Tumour suppressor gene methylation and renal cell carcinoma risk: a comprehensively systematic review and meta-analysis

Purpose: Renal cell carcinoma (RCC) is becoming more common as a urinary system malignancy. There is a growing body of evidence supporting an important role of DNA methylation alteration involved in the initiation of RCC, but the current findings are inconsistent and controversial. Thus, we performed this systematic review and meta-analysis to comprehensively assess the associations between methylation status of tumour suppressor genes and the incidence risk of RCC. Methods: This study has been registered on PROSPERO (CRD42019130782) and was reported according to the PRISMA guidelines. We systematically searched the PubMed, EMBASE and CNKI databases for relevant studies. The effect estimates were summarized using random-effect models. Results: A total of 21 case-control studies containing 1,912 participants were included. Overall, abnormal hypermethylation of RASSF1A was associated with a significantly increased risk of RCC (OR, 6.612, 95% CI: 1.926-22.697, P = 0.003), especially in the American populations (OR, 18.429, 95% CI: 3.072-110.536, P = 0.001). An increased RCC risk was also associated with hypermethylation of SFRP1 and GSTP1 (OR, 3.995, 95% CI: 1.607-9.934, P = 0.003; OR, 4.508, 95% CI: 1.004-20.239, P = 0.049; respectively); however, the results for SFRP1 and GSTP1 were non-conclusive due to the limited number of studies included and the inconsistency across sensitivity analyses. There was no obvious association for the other genes. Conclusion: This study demonstrated a statistically and robustly positive association of aberrant hypermethylation of RASSF1A with an increased risk of developing RCC, indicating a potentially useful biomarker to predict the RCC incidence risk.