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The Prognostic Role of RASSF1A Promoter Methylation in Breast Cancer: A Meta-Analysis of Published Data  [PDF]
Yong Jiang, Lin Cui, Wen-de Chen, Shi-hai Shen, Li-dong Ding
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0036780
Abstract: Purpose Epigenetic alterations have been investigated as prognostic indicators in breast cancer but their translation into clinical practice has been impeded by a lack of appropriate validation. We present the results of a meta-analysis of the associations between RASSF1A promoter methylation status and both disease free survival (DFS) and overall survival (OS) in female breast cancer. Methods Eligible studies were identified through searching the PubMed, Web of Science and Embase databases. Studies were pooled and summary hazard ratios (HR) with corresponding confidence intervals (CIs) were calculated. Funnel plots were also carried out to evaluate publication bias. Results A total of 1795 patients from eight studies were included in the meta-analysis. There are eight studies which investigated DFS in 1795 cases. The relative hazard estimates ranged from 1.77–5.64 with a combined HR of 2.75 (95%CI 1.96–3.84). The HR of RASSF1A promoter methylation on DFS adjusted for other potential prognostic factors was 2.54 (95%CI 1.77–3.66). There has been five trials which analyzed the associations of RASSF1A promoter methylation status with OS in 1439 patients. The hazard estimates ranged from 1.21–6.90 with a combined random-effects estimates of 3.47 (95%CI 1.44–8.34). OS reported in multivariate analysis was evaluated in four series comprising 1346 cases and the summarized random-effects HR estimate was 3.35 (95%CI 1.14–9.85). Additionally, no publication bias was detected for both OS and DFS. Conclusion The results of this meta-analysis suggest that RASSF1A promoter hypermethylation confers a higher risk of relapse and a worse survival in patients with breast cancer. Large prospective studies are now needed to establish the clinical utility of RASSF1A promoter methylation.
Association between RASSF1A Promoter Methylation and Prostate Cancer: A Systematic Review and Meta-Analysis  [PDF]
Jincheng Pan, Junxing Chen, Bo Zhang, Xu Chen, Bin Huang, Jintao Zhuang, Chengqiang Mo, Shaopeng Qiu
PLOS ONE , 2013, DOI: 10.1371/journal.pone.0075283
Abstract: Prostate cancer (PCa) remains as one of the most common cause of cancer related death among men in the US. The widely used prostate specific antigen (PSA) screening is limited by low specificity. The diagnostic value of other biomarkers such as RAS association domain family protein 1 A (RASSF1A) promoter methylation in prostate cancer and the relationship between RASSF1A methylation and pathological features or tumor stage remains to be established. Therefore, a meta-analysis of published studies was performed to understand the association between RASSF1A methylation and prostate cancer. In total, 16 studies involving 1431 cases and 565 controls were pooled with a random effect model in this investigation. The odds ratio (OR) of RASSF1A methylation in PCa case, compared to controls, was 14.73 with 95% CI = 7.58–28.61. Stratified analyses consistently showed a similar risk across different sample types and, methylation detection methods. In addition, RASSF1A methylation was associated with high Gleason score OR=2.35, 95% CI: 1.56–3.53. Furthermore, the pooled specificity for all included studies was 0.87 (95% CI: 0.72–0.94), and the pooled sensitivity was 0.76 (95% CI: 0.55–0.89). The specificity in each subgroup stratified by sample type remained above 0.84 and the sensitivity also remained above 0.60. These results suggested that RASSF1A promoter methylation would be a potential biomarker in PCa diagnosis and therapy.
Meta-analysis of the Association between RASSF1A Gene ?Promoter Methylation and Non-small Cell Lung Cancer  [PDF]
Huijun WEI, Nianzhen FANG, Lili GUO, Zhihao WU, Qinghua ZHOU
- , 2015, DOI: : 10.3779/j.issn.1009-3419.2015.07.09
Abstract: Background and objective The CpG island aberrant promoter methylation in the tumor suppressor gene region plays an important role in the process of tumorigenesis. Relevant evidence shows that the promoter methylation of RAS association domain family 1A (RASSF1A) gene, a tumor suppressor gene, has a close relationship with non-small cell lung cancer (NSCLC) development; therefore, RASSF1A may be a potential NSCLC biomarker. This paper discussed and summarized the relationship between RASSF1A gene promoter methylation frequency and NSCLC through meta-analysis. Methods By searching Medline, EMBASE, CNKI, and Wanfang database, we selected and collected the published articles regarding RASSF1A gene promoter methylation and NSCLC risk according to the marked inclusion and exclusion criteria. Through meta-analysis, combined odds ratio (OR) and 95% confidence interval (CI) data were used to analyze the RASSF1A gene promoter methylation and NSCLC relationship. Results A total of 23 articles were utilized in this study. Results indicated that the RASSF1A gene promoter methylation rate was 41.50% (95%CI: 34%-49%) in NSCLC tissue and was 5.58% (95%CI: 2%-9%) for the control group. Compared with normal lung tissue, RASSF1A methylation frequency in tumor tissue was significantly higher than that of the control group (OR=8.72, 95%CI: 4.88-15.58, P<0.05). Subgroup analysis showed that the RASSF1A gene promoter methylation rate of tumor tissue was higher than that of plasma group (OR=10.99, 95%CI: 2.48-48.68) and normal control tissue group (OR=8.74, 95%CI: 4.39-17.41). Conclusion The rate of RASSF1A promoter gene methylation in NSCLC patient tissue samples was higher than that of normal lung samples, whereas the rate of RASSF1A promoter gene methylation in the tissue has more significant effect on lung cancer occurrence. This finding indicates that RASSF1A gene promoter methylation could be used as an NSCLC biomarker and was involved in NSCLC carcinogenic effects.
The Association of RAS Association Domain Family Protein1A (RASSF1A) Methylation States and Bladder Cancer Risk: A Systematic Review and Meta-Analysis  [PDF]
Tianyi Gao, Shukui Wang, Bangshun He, Yuqin Pan, Guoqi Song, Ling Gu, Liping Chen, Zhenling Nie, Yeqiong Xu, Rui Li
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0048300
Abstract: RAS association domain family protein 1a (RASSF1A) is a putative tumor suppressor gene located on 3p21, has been regarded playing important roles in the regulation of different types of human tumors. Previous reports demonstrated that the frequency of RASSF1A methylation was significantly higher in patients group compared with controls, but the relationship between RASSF1A promoter methylation and pathological features or the tumor grade of bladder cancer remains controversial. Therefore, A meta-analysis of published studies investigating the effects of RASSF1A methylation status in bladder cancer occurrence and association with both pTNM (p, pathologic stage; T, tumor size; N, node status; M, metastatic status) and tumor grade in bladder cancer was performed in the study. A total of 10 eligible studies involving 543 cases and 217 controls were included in the pooled analyses. Under the fixed-effects model, the OR of RASSF1A methylation in bladder cancer patients, compared to non-cancer controls, was 8. 40 with 95%CI = 4. 96–14. 23. The pooled OR with the random-effects model of pTNM and tumor grade in RASSF1A methylated patients, compared to unmethylated patients, was 0. 75 (95%CI = 0. 28–1. 99) and 0. 39 (95%CI = 0. 14–1. 09). This study showed that RASSF1A methylation appears to be an independent prognostic factor for bladder cancer. The present findings also require confirmation through adequately designed prospective studies.
RASSF1A and the Taxol Response in Ovarian Cancer  [PDF]
Susannah Kassler,Howard Donninger,Michael J. Birrer,Geoffrey J. Clark
Molecular Biology International , 2012, DOI: 10.1155/2012/263267
Abstract: The RASSF1A tumor suppressor gene is frequently inactivated by promoter methylation in human tumors. The RASSF1A protein forms an endogenous complex with tubulin and promotes the stabilization of microtubules. Loss of RASSF1A expression sensitizes cells to microtubule destabilizing stimuli. We have observed a strong correlation between the loss of RASSF1A expression and the development of Taxol resistance in primary ovarian cancer samples. Thus, we sought to determine if RASSF1A levels could dictate the response to Taxol and whether an epigenetic therapy approach might be able to reverse the Taxol resistant phenotype of RASSF1A negative ovarian tumor cells. We found that knocking down RASSF1A expression in an ovarian cancer cell line inhibited Taxol-mediated apoptosis and promoted cell survival during Taxol treatment. Moreover, using a combination of small molecule inhibitors of DNA Methyl Transferase enzymes, we were able restore RASSF1A expression and Taxol sensitivity. This identifies a role for RASSF1A in modulating the tumor response to Taxol and provides proof of principal for the use of epigenetic therapy to overcome Taxol resistance. 1. Introduction RASSF1A is a poorly understood tumor suppressor that can modulate the cell cycle, tubulin dynamics and apoptosis [1–3]. It is subjected to epigenetic inactivation at high frequency in a broad range of human tumors, including approximately 50% of ovarian tumors [1, 4, 5]. Overexpression of RASSF1A promotes hyperstabilization of microtubules reminiscent of Taxol [6, 7], and previous investigations have shown that loss of RASSF1A sensitizes cells to microtubule destabilizing drugs such as nocodazole [7]. Thus, RASSF1A appears to play an important role in modulating microtubule stabilization. This implies that the RASSF1A levels in a tumor cell may impact how the cell responds to Taxol treatment. The development of resistance to Taxol remains a serious problem in the treatment of ovarian cancer. The most frequent mechanism by which RASSF1A is inactivated in tumors is by hypermethylation promoter leading to transcriptional silencing [1, 4, 5]. Thus, the gene remains intact, just dormant. Over recent years, a series of small molecules have been identified that can inhibit the DNA methylation system and restore expression of genes that have suffered aberrant promoter methylation [8]. This has given rise to the concept of epigenetic therapy, whereby a tumor would be treated with drugs to restore the expression and function of RASSF1A or some other epigenetically inactivated target. If RASSF1A plays a key
Tumor Suppressor RASSF1A Promoter: p53 Binding and Methylation  [PDF]
Yihao Tian,Yu Hou,Xiang Zhou,Hanhua Cheng,Rongjia Zhou
PLOS ONE , 2012, DOI: 10.1371/journal.pone.0017017
Abstract: Oncogenes and tumor suppressors work in concert to regulate cell growth or death, which is a pair of antagonist factors for regulation of tumorigenesis. Here we show promoter characteristic of tumor suppressor RASSF1A, which revealed a p53 binding site in the distal and a GC-rich region in the proximal promoter region of RASSF1A, in despite of TATA box-less. The GC-rich region, which is ~300 bp upstream from the RASSF1A ATG, showed the strongest promoter activity in an assay of RASSF1A-driving GFP expression. Methylation analysis of the CpG island showed that 78.57% of the GC sties were methylated in testis tumor samples compared with methylation-less in normal testis. Hypermethylation of the GC-rich region is associated with RASSF1A silencing in human testis tumors. In addition, electrophoretic mobility shift assay indicated that p53 protein bound to the RASSF1A promoter. Further chromatin immunoprecipitation confirmed p53 binding to the RASSF1A. Moreover, p53 binding to the promoter down-regulated RASSF1A expression. These results suggest that p53 protein specifically binds to the RASSF1A promoter and inhibits its expression. Our results provide new insight into the mechanism of action of tumor suppressors and may be a starting point for development of new approaches to cancer treatment.
Promoter Methylation status of HIN-1 associated with outcomes of ovarian clear cell adenocarcinoma  [cached]
Ho Chih-Ming,Huang Chi-Jung,Huang Chia-Yen,Wu Yih-Yiing
Molecular Cancer , 2012, DOI: 10.1186/1476-4598-11-53
Abstract: Background This study is to analyze promoter methylation of various tumor suppressor genes in different types of ovarian carcinoma and to identify potential therapeutic targets of ovarian clear cell adenocarcinoma (OCCA). Materials and methods The promoter methylation statuses of 40 genes in primary ovarian carcinomas including 47 clear- and 63 non-clear-cell type tissues, 6 OCCA cell lines, 29 benign ovarian endometriotic cysts, and 31 normal controls were analyzed by methylation-specific multiplex ligation-dependent probe amplification (MS-MLPA). The MS-MLPA results were correlated with clinicopathological features and outcomes of 47 OCCA patients. Functions of the target genes were further explored by Western Blot Analysis, apoptosis assay, and caspase-3/7 activity analysis. Results Frequencies of methylated RASSF1A, CDH13, CACNA1A, HIN-1, and sFRP5 genes in OCCA tissues were significantly higher than those in non-OCCA cancerous tissues and benign endometriotic cysts. The expected OS for patients with methylated promoters of HIN-1 was significantly worse than those for patients without methylated HIN-1 (30% vs. 62%, p = 0.002). The HIN-1 gene was over-expressed in ES2 cells, a significant reduction in cell growth and induction of apoptosis, and increasing paclitaxel sensitivity by reducing phosphorylation of Akt were observed. Conclusions Methylation of HIN-1 promoter is a novel epigenetic biomarker associated with poor outcomes in OCCA patients. Ectopic expression of the HIN-1 gene increased paclitaxel sensitivity which is partly through Akt pathway.
Association of diminished expression of RASSF1A with promoter methylation in primary gastric cancer from patients of central China
Mei Ye, Bing Xia, Qiusha Guo, Feng Zhou, Xiaolian Zhang
BMC Cancer , 2007, DOI: 10.1186/1471-2407-7-120
Abstract: Fifty-four patients with primary gastric cancers were included in the study of RASSF1A mRNA expression and methylation status between the cancer tissue and the corresponding adjacent normal tissue. 20 out of 54 patients were included for study of RASSF1A protein expression. The expression of RASSF1A at mRNA and protein levels was determined by RT-PCR and Western-blotting, respectively. The RASSF1A promoter methylation was detected by methylation-specific PCR.RASSF1A mRNA and protein expressions in GC were reduced significantly with comparison to the corresponding normal tissues (OD value: 0.2589 ± 0.2407 vs 0.5448 ± 0.2971, P < 0.0001; 0.1874 ± 0.0737 vs 0.6654 ± 0.2201, P < 0.0001, respectively). Methylation frequency of RASSF1A in primary GC is higher than that in the corresponding normal tissues (66.7% vs. 14.8%, P < 0.0001). Furthermore, RASSF1A mRNA expression in methylation group of GC was further reduced when compared to the unmethylation group of GC (0.1384 ± 0.1142 vs. 0.5018 ± 0.2463, P < 0.0001).Expression of RASSF1A was reduced in tissue of GC at mRNA and protein levels. Diminished expression of RASSF1A was associated with the promoter methylation.Gastric cancer (GC) is one of the most common malignancies in gastrointestinal diseases. Although incidence of GC is declining in the developed counties, it is still a leading cause of death from cancers in most developing countries. Both genetic and environmental factors including H. pylori infection have been considered to contribute to the development of GC. Recently, several studies have shown that silence of tumor suppressor genes by epigenetic modification is a fundamental mechanism for inactivation of cancer-related genes in the pathogenesis of human cancer [1]. Of the particular note is the fact that promoter hypermethylation plays an essential role in the loss of function of tumor suppressor genes.Allelic loss at chromosome 3p21.3 is one of the most frequent genetic changes in various types of human ca
Combined RASSF1A and RASSF2A Promoter Methylation Analysis as Diagnostic Biomarker for Bladder Cancer  [PDF]
Wei Meng,Alexander Huebner,Ahmad Shabsigh,Arnab Chakravarti,Tim Lautenschlaeger
Molecular Biology International , 2012, DOI: 10.1155/2012/701814
Abstract: Promoter hypermethylation, a widely studied epigenetic event known to influence gene expression levels, has been proposed as a potential biomarker in multiple types of cancer. Clinical diagnostic biomarkers are needed for reliable prediction of bladder cancer recurrence. In this paper, DNA promoter methylation of five C-terminal Ras-association family members (RASSF1A, RASSF2A, RASSF4, RASSF5, and RASSF6) was studied in 64 formalin-fixed paraffin-embedded (FFPE) bladder cancer and normal adjacent tissues using methylation-specific high-resolution melting (MS-HRM) analysis. Results showed that 73% (30/41) of transitional cell carcinoma, 100% (3/3) of squamous cell carcinoma, and 100% (4/4) of small cell carcinoma demonstrated promoter methylation of the RASSF1A or RASSF2A gene, but only 6% (1/16) of normal tissues had promoter methylation of RASSF genes. Testing positive for hypermethylation of RASSF1A or RASSF2A promoter provided 77% sensitivity and 94% specificity for identification of cancer tissues with an area under the curve of 0.854, suggesting that promoter methylation analysis of RASSF1A and RASSF2A genes has potential for use as a recurrence biomarker for bladder cancer patients. 1. Introduction In 2011, about 52,000 men and 17,000 women will be diagnosed with bladder cancer in the United States. Before a normal cell transforms into a bladder cancer cell, a series of molecular alterations are accumulated to initiate the process of transformation. Although we do not fully understand the mechanisms, DNA alterations including hypermethylation and somatic mutation are commonly observed events in human cancer. In a recent bladder cancer study FGFR3 mutation in combination with APC, RASSF1A, and SFRP2 methylation markers provided a sensitivity of 90% using tissue samples and 62% using paired urine samples to identify the presence of cancer with 100% specificity [1]. In nonsmall cell lung cancer (NSCLC) and breast cancer, studies showed that RASSF1A had different frequencies of methylation depending on histology [2, 3]. In nasopharyngeal carcinoma, RASSF2A was frequently inactivated by its promoter methylation and the methylation correlated with lymph node metastasis [4]. The Ras-association family, also called RASSF tumor suppressor genes, currently includes 10 members. All of the RASSF proteins contain a Ras-association domain on their C-terminus (RASSF 1–6) or N-terminus (RASSF 7–10). Two important issues that are not previously addressed by studies of RASSF gene methylation are (1) whether all of the RASSF family members show aberrant methylation
RASSF1A promoter methylation and expression analysis in normal and neoplastic kidney indicates a role in early tumorigenesis
Inga Peters, Kristina Rehmet, Nadine Wilke, Markus A Kuczyk, J?rg Hennenlotter, Tyark Eilers, Stefan Machtens, Udo Jonas, Jürgen Serth
Molecular Cancer , 2007, DOI: 10.1186/1476-4598-6-49
Abstract: Using combined bisulfite restriction analysis (COBRA) we compared RASSF1A methylation in 90 paired tissue samples obtained from primary kidney tumors and corresponding normal tissue. Bisulfite sequence analysis was carried out using both pooled amplicons from the tumor and normal tissue groups and subclones obtained from a single tissue pair. Expression of RASSF1A was analyzed by the use of tissue arrays and immunohistochemistry. We found significantly increased methylation in tumor samples (mean methylation, 20%) compared to corresponding normal tissues (mean methylation, 11%; P < 0.001). Densely methylated sequences were found both in pooled and individual sequences of normal tissue. Immunohistochemical analysis revealed a significant reduced expression of RASSF1A in most of the tumor samples. Heterogeneous expression patterns of RASSF1A were detected in a subgroup of histologically normal tubular epithelia.Our methylation and expression data support the hypothesis that RASSF1A is involved in early tumorigenesis of renal cell carcinoma.Renal cell carcinoma (RCC) accounts for 2–3% of human malignancies and is the seventh most frequent cause of tumor-dependent death among men [1,2]. The most common histological subtypes of sporadic kidney tumors are clear cell RCC (CC-RCC) and papillary tumors [3].Tumorigenesis of CC-RCC is frequently associated with loss and/or alteration of the short arm of chromosome 3 [4]. At least two tumor suppressors are localized on 3p21-3p25, the von Hippel-Lindau (VHL) and the RAS association domain family 1A (RASSF1A) genes, both found to be altered in sporadic RCC. Chromosomal alterations, point mutations and epigenetic silencing have been described to affect VHL function [5-7], while RASSF1A has frequently been detected to undergo promoter hypermethylation and epigenetic silencing in CC-RCC [8-11].RASSF1A is functionally involved in cell cycle control, microtubule stabilization, cellular adhesion and motility as well as apoptosis (revie
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