Aberrant methylation of RASSF1A is associated with poor survival in Tunisian breast cancer patients
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Epigenetic gene silencing is one of the major causes of inactivation of tumor-suppressor genes in many human cancers.
Materials and methods
The aim of the present study was to determine the methylation status of the promoter region CpG islands of four cancer-related genes RASSF1A, RARβ2, CDH1, and p16 INK4a in 78 breast cancer specimens and to evaluate whether the methylation status is associated with estrogen receptor (ER), progesterone receptor (PR), and human epidermal growth factor receptor 2 (HER2/neu) together with the major clinico-pathological parameters.
We showed that the methylation frequencies ranged from 19.6% (p16 INK4a ) to 87% (RASSF1A) in primary breast tumors of Tunisian patients. Aberrant methylation of RARβ2 was observed in 66.6% of cases and associated with age at diagnosis (P = 0.043), while CDH1 was methylated in 47.4% of tumors and was correlated with tumor size (P = 0.013). RASSF1A presented the highest percentage of methylation (87%) and was strongly associated with poor survival (P = 0.014), with age (P = 0.048), and tumor stage (P = 0.033). Loss of ER and PR was strongly associated with GIII tumors (P = 0.000 and 0.037 respectively) while HER2/neu was associated with lymph node involvement (P = 0.026) and 5-year survival rate (P = 0.028).
Our preliminary findings suggested that aberrant methylation of RASSF1A and RARβ2 occurs frequently in Tunisian breast cancer patients compared with others. Furthermore, RASSF1A hypermethylation could be used as a potential marker of poor prognosis.
KeywordsPromoter methylation Methylation-specific PCR Tumor suppressor genes Breast cancer Disease-free survival
This work was supported by a grant of the Ministère de l’Enseignement Supérieur et de la Recherche Scientifique Tunisien.
- Elston CW, Ellis IO, Goulging H, Pindre SE (1998) Role of pathology in the prognosis and management of breast cancer. In: Elston CW, Ellis IO (eds) Systemic pathology, vol 13, 3rd edn. Churchill Livingstone, London, pp 385–433Google Scholar
- Fendri A, Masmoudi A, Khabir A, Sellami-Boudawara T, Daoud J, Frikha M, Ghorbel A, Gargouri A, Mokdad-Gargouri R (2008) Inactivation of RASSF1A, RARβ2 and DAP-kinase by promoter methylation correlates with lymph node metastasis in nasopharyngeal carcinoma. Cancer Biol Ther [Epub ahead of print]Google Scholar
- Lee JS, Fackler LPK, Argani MJ, Zhang P, Garrett-Mayer Z, Sukumar ES (2007) A comparative study of Korean with Caucasian breast cancer reveals frequency of methylation in multiple genes correlates with breast cancer in young, ER, PR-negative breast cancer in Korean women. Cancer Biol Ther 6:1114–1120. doi: 10.1158/1535-7163.MCT-07-0002 CrossRefPubMedGoogle Scholar
- Mehrotra J, Ganpat MM, Kanaan Y, Fackler MJ, McVeigh M, Lahti-Domenici J et al (2004) Estrogen receptor/progesterone receptor negative breast cancers of young African-American women have a higher frequency of methylation of multiple genes than those of Caucasian women. Clin Cancer Res 10:2052–2057. doi: 10.1158/1078-0432.CCR-03-0514 CrossRefPubMedGoogle Scholar
- Mourali N, Muenz LR, Tabbane F, Belhassen S, Bahi J, Levine PH (1980) Epidemiologic features of rapidly progressing breast cancer in Tunisia. Cancer 46:2741–2746. doi: 10.1002/1097-0142(19801215)46:12<2741::AID-CNCR2820461234>3.0.CO;2-W CrossRefPubMedGoogle Scholar
- Parkin DM, Ferlay J, Hamdi-Cherif M, Sitas F, Thomas J, Wabinga H et al (2003) Breast cancer in Africa: epidemiology and prevention. IARC Scientific Publication No. 153. IARC, Lyon, pp 262–267Google Scholar
- Sambrook J, Russell DW (2001) Molecular cloning. A laboratory manual. Cold Spring Harbor Laboratory Press, Cold Spring HarborGoogle Scholar
- Sobin LH, Wittekind CH (eds) (1997) International Union Against Cancer, TNM classification of malignant tumours, 5th edn edn. Wiley-Liss, New York, pp 25–32Google Scholar
- Sunami E, Shinozaki M, Sim MS, Nguyen SL, Vu AT, Giuliano AE, Hoon DSB (2008) Estrogen receptor and HER2/neu status affect epigenetic differences of tumor-related genes in primary breast tumors. Breast Cancer Res [Epub ahead of print]Google Scholar