Background The RAS association domain family protein 1a gene (RASSF1A) is one of the tumor suppressor genes (TSG). Inactivation of RASSF1A is critical to the pathogenesis of cancer. Aberrant TSG methylation was considered an important epigenetic silencing mechanism in the progression of ovarian cancer. A number of studies have discussed association between RASSF1A promoter methylation and ovarian cancer. However, they were mostly based on a small number of samples and showed inconsist results, Therefore, we conducted a meta-analysis to better identify the association. Methods Eligible studies were identified by searching the PubMed, EMBASE, Web of Science, and CNKI databases using a systematic searching strategy. We pooled the odds ratio (ORs) from individual studies using a fixed-effects model. We performed heterogeneity and publication bias analysis simultaneously. Results Thirteen studies, with 763 ovarian cancer patients and 438 controls were included in the meta-analysis. The frequencies of RASSF1A promoter methylation ranged from 30% to 58% (median is 48%) in the cancer group and 0 to 21% (median is 0) in the control group. The frequencies of RASSF1A promoter methylation in the cancer group were significantly higher than those in the control group. The pooled odds ratio was 11.17 (95% CI = 7.51–16.61) in the cancer group versus the corresponding control group under the fixed-effects model. Conclusion The results suggested that RASSF1A promoter methylation had a strong association with ovarian cancer.
References
[1]
Ozdemir F, Altinisik J, Karateke A, Coksuer H, Buyru N (2012) Methylation of tumor suppressor genes in ovarian cancer. Exp Ther Med 4: 1092–1096.
[2]
Lee JY, Jeong W, Lim W, Lim CH, Bae SM, et al. (2013) Hypermethylation andpost-transcriptional regulation of DNA methyltransferases in the ovarian carcinomas of the laying hen. PLoS One 8: e61658.
[3]
Hall M, Gourley C, McNeish I, Ledermann J, Gore M, et al. (2013) Targeted anti-vascular therapies for ovarian cancer: current evidence. Br J Cancer 108: 250–258.
[4]
Barnholtz-Sloan JS, Schwartz AG, Qureshi F, Jacques S, Malone J, et al. (2003) Ovarian cancer: changes in patterns at diagnosis and relative survival over the last three decades. Am J Obstet Gynecol 189: 1120–1127.
[5]
Hesson LB, Cooper WN, Latif F (2007) The role of RASSF1A methylation in cancer. Dis Markers 23: 73–87.
[6]
Barton CA, Hacker NF, Clark SJ, O’Brien PM (2008) DNA methylation changes in ovarian cancer: implications for early diagnosis, prognosis and treatment. Gynecol Oncol 109: 129–139.
[7]
Bondurant AE, Huang Z, Whitaker RS, Simel LR, Berchuck A, et al. (2011) Quantitative detection of RASSF1A DNA promoter methylation in tumors and serum of patients with serous epithelial ovarian cancer. Gynecol Oncol 123: 581–587.
[8]
Teodoridis JM, Hall J, Marsh S, Kannall HD, Smyth C, et al. (2005) CpG islandmethylation of DNA damage response genes in advanced ovarian cancer. Cancer Res 65: 8961–8967.
[9]
Donninger H, Vos MD, Clark GJ (2007) The RASSF1A tumor suppressor. J Cell Sci 120: 3163–3172.
[10]
Imura M, Yamashita S, Cai LY, Furuta J, Wakabayashi M, et al. (2006) Methylation and expression analysis of 15 genes and three normally-methylated genes in 13 Ovarian cancer cell lines. Cancer Lett 241: 213–220.
[11]
Higgins JP, Thompson SG (2002) Quantifying heterogeneity in a meta-analysis. Stat Med 21: 1539–1558.
[12]
Begg CB, Mazumdar M (1994) Operating characteristics of a rank correlation test for publication bias. Biometrics 50: 1088–1101.
[13]
Egger M, Davey Smith G, Schneider M, Minder C (1997) Bias in meta-analysis detected by a simple, graphical test. BMJ 315: 629–634.
[14]
Robert R (1979) The file drawer problem and tolerance for null results. Psychological bulletin 86: 638–641.
[15]
Jiang WH, Chen BW, Zheng JG, Li WQ, Li J (2011) Application of meta Package of R in the Meta-Analysis. The Journal of Evidence-Based Medicine 11: 305–309.
[16]
Montavon C, Gloss BS, Warton K, Barton CA, Statham AL, et al. (2012) Prognostic and diagnostic significance of DNA methylation patterns in high grade serous ovarian cancer. Gynecol Oncol 124: 582–588.
[17]
Chen DL, Chen SX, Feng J, Zhang CL, Liu YZ, et al. (2010) Detection and clinical significance of RASSF1A gene methylation in epithelial ovarian tumors. Chinese Journal of Cancer 20: 712–714.
[18]
Wu Q, Lothe RA, Ahlquist T, Silins I, Trope CG, et al. (2007) DNA methylation profiling of ovarian carcinomas and their in vitro models identifies HOXA9, HOXB5, SCGB3A1, and CRABP1 as novel targets. Mol Cancer 6: 45.
[19]
Ma L, Zhang JH, Liu FR, Zhang X (2005) Hypermethylation of promoter region of RASSF1A gene in ovarian malignant epithelial tumors. Zhonghua Zhong Liu Za Zhi 27: 657–659.
[20]
Ibanez de Caceres I, Battagli C, Esteller M, Herman JG, Dulaimi E, et al. (2004) Tumor cell-specific BRCA1 and RASSF1A hypermethylation in serum, plasma, and peritoneal fluid from ovarian cancer patients. Cancer Res 64: 6476–6481.
[21]
Yoon JH, Dammann R, Pfeifer GP (2001) Hypermethylation of the CpG island of the RASSF1A gene in ovarian and renal cell carcinomas. Int J Cancer 94: 212–217.
[22]
Ho CM, Huang CJ, Huang CY, Wu YY, Chang SF, et al. (2012) Promoter methylation status of HIN-1 associated with outcomes of ovarian clear cell adenocarcinoma. Mol Cancer 11: 53.
[23]
Bhagat R, Chadaga S, Premalata CS, Ramesh G, Ramesh C, et al. (2012) Aberrant promoter methylation of the RASSF1A and APC genes in epithelial ovarian carcinoma development. Cellular Oncology 35: 473–479.
[24]
He Y, Jin MS, Du DL, Wang CZ (2011) The study of RASSF 1A gene methylationin ovarian cancer and peritoneal washing. Journal of Bengbu Medical College 36: 35–37+41.
[25]
Shen WJ, Dai DQ, Guo KJ, Li XM (2008) RASSF1A and BRCA1 and p16 gene aberrant methylation detection and its clinical significance in epithelial ovarian cancer. Chinese Journal of Cancer Prevention and Treatment 15: 530–533.
[26]
Li QR, Liu PS, Zhang Y (2007) The detection of RASSF1A gene methylation in ovarian cancer tissue and serum and its clinical significance Journal of Shandong University (Medical Sciences): 1046–1049.
[27]
Makarla PB, Saboorian MH, Ashfaq R, Toyooka KO, Toyooka S, et al. (2005) Promoter hypermethylation profile of ovarian epithelial neoplasms. Clin Cancer Res 11: 5365–5369.
[28]
Rathi A, Virmani AK, Schorge JO, Elias KJ, Maruyama R, et al. (2002) Methylation profiles of sporadic ovarian tumors and nonmalignant ovaries from high-risk women. Clin Cancer Res 8: 3324–3331.
[29]
Peters JL, Sutton AJ, Jones DR, Abrams KR, Rushton L (2006) Comparison of two methods to detect publication bias in meta-analysis. JAMA 295: 676–680.
[30]
Agathanggelou A, Cooper WN, Latif F (2005) Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. Cancer Res 65: 3497–3508.
[31]
Pfeifer GP, Dammann R (2005) Methylation of the tumor suppressor gene RASSF1A in human tumors. Biochemistry (Mosc) 70: 576–583.
[32]
Burbee DG, Forgacs E, Zochbauer-Muller S, Shivakumar L, Fong K, et al. (2001) Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. J Natl Cancer Inst 93: 691–699.
[33]
Byun DS, Lee MG, Chae KS, Ryu BG, Chi SG (2001) Frequent epigenetic inactivation of RASSF1A by aberrant promoter hypermethylation in human gastric adenocarcinoma. Cancer Res 61: 7034–7038.
[34]
Kuroki T, Trapasso F, Yendamuri S, Matsuyama A, Alder H, et al. (2003) Allele loss and promoter hypermethylation of VHL, RAR-beta, RASSF1A, and FHIT tumor suppressor genes on chromosome 3 p in esophageal squamous cell carcinoma. Cancer Res 63: 3724–3728.
[35]
Lee MG, Kim HY, Byun DS, Lee SJ, Lee CH, et al. (2001) Frequent epigenetic inactivation of RASSF1A in human bladder carcinoma. Cancer Res 61: 6688–6692.
[36]
Wong N, Li L, Tsang K, Lai PB, To KF, et al. (2002) Frequent loss of chromosome 3p and hypermethylation of RASSF1A in cholangiocarcinoma. J Hepatol 37: 633–639.
[37]
Fraser HB, Lam LL, Neumann SM, Kobor MS (2012) Population-specificity of human DNA methylation. Genome Biol 13: R8.
[38]
Choi YL, Kang SY, Shin YK, Choi JS, Kim SH, et al. (2006) Aberrant hypermethylation of RASSF1A promoter in ovarian borderline tumors and carcinomas. Virchows Arch 448: 331–336.
