Abstract
BackgroundAberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma. However, it is unknown the predictive role of methylation to contralateral new upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). We retrospectively investigated the predictive role of DNA methylation and other clinicopathological factors in the contralateral upper tract urothelial carcinoma (UTUC) recurrence after radical nephroureterectomy (RNU) in a large single-center cohort of patients.MethodsIn a retrospective design, methylation of 10 genes was analyzed on tumor specimens belonging to 664 consecutive patients treated by RNU for primary UTUC. Median follow-up was 48 mo (range: 3–144 mo). Gene methylation was accessed by methylation-sensitive polymerase chain reaction, and we calculated the methylation index (MI), a reflection of the extent of methylation. The log-rank test and Cox regression were used to identify the predictor of contralateral UTUC recurrence.ResultsThirty (4.5%) patients developed a subsequent contralateral UTUC after a median follow-up time of 27.5 (range: 2–139) months. Promoter methylation for at least one gene promoter locus was present in 88.9% of UTUC. Fewer methylation and lower MI (P = 0.001) were seen in the tumors with contralateral UTUC recurrence than the tumors without contralateral recurrence. High MI (P = 0.007) was significantly correlated with poor cancer-specific survival. Multivariate analysis indicated that unmethylated RASSF1A (P = 0.039), lack of bladder recurrence prior to contralateral UTUC (P = 0.009), history of renal transplantation (P < 0.001), and preoperative renal insufficiency (P = 0.002) are independent risk factors for contralateral UTUC recurrence after RNU.ConclusionsOur data suggest a potential role of DNA methylation in predicting contralateral UTUC recurrence after RNU. Such information could help identify patients at high risk of new contralateral UTUC recurrence after RNU who need close surveillance during follow up.
Highlights
Aberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma
156 patients were excluded from the study: 76 for concomitant or previous bladder tumor, 30 for bilateral upper tract urothelial carcinoma (UTUC), 23 for undergoing nephronsparing surgery instead of radical nephroureterectomy (RNU), and 27 for inability to extract DNA as there was only one paraffin specimen stored in our bank. 664 patients were included for evaluation
In multivariate analysis, unmethylated RASSF1A (P = 0.039, Figure 2A), renal transplant history (P < 0.001, Figure 2B), preoperative renal insufficiency (P = 0.002, Figure 2C), and lack of bladder recurrence before the development of contralateral UTUC (P = 0.007, Figure 2D) were found to be independent risk factors of contralateral UTUC recurrence after RNU
Summary
Aberrant methylation of genes is one of the most common epigenetic modifications involved in the development of urothelial carcinoma. It is unknown the predictive role of methylation to contralateral new upper tract urothelial carcinoma (UTUC) after radical nephroureterectomy (RNU). We retrospectively investigated the predictive role of DNA methylation and other clinicopathological factors in the contralateral upper tract urothelial carcinoma (UTUC) recurrence after radical nephroureterectomy (RNU) in a large single-center cohort of patients. A growing body of evidence indicates that aberrant methylation of cytosineguanine dinucleotide (CpG) islands in the DNA promoter regions is one of the most common epigenetic modifications involved in the development of urothelial carcinoma [13,14,15,16,17]. Detecting gene promoter methylation may be a promising method for predicting contralateral UTUC recurrence after surgery
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