Association between RASSF1A Ala133Ser Polymorphism and Cancer Susceptibility: A Meta-Analysis Involving 8,892 Subjects

  • Bayram, Suleyman (Department of Nursing, School of Health, Adıyaman University)
  • Published : 2014.04.30


Background: Published studies on the association between the Ras Association Domain Family 1 isoform A (RASSF1A) Ala133Ser polymorphism and cancer susceptibility have yielded conflicting results. Thus, a meta-analysis was here performed to assess the possible association. Materials and Methods: All eligible case-control studies published up to November 2013 on the association between RASSF1A Ala133Ser polymorphism and cancer susceptibility were identified by searching PubMed, Web of Science, Science Direct and hand search. Bothfixed-effect and random-effect models were used to calculate pooled odds ratios (ORs) with 95% confidence intervals (CIs) by using the Comprehensive Meta-Analysis software version 2.2. Results: A total of 10 studies including 4,572 cancer cases and 4,320 controls were included in the meta-analysis. Overall, significantly increased cancer risk was associated with the variant Ser133 when all studies were pooled (Ser vs Ala: OR=1.51, 95% CI=1.08-2.12, $P_{heterogeneity}{\leq}0.001$; Ser/Ser+Ala/Ser vs Ala/Ala: OR=1.55, 95% CI=1.08-2.22, $P_{heterogeneity}{\leq}0.001$). Moreover, in subgroup analyses by cancer types, a significant association between RASSF1A Ala133Ser polymorphism and lung cancer risk was found (Ser vs Ala: OR=2.27, 95% CI=1.29-4.02, $P_{heterogeneity}$=0.61; Ser/Ser+Ala/Ser vs Ala/Ala: OR=2.42, 95% CI=1.33-4.42, $P_{heterogeneity}=0.75$). In addition, in subgroup analyses by ethnicity, it was found that the RASSF1A Ala133Ser polymorphism was associated with overall cancer risk in Asians (Ser vs Ala: OR=1.37, 95% CI=1.06-1.77, $P_{heterogeneity}=0.06$) and Caucasians (Ser/Ser+Ala/Ser vs Ala/Ala: OR=2.21, 95% CI=1.01-4.82, $P_{heterogeneity}{\leq}0.001$). Conclusions: This meta-analysis suggests, for the first time, that RASSF1A Ala133Ser polymorphism may contribute to cancer susceptibility, especially for lung cancer. Besides, additional well-designed studies with larger sample size focusing on different ethnicities and cancer types are needed to confirm these findings.


  1. Xiao G, Zhang T, Yao J, et al (2009). The association between RASSF1 gene polymorphisms and lung cancer susceptibility among people in Hubei Province of China. J Huazhong Univ Sci Technolog Med Sci, 29, 646-9.
  2. Zhou SL, Cui J, Fan ZM, et al (2013). Polymorphism of A133S and promoter hypermethylation in Ras association domain family 1A gene (RASSF1A) is associated with risk of esophageal and gastric cardia cancers in Chinese population from high incidence area in northern China. BMC Cancer, 13, 259.
  3. Meyer A, Coinac I, Bogdanova N, et al (2013). Apoptosis gene polymorphisms and risk of prostate cancer: a hospital-based study of German patients treated with brachytherapy. Urol Oncol, 31, 74-81.
  4. Kawai Y, Sakano S, Okayama N, et al (2012). Association of genotype and haplotype with the progression of clear cell renal cell carcinoma in Japanese patients. BJU Int, 110, 1070-5.
  5. Liu WJ, Tan XH, Guo BP, et al (2013). Associations between RASSF1A promoter methylation and NSCLC: a metaanalysis of published data.. Asian Pac J Cancer Prev, 14, 3719-24.
  6. Mantel N, Haenszel W (1959). Statistical aspects of the analysis of data from retrospective studies of disease. J Natl Cancer Inst, 22, 719-48.
  7. Qin Q, Zhang C, Zhu H, et al (2014). Association between survivin-31G>C polymorphism and cancer risk: metaanalysis of 29 studies. J Cancer Res Clin Oncol, 140, 179-88.
  8. Richter AM, Pfeifer GP, Dammann RH (2009). The RASSF proteins in cancer; from epigenetic silencing to functional characterization. Biochim Biophys Acta, 1796, 114-28.
  9. Schagdarsurengin U, Seidel C, Ulbrich EJ, et al (2005). A polymorphism at codon 133 of the tumor suppressor RASSF1A is associated with tumorous alteration of the breast. Int J Oncol, 27, 185-91.
  10. Shivakumar L, Minna J, Sakamaki T, Pestell R, White MA (2002). The RASSF1A tumor suppressor blocks cell cycle progression and inhibits cyclin D1 accumulation. Mol Cell Biol, 22, 4309-18.
  11. van der Weyden L, Adams DJ (2007). The Ras-association domain family (RASSF) members and their role in human tumourigenesis. Biochim Biophys Acta, 1776, 58-85.
  12. Vo LT, Thuan TB, Thu DM, et al (2013). Methylation profile of BRCA1, RASSF1A and ER in Vietnamese women with ovarian cancer.. Asian Pac J Cancer Prev, 14, 7713-8..
  13. Donninger H, Barnoud T, Nelson N, et al (2011). RASSF1A and the rs2073498 cancer associated SNP. Front Oncol, 1, 54.
  14. Bergqvist J, Latif A, Roberts SA, et al (2010). RASSF1A polymorphism in familial breast cancer. Fam Cancer, 9, 263-5.
  15. Borenstein M, Hedges L, Higgins J, Rothstein H (2007). Comprehensive Meta-analysis version 2. Biostat, Inc. Englewood, NJ.
  16. DerSimonian R, Laird N (1986). Meta-analysis in clinical trials. Control Clin Trials, 7, 177-88.
  17. Donninger H, Vos MD, Clark GJ (2007). The RASSF1A tumor suppressor. J Cell Sci, 120, 3163-72.
  18. Egger M, Davey Smith G, Schneider M, Minder C (1997). Bias in meta-analysis detected by a simple, graphical test. BMJ, 315, 629-34.
  19. El-Kalla M, Onyskiw C, Baksh S (2010). Functional importance of RASSF1A microtubule localization and polymorphisms. Oncogene, 29, 5729-40.
  20. Gao B, Xie XJ, Huang C, et al (2008). RASSF1A polymorphism A133S is associated with early onset breast cancer in BRCA1/2 mutation carriers. Cancer Res, 68, 22-5.
  21. Gordon M, Baksh S (2011). RASSF1A: not a prototypical Ras effector. Small GTPases, 2, 148-57.
  22. Higgins JP, Thompson SG, Deeks JJ, Altman DG (2003). Measuring inconsistency in meta-analyses. BMJ, 327, 557-60.
  23. Higgins JP, Thompson SG (2002). Quantifying heterogeneity in a meta-analysis. Stat Med, 21, 1539-58.
  24. Kanzaki H, Hanafusa H, Yamamoto H, et al (2006). Single nucleotide polymorphism at codon 133 of the RASSF1 gene is preferentially associated with human lung adenocarcinoma risk. Cancer Let, 238, 128-34.
  25. Akkız H, Bayram S, Bekar A, Akgollu E, Uskudar O (2011). Genetic variation in the MicroRNA-499 gene and hepatocellular carcinoma risk in a Turkish population: lack of any association in a case-control study. Asian Pac J Cancer Prev, 12, 3107-12.
  26. Bayram S, Akkız H, Bekar A, Akgollu E, Yıldırım S (2011). No association of exonuclease 1 T439M polymorphism and risk of hepatocellular carcinoma development in Turkish population: a case-control study. Asian Pac J Cancer Prev, 12, 2455-60.
  27. Bayram S (2012). RASSF1A Ala133Ser polymorphism is associated with increased susceptibility to hepatocellular carcinoma in a Turkish population. Gene, 498, 264-9.
  28. Begg CB, Mazumdar M (1994). Operating characteristics of a rank correlation test for publication bias. Biometrics, 50, 1088-101.

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