Associations Between RASSF1A Promoter Methylation and NSCLC: A Meta-analysis of Published Data

Background: RASSF1A has been reported to be a candidate tumor suppressor in non-small cell lung cancer (NSCLC). However, the association between RASSF1A promoter methylation and NSCLC remains unclear, particularly in regarding links to clinicopathologic features. Methods: Eligible studies were identified through searching PubMed, EMBASE, Cochrane Library and China National Knowledge Infrastructure (CNKI) databases. Studies were pooled and odds ratios (ORs) with corresponding confidence intervals (CIs) were calculated. Funnel plots were also performed to evaluate publication bias. Results: Nineteen studies involving 2,063 cases of NSCLC and 1,184 controls were included in this meta-analysis. A significant association was observed between RASSF1A methylation and NSCLC in the complete data set (OR = 19.42, 95% CI: 14.0426.85, P < 0.001). Pooling the control tissue subgroups (heterogeneous/autologous) gave pooled ORs of 32.4 (95% CI, 12.4-84.5) and 17.7 (95% CI, 12.5-25.0) respectively. Racial subgroup (Caucasian/Asian) analysis gave pooled ORs of 26.6 (95% CI, 10.9-64.9) and 20.9 (95% CI, 14.4-30.4) respectively. The OR for RASSF1A methylation in poorly-differentiated vs. moderately/well-differentiated NSCLC tissues was 1.88 (95% CI, 1.322.68, P<0.001), whereas there were no significant differences in RASSF1A methylation in relation to gender, pathology, TNM stage and smoking behavior among NSCLC cases. Conclusion: This meta-analysis suggests a significant association between RASSF1A methylation and NSCLC, confirming the role of RASSF1A as a tumor suppressor gene. Large-scale and well-designed case-control studies are needed to validate the associations identified in the present meta-analysis.

[1]  A. Samadani,et al.  DNA Methylation and Cancer Development: Molecular Mechanism , 2013, Cell Biochemistry and Biophysics.

[2]  H. Nelson,et al.  Aberrant promoter methylation of CDH13 and MGMT genes is associated with clinicopathologic characteristics of primary non-small-cell lung carcinoma. , 2012, Clinical lung cancer.

[3]  Pei Jiang,et al.  Methylation of the RASSF1A and RARβ genes as a candidate biomarker for lung cancer. , 2012, Experimental and therapeutic medicine.

[4]  Hui Zhou,et al.  Values of promoter hypermethylation of FHIT, p16, MGMT and RASSF1A genes in plasma in the diagnosis of lung cancer , 2011 .

[5]  Yun Zheng,et al.  Methylation of multiple genes as a candidate biomarker in non-small cell lung cancer. , 2011, Cancer letters.

[6]  Long-Bang Chen,et al.  染色体3p区抑癌基因在非小细胞肺癌中的甲基化状况与临床意义 , 2011, Zhongguo fei ai za zhi = Chinese journal of lung cancer.

[7]  Jun Wang,et al.  The prognostic value of RASSF1A promoter hypermethylation in non-small cell lung carcinoma: a systematic review and meta-analysis. , 2011, Carcinogenesis.

[8]  Shucai Zhang,et al.  RASSF1A基因甲基化与非小细胞肺癌预后的相关性研究 , 2010, Zhongguo fei ai za zhi = Chinese journal of lung cancer.

[9]  Changting Shan,et al.  [Value of promoter methylation of RASSF1A, p16, and DAPK genes in induced sputum in diagnosing lung cancers]. , 2010, Zhong nan da xue xue bao. Yi xue ban = Journal of Central South University. Medical sciences.

[10]  Jingde Zhu,et al.  RASSF1A, APC, ESR1, ABCB1 and HOXC9, but not p16INK4A, DAPK1, PTEN and MT1G genes were frequently methylated in the stage I non-small cell lung cancer in China , 2009, Journal of Cancer Research and Clinical Oncology.

[11]  Dong Sun Kim,et al.  Aberrant methylation of ADAMTS1 in non-small cell lung cancer. , 2008, Cancer genetics and cytogenetics.

[12]  T. Alonzo,et al.  Molecular Cancer BioMed Central Review , 2007 .

[13]  Hongyu Liu,et al.  CpG island methylator phenotype involving tumor suppressor genes located on chromosome 3p in non-small cell lung cancer. , 2008, Lung cancer.

[14]  Chein-Hui Hung,et al.  Characterization of a multiple epigenetic marker panel for lung cancer detection and risk assessment in plasma , 2007, Cancer.

[15]  C. H. Kim,et al.  Aberrant DNA methylation profiles of non-small cell lung cancers in a korean population , 2007 .

[16]  Gen Tamura,et al.  Promoter hypermethylation of RASSF1A and RUNX3 genes as an independent prognostic prediction marker in surgically resected non-small cell lung cancers. , 2007, Lung cancer.

[17]  L. Hesson,et al.  The Role of RASSF1A Methylation in Cancer , 2007, Disease markers.

[18]  Miki Ohira,et al.  Aberrant methylation of RASGRF2 and RASSF1A in human non-small cell lung cancer. , 2006, Oncology reports.

[19]  S. Baylin,et al.  DNA methylation and gene silencing in cancer , 2005, Nature Clinical Practice Oncology.

[20]  G. Ito,et al.  Frequent inactivation of RASSF1A, BLU, and SEMA3B on 3p21.3 by promoter hypermethylation and allele loss in non-small cell lung cancer. , 2005, Cancer letters.

[21]  Hojoong Kim,et al.  RASSF1A is not appropriate as an early detection marker or a prognostic marker for non‐small cell lung cancer , 2005, International journal of cancer.

[22]  S. Burdach,et al.  CpG island methylation and expression of tumour-associated genes in lung carcinoma. , 2005, European journal of cancer.

[23]  F. Latif,et al.  Role of the Ras-association domain family 1 tumor suppressor gene in human cancers. , 2005, Cancer research.

[24]  Diane D. Liu,et al.  Value of p16INK4a and RASSF1A Promoter Hypermethylation in Prognosis of Patients with Resectable Non–Small Cell Lung Cancer , 2004, Clinical Cancer Research.

[25]  J. Herman,et al.  Promoter Hypermethylation of Resected Bronchial Margins , 2004, Clinical Cancer Research.

[26]  T. Motoyama,et al.  Promoter hypermethylation of tumor suppressor and tumor‐related genes in non‐small cell lung cancers , 2003, Cancer science.

[27]  A. Chan,et al.  Hypermethylation of the tumor suppressor gene RASSFIA and frequent concomitant loss of heterozygosity at 3p21 in cervical cancers , 2003, International journal of cancer.

[28]  A. Chan,et al.  Frequent hypermethylation of promoter region of RASSF1A in tumor tissues and voided urine of urinary bladder cancer patients , 2003, International journal of cancer.

[29]  J. Minna,et al.  Smoke exposure, histologic type and geography‐related differences in the methylation profiles of non‐small cell lung cancer , 2003, International journal of cancer.

[30]  Jun Yu,et al.  Promoter hypermethylation of tumor‐related genes in gastric intestinal metaplasia of patients with and without gastric cancer , 2002, International journal of cancer.

[31]  J. Minna,et al.  The RASSF1A Tumor Suppressor Blocks Cell Cycle Progression and Inhibits Cyclin D1 Accumulation , 2002, Molecular and Cellular Biology.

[32]  J. Minna,et al.  Epigenetic inactivation of RASSF1A in lung and breast cancers and malignant phenotype suppression. , 2001, Journal of the National Cancer Institute.

[33]  Chun Xing Li,et al.  Epigenetic inactivation of a RAS association domain family protein from the lung tumour suppressor locus 3p21.3 , 2000, Nature Genetics.

[34]  J. Minna,et al.  Molecular analysis of the short arm of chromosome 3 in small-cell and non-small-cell carcinoma of the lung. , 1987, The New England journal of medicine.

[35]  A. Jemal,et al.  Global Cancer Statistics , 2011 .

[36]  Li-hua Sun Methylation of antioncogen at 3p in non-small cell lung cancer , 2007 .

[37]  P. Johnson,et al.  Promoter hypermethylation of multiple genes in nasopharyngeal carcinoma. , 2002, Clinical cancer research : an official journal of the American Association for Cancer Research.