Aberrant methylation of RASSF1A is associated with poor survival in Tunisian breast cancer patients.
BACKGROUND
Epigenetic gene silencing is one of the major causes of inactivation of tumor-suppressor genes in many human cancers.


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, RARbeta2, 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.


RESULTS
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 RARbeta2 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).


CONCLUSIONS
Our preliminary findings suggested that aberrant methylation of RASSF1A and RARbeta2 occurs frequently in Tunisian breast cancer patients compared with others. Furthermore, RASSF1A hypermethylation could be used as a potential marker of poor prognosis.
Karray-Chouayekh
Sondes
S
Unité de Recherche Génétique du Cancer et Production de Protéines Thérapeutiques, Centre de Biotechnologie de Sfax, BP 1177, Route Sidi Mansour, Sfax, Tunisia.
Trifa
Fatma
F
Khabir
Abdelmajid
A
Boujelbane
Nouredine
N
Sellami-Boudawara
Tahia
T
Daoud
Jamel
J
Frikha
Mounir
M
Jlidi
Rachid
R
Gargouri
Ali
A
Mokdad-Gargouri
Raja
R
D000328:Adult; D000368:Aged; D015703:Antigens, CD; D014408:Biomarkers, Tumor / Q000235:genetics* / Q000378:metabolism; D001943:Breast Neoplasms / Q000235:genetics* / Q000378:metabolism / Q000401:mortality*; D015820:Cadherins / Q000235:genetics; D018270:Carcinoma, Ductal, Breast / Q000235:genetics / Q000401:mortality; D018899:CpG Islands / Q000235:genetics; D019941:Cyclin-Dependent Kinase Inhibitor p16 / Q000235:genetics; D019175:DNA Methylation; D005260:Female; D015972:Gene Expression Regulation, Neoplastic; D006801:Humans; D007150:Immunohistochemistry; D008875:Middle Aged; D009367:Neoplasm Staging; D016133:Polymerase Chain Reaction; D018719:Erb-b2 Receptor Tyrosine Kinases / Q000378:metabolism; D011960:Receptors, Estrogen / Q000378:metabolism; D011980:Receptors, Progesterone / Q000378:metabolism; D018168:Receptors, Retinoic Acid / Q000235:genetics*; D016019:Survival Analysis; D025521:Tumor Suppressor Proteins / Q000235:genetics*; D014416:Tunisia / Q000453:epidemiology
D015703:Antigens, CD; D014408:Biomarkers, Tumor; D015820:Cadherins; D019941:Cyclin-Dependent Kinase Inhibitor p16; D018719:Erb-b2 Receptor Tyrosine Kinases; D011960:Receptors, Estrogen; D011980:Receptors, Progesterone; D018168:Receptors, Retinoic Acid; D025521:Tumor Suppressor Proteins; C513384:CDH1 protein, human; C411762:RASSF1 protein, human; C540966:retinoic acid receptor, beta2, human; C508053:ERBB2 protein, human