Abstract
The inactivation of p16INK4A and p14ARF via promoter methylation has been investigated in various cancers. However, the clinical effects of p16INK4A and p14ARF promoter methylation on renal cell carcinoma (RCC) remain to be clarified. The pooled data were calculated and summarized. Finally, an investigation of 14 eligible studies with 1231 RCC patients and 689 control patients was performed. Methylated p16INK4A and p14ARF were observed to be significantly higher in RCC than in control subjects without malignancies (OR = 2.77, P = 0.005; OR = 11.73, P < 0.001, respectively). Methylated p16INK4A was significantly associated with the risk of RCC in the tissue subgroup, but not in the serum and urine subgroups. Methylated p16INK4A was significantly associated with tumor size. We did not find that p16INK4A promoter methylation was associated with sex, tumor grade, lymph node status, and tumor histology. Methylated p14ARF was significantly correlated with sex and tumor histology. Three studies reported that p16INK4A methylation was not significantly correlated with the prognosis of RCC. The results suggested that p16INK4A and p14ARF promoter methylation may be correlated with the carcinogenesis of RCC, and that methylated p14ARF, especially, can be a major susceptibility gene. We also found the different clinicopathological significance of 16INK4A and p14ARF in RCC. Additional studies with sufficient data are essential to further evaluate the clinical features and prognostic effect of p16INK4A and p14ARF promoter methylation in RCC.
Highlights
Renal cell carcinoma (RCC) is one of the most common cancers of the human urinary system
Of these studies, which involved p16INK4A and p14ARF gene promoter methylation, nine studies evaluated the association between p16INK4A promoter methylation and renal cell carcinoma (RCC) risk, five studies assessed the correlation between p14ARF promoter methylation and RCC risk, ten studies evaluated the relation between p16INK4A promoter methylation and clinicopathological features, and four studies evaluated the relation between p14ARF promoter methylation and clinicopathological features
The p16INK4A is formed from an alternative transcript of exons 1α, 2, and 3, whereas p14ARF is translated from alternative reading frames (ARF) consisting of exons 1β, 2, and 3 [32]
Summary
Renal cell carcinoma (RCC) is one of the most common cancers of the human urinary system. Clear cell renal cell carcinoma (ccRCC) is the most common histological type of RCC, accounting for 70% to 75% of all RCCs [2]. DNA methylation is an important mechanism of epigenetic alterations involved in gene expression, which is closely associated with the carcinogenesis and progression of various carcinomas [7,8,9]. The inactivation of p16INK4A and p14ARF through promoter methylation has been reported in many cancers [15,16,17]. Promoter methylation of p16INK4A and p14ARF has been shown in different sample types of RCC, including blood, urine, and tissue samples [18,19,20,21]
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