Abstract
BackgroundWilms tumor (WT) is a curable pediatric renal malignancy, but there is a need for new molecular biomarkers to improve relapse risk-directed therapy. Somatic alterations occur at relatively low frequencies whereas epigenetic changes at 11p15 are the most common aberration. We analyzed long interspersed element-1 (LINE-1) methylation levels in the blastemal component of WT and normal kidney samples to explore their prognostic significance.ResultsWT samples presented a hypomethylated pattern at all five CpG sites compared to matched normal kidney samples; therefore, the averaged methylation levels of the five CpG sites were used for further analyses. WT presented a hypomethylation profile (median 65.0%, 47.4–73.2%) compared to normal kidney samples (median 71.8%, 51.5–77.5%; p < 0.0001). No significant associations were found between LINE-1 methylation levels and clinical–pathological characteristics. We observed that LINE-1 methylation levels were lower in tumor samples from patients with relapse (median methylation 60.5%) compared to patients without relapse (median methylation 66.5%; p = 0.0005), and a receiving operating characteristic curve analysis was applied to verify the ability of LINE-1 methylation levels to discriminate WT samples from these patients. Using a cut-off value of 62.71% for LINE-1 methylation levels, the area under the curve was 0.808, with a sensitivity of 76.5% and a specificity of 83.3%. Having identified differences in LINE-1 methylation between WT samples from patients with and without relapse in this cohort, we evaluated other prognostic factors using a logistic regression model. This analysis showed that in risk stratification, LINE-1 methylation level was an independent variable for relapse risk: the lower the methylation levels, the higher the risk of relapse. The logistic regression model indicated a relapse risk increase of 30% per decreased unit of methylation (odds ratio 1.30; 95% confidence interval 1.07–1.57).ConclusionOur results reinforce previous data showing a global hypomethylation profile in WT. LINE-1 methylation levels can be suggested as a marker of relapse after chemotherapy treatment in addition to risk classification, helping to guide new treatment approaches.
Highlights
Wilms tumor (WT) is a curable pediatric renal malignancy, but there is a need for new molecular biomarkers to improve relapse risk-directed therapy
Methylation levels of five CpG sites located in the long interspersed element-1 (LINE-1) sequence were evaluated by pyrosequencing in matched WT blastemal component and renal cortex tissues
WT samples presented a hypomethylated pattern in all five CpG sites compared to matched kidney samples; the averaged methylation levels of the five CpG sites were used for further analyses
Summary
Wilms tumor (WT) is a curable pediatric renal malignancy, but there is a need for new molecular biomarkers to improve relapse risk-directed therapy. Renal tumors represent 5 to 10% of tumors in childhood, with approximately 93% of these being Wilms tumors (WTs) [1]. In Brazil, the annual incidence rate is approximately 9.4 cases per million [2]. WT is highly curable, with a survival rate of 90% [3], a subset of patients present with tumor relapse (15–20%); in these cases, overall survival decreases to 50–60% [4]. Two therapeutic approaches are used to treat WT; both present the same survival and relapse rates, differing only in the classification of risk factors. Pre-treated WTs with predominance of the blastemal component classify the patients as high risk [6]
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