Changes in CpG islands promoter methylation patterns during ductal breast carcinoma progression.
Changes in CpG islands promoter methylation patterns during ductal breast carcinoma progression.
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DOI：
10.1158/1055-9965.epi-08-0821
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发表时间：
2009-10
期刊：
影响因子：
--
通讯作者：
Parrella P
中科院分区：
文献类型：
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作者：
Hoque MO;Prencipe M;Poeta ML;Barbano R;Valori VM;Copetti M;Gallo AP;Brait M;Maiello E;Apicella A;Rossiello R;Zito F;Stefania T;Paradiso A;Carella M;Dallapiccola B;Murgo R;Carosi I;Bisceglia M;Fazio VM;Sidransky D;Parrella P
CpG岛高甲基化是乳腺癌发生过程中肿瘤相关基因失活的主要机制之一。我们研究了导管乳腺癌从不典型导管增生到原位癌和浸润性癌进展过程中甲基化模式的变化。对31例乳腺浸润性癌和31例乳腺浸润性癌前病变(不典型导管增生症和/或导管原位癌)和24例乳腺浸润性癌患者的孤立病变进行研究。采用定量甲基化特异性聚合酶链式反应(QMSP)技术，对95例乳腺癌组织和20例正常乳腺组织中的9个基因启动子(ESR1、APC、CDH1、CTNNB1、GSTPI、THBS1、MGMT、TSM1和TIMP3)进行检测。与正常乳腺组织相比，病理标本中APC、CDH1和CTNNB1启动子区域的甲基化频率和甲基化水平增加。对同步配对乳腺病变的分析还表明，在进展过程中，APC、CDH1和CTNNB1基因的甲基化频率和水平增加。通过建立一个临界值，我们能够区分侵袭性和侵袭性病变。APC、CDH1和CTNNB1的同步甲基化仅与浸润性病变有关，而APC和CDH1或APC和CTNNB1的同步甲基化在导管原位癌和浸润性癌中更为常见。我们的数据表明，APC、CDH1和CTNNB1 CpG岛启动子甲基化直接参与了乳腺癌进展的早期阶段，并提示这些分子变化可能参与了向侵袭性表型的转变。
CpG island hypermethylation is emerging as one of the main mechanisms for inactivation of cancer related genes in breast tumorigenesis. We examined the changes in methylation patterns during ductal breast cancer progression from atypical ductal hyperplasia to in situ and invasive carcinoma. Paired samples of synchronous pre invasive lesions (Atypical Ductal Hyperplasia and/or Ductal Carcinoma in situ) and invasive ductal breast carcinoma from 31 patients, together with isolated lesions from additional 24 patients were studied. Overall, 95 pathological samples and 20 normal breast tissues were analyzed by Quantitative Methylation Specific PCR (QMSP) on a panel of 9 gene promoters (ESR1, APC, CDH1, CTNNB1, GSTPI, THBS1, MGMT, TMS1 and TIMP3). APC, CDH1, and CTNNB1 promoter regions showed an increase in frequency of methylation and increased methylation levels in pathological samples when compared with normal breast tissues. The analysis of the syncronous paired breast lesions demonstrated also an increase in methylation frequency and level for APC, CDH1, and CTNNB1 genes during progression. By establishing a cutoff value, we were able to distinguish among -invasive and invasive lesions. Synchronous methylation of APC, CDH1, and CTNNB1 was associated only with invasive lesions, whereas simultaneous methylation of APC and CDH1 or APC and CTNNB1 were more frequent in ductal carcinoma in situ and invasive carcinoma. Our data point to direct involvement of APC, CDH1, and CTNNB1 CpG island promoter methylation in the early stages of breast cancer progression, and suggest that these molecular alterations might be involved in the transition to an invasive phenotype.