Rasti Mozhgan, Tavasoli Parastoo, Monabati Ahmad, Entezam Mona
Dept. of Biochemistry, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran.
Dept. of Pathology, Medical School, Shiraz University of Medical Sciences, Shiraz, Iran.
Iran Biomed J. 2009 Oct;13(4):199-206.
Ras-associated domain family 1 (RASSF1A) and hypermethylated in cancer (HIC1) genes are methylated more frequently in breast cancer. Genetic factors that alter the DNA methylation levels in normal and tumor tissues could therefore influence the susceptibility to this tumor phenotype. We determined the frequency of aberrant methylation of HIC1 and RASSF1A gene promoters and their association with methylene tetrahydrofolate dehydrogenase (MTHFD1) G1958A polymorphism and major clinical and pathological features of breast cancer in Iranian women.
DNA was extracted from 81 primary breast tumors and 100 control blood samples. Gene promoter methylation was analyzed by methylation-specific polymerase chain reaction.
Eighty four percent of the breast cancer samples showed total methylation in at least one of two tested loci. We detected HIC1 hypermethylation in 79% of invasive and metastasis tumors and RASSF1A gene hypermethylation in 51% of them. We found no association between HIC1 and RASSF1A gene hypermethylation and MTHFD1 G1958A polymorphism, but a significant correlation between methylation of HIC1 and RASSF1A promoters was indicated (r = 0.24, P = 0.02). There was a combination between hypermethylation of HIC1 locus and nodal involvement in the studied population (p=0.03). We found a significant association between total methylation and nodal involvement (P = 0.01) as well as tumor size more than 2 cm in all cases (P = 0.02).
Methylation of HIC1 and RASSF1A promoters can be used as epigenetic markers to detect the malignant progression of breast carcinoma in Iranian women patients.
Ras相关结构域家族1（RASSF1A）和癌症高甲基化（HIC1）基因在乳腺癌中更频繁地发生甲基化。因此，改变正常组织和肿瘤组织中DNA甲基化水平的遗传因素可能影响对这种肿瘤表型的易感性。我们确定了伊朗女性中HIC1和RASSF1A基因启动子异常甲基化的频率及其与亚甲基四氢叶酸脱氢酶（MTHFD1）G1958A多态性以及乳腺癌主要临床和病理特征的关联。
从81例原发性乳腺肿瘤和100份对照血样中提取DNA。通过甲基化特异性聚合酶链反应分析基因启动子甲基化。
84%的乳腺癌样本在两个检测位点中的至少一个显示完全甲基化。我们在79%的浸润性和转移性肿瘤中检测到HIC1高甲基化，在其中51%的肿瘤中检测到RASSF1A基因高甲基化。我们发现HIC1和RASSF1A基因高甲基化与MTHFD1 G1958A多态性之间无关联，但HIC1和RASSF1A启动子甲基化之间存在显著相关性（r = 0.24，P = 0.02）。在研究人群中，HIC1位点高甲基化与淋巴结受累之间存在联合关系（p = 0.03）。我们发现完全甲基化与淋巴结受累（P = 0.01）以及所有病例中肿瘤大小超过2 cm之间存在显著关联（P = 0.02）。
HIC1和RASSF1A启动子的甲基化可作为表观遗传标记物，用于检测伊朗女性乳腺癌患者的恶性进展。
