The association between RASSF1A promoter methylation and prostate cancer: evidence from 19 published studies

Abstract

Ras-associated domain family 1A (RASSF1A) is a putative tumor suppressor gene located at 3p21.3, and the epigenetic inactivation of RASSF1A by hypermethylation of CpG islands within the promoter region has been observed in various cancer types, including prostate cancer (PCa). However, results from published studies on the association between RASSF1A promoter methylation and PCa risk are conflicting and inconclusive. Hence, we conducted a meta-analysis of 19 eligible studies with odds ratio (OR) and its corresponding 95% confidence intervals (95% CI) in order to investigate the strength of relationship of RASSF1A promoter methylation with PCa risk and its clinicopathological variables. Overall, the RASSF1A promoter methylation was significantly associated with PCa risk (OR = 9.58, 95% CI 5.64-16.88, P heterogeneity <0.001) and Gleason score (GS) (OR = 2.58, 95% CI 1.64-4.04, P(heterogeneity) = 0.019). In addition, subgroup analysis by testing material demonstrated the significant association between RASSF1A methylation and GS (OR = 3.09, 95% CI 1.92-4.97, P heterogeneity =0.042), PSA level (OR = 2.75, 95% CI 1.67-4.52, P(heterogeneity) = 0.639), and tumor stage (OR = 1.74, 95% CI 1.05-2.87, P(heterogeneity) = 0.026) in tissue rather than urine samples. In conclusion, this meta-analysis suggested that RASSF1A promoter methylation was significantly associated with an increased risk for PCa; furthermore, the RASSF1A methylation status in tissue rather than urine was positively correlated with GS, serum PSA level, and tumor stage, which can be utilized for the early detection and prognosis prediction of PCa.

Disparities in prostate cancer incidence and mortality rates: Solvable or not?

“…The common thread observed in these studies is that more than 90% of these investigations are conducted in MEA. As a result, significant strides have been made in the design of serum and urine diagnostic biomarkers, whereby some are currently clinically applicable as mentioned earlier and these were recently reviewed in Sharma et al Some include (a) the noncoding RNA, PCA3 that is believed to be overexpressed in 95% of PCa cases in MEA, presents in high levels in some men but is unaccompanied by malignancy meanwhile additional studies confirmed an association of this biomarker in Chinese men; b) the kallikrein panel (comprises of total PSA, free PSA, intact PSA and human kallikrein‐related peptidase 2 (KLK2)) was reported to improve the predictive accuracy of PCa detection over PSA alone with a reduction in the biopsy rate by 362 for every 1000 men with elevated PSA and these studies were primarily conducted on MEA; (c) TMPRSS2: ERG fusion & β‐microseminoprotein, identification of the fusion gene in urine was reported to enhance PCa detection by more than 90% specificity and 94% predictive value, a research that began by Tomlins and later a GWAS study reported in Germany and across other ethnicities, confirmed the importance of this biomarker among MEA, conversely, other studies did not reveal the ethnicity of the men investigated although given the geographical locale, it is believed they too are primarily of a European ancestry and (d) DNA methylation of genes, for example a) Glutathione ‐S‐Transferase‐Pi (GSTP1) that is involved in DNA detoxification and cell cycle regulation, to the best of our knowledge no GWAS research has been conducted on this epigenetic biomarker but smaller studies conducted in Germany, Korea, Italy and meta‐analysis on MAA in America, the Caribbean and in Africa have confirmed an association of this protein to an elevated risk of PCa; b) the promoter region of adenomatous polyposis coli (APC) that is involved in cell apoptosis, migration and adhesions have been associated with PCa occurrence among Chinese, Italians, Pakistanis and other ethnicities, furthermore, fairly recent meta‐analysis that covered seven studies (1227 patients for North America and Europe) calculated the pooled hazard ratio to be 1.74 that correlates methylated APC to unfavorable impact on biochemical recurrence of PCa confirming the PCa prognostic potential of this biomarker as well, and; c) the putative tumor suppressor Ras‐associated domain family 1 A (RASSF1A) whereby meta‐analysis conducted on 1123 cases primarily in MEA associated the hypermethylation of CpG islands within the promoter region of these genes to PCa . Research has also demonstrated that PCA3, TMPRSS2:ERG fusion and PTEN among others possess PCa prognostic poten...…”

The epigenetics of prostate cancer diagnosis and prognosis

“…9 A smaller study also using biopsy specimens reported APC methylation predicted either BCR, metastasis and/or death in a multivariate analysis. 10 In a recent meta-analysis of RASSF1A in 19 studies 11 , hypermethylation was associated with Gleason score, PSA level, and tumor stage in tissue and presented evidence for its role in predicting BCR. 12 Other genes with promising earlier data include ABDHD9, 13 PTGS2, 14 EVX1 15 and CDH13.…”

Epigenetic reactivation of RASSF1A by phenethyl isothiocyanate (PEITC) and promotion of apoptosis in LNCaP cells

“…In light of the tumor suppression functions of RASSF1A and the observation that restoring RASSF1A expression in tumor cell lines decreases tumorigenicity, restoring RASSF1A expression and elucidating the mechanism by which hypomethylation occurs have significant implications in the context of preventing tumor growth[22, 26, 28]. Recent meta-analyses have revealed that RASSF1A methylation in tumor tissues was directly correlated with the Gleason Score (GS), serum prostate-specific antigen (PSA) level and tumor stage in PCa, indicating that RASSF1A promoter methylation might be a potential biomarker for prostate cancer prognosis and therapy[29, 30]. Several studies have described the effect of phytochemicals, such as curcumin and mahanine, in reversing RASSF1A promoter hypermethylation and restoring RASSF1A expression in breast cancer and prostate cancer cells[31, 32].…”