATA5 have been reported for a few types of human cancer. Whether high-density CGI methylation of GATA3 or GATA5 is associated with the clinical course of patients with renal cell cancer (RCC) has not been clarified. Quantitative methylation-specific PCR assays were carried out to analyze 25 tumor cell lines including 6 RCC lines and 119 RCC and 87 adjacent normal tissues for the presence of densely methylated sequences. Methylation values were statistically compared with clinicopathological and recurrence-free survival (RFS) data for patients. Comparison of GATA3 and GATA5 methylation in different tumor cell lines revealed a marker-specific methylation characteristic with high and frequent signals for both methylation marks in RCC lines. GATA3 and GATA5 CGI relative methylation levels were found to be strongly associated with the state of metastasis (P=0.003 and P<0.001, respectively) and advanced disease (P=0.024 and P<0.001, respectively). Moreover, an independent decrease in RFS in Cox proportional hazard analysis was found for tumors exhibiting high GATA5 methylation (P<0.001, hazard ratio, 19.3; 95% confidence interval, 4.58–81.6). Epigenetic alterations in GATA family members may be associated with aggressive tumor phenotypes in RCC, and in the case of GATA5, may serve as a new independent molecular marker for aggressiveness and disease progression.

Prognostic DNA Methylation Markers for Renal Cell Carcinoma: A Systematic Review

“…The prognostic value of SCUBE3 was confirmed using data derived from the TCGA KIRC project [29] (Supplementary Table 5 & Figure 4D). In 2012, Peters et al [33] showed that promoter methylation of GATA5 is common in RCC and was associated with shorter progression-free survival (PFS), both in the overall RCC population (HR: 3.48; 95% CI: 1.38-8.83; p = 0.008) future science group www.futuremedicine.com and in the ccRCC subgroup (HR: 4.59; 95% CI: 1.57-13.40; p = 0.005), which was confirmed in an independent patient cohort [34]. Moreover, Ricketts and colleagues confirmed these results using data from the TCGA KIRC project [29] (Supplementary Table 5 & Figure 4E).…”

“…For several other genes statistically significant associations between methylation and patient survival were found, but were only reported in a single study [27,31,39,, and for some other genes null associations were reported [26][27]32,[34][35]39,42,[67][68][69][70] (Figure 3 & Supplementary Table 4).…”

“…Promoter methylation of BNC1 [27,29] and SCUBE3 [29,32] was shown to be associated with poorer OS in two studies. Promoter CpG island methylation of GATA5 [29,[33][34] was associated with poorer prognosis in three studies, although different end points were used. Promoter methylation of LAD1 [31,39] and NEFH [31,40] not only predicted patient survival, but also response to treatment with antiangiogenic agents.…”

Loss of GATA5 expression due to gene promoter methylation induces growth and colony formation of hepatocellular carcinoma cells

“…In conclusion, the results of the present study suggest that GATA4 and GATA5 may have a role in the suppression of HCC development. A previous study revealed that loss of GATA4 and GATA5 expression was due to gene promoter methylation in gastric and ovarian cancer, which was also confirmed in lung cancer, esophageal cancer and pancreatic cancer (14)(15)(16)). In the current study, it was demonstrated that the methylation of GATA4 and GATA5 promoters were in accordance with these previous studies.…”

“…A previous study revealed that GATA4 and GATA5 expression was lost in ovarian and gastric cancer, and demonstrated that chromosomal regions of GATA4 (8p23.1-p22) and GATA5 (20q13.2-q13.3) loci were frequently deleted in various types of human cancer (13). Additional studies identified that loss of GATA4 and GATA5 expression during human neoplastic progression, including that of pancreatic, non-small cell lung, esophageal and renal cancer, was due to promoter methylation (14)(15)(16). Loss of GATA4 and GATA5 expression may also alter the typical expression patterns of numerous downstream gene networks with antineoplastic properties (11).…”