Vasilatos Shauna N, Broadwater Gloria, Barry William T, Baker Joseph C, Lem Siya, Dietze Eric C, Bean Gregory R, Bryson Andrew D, Pilie Patrick G, Goldenberg Vanessa, Skaar David, Paisie Carolyn, Torres-Hernandez Alejandro, Grant Tracey L, Wilke Lee G, Ibarra-Drendall Catherine, Ostrander Julie H, D'Amato Nicholas C, Zalles Carola, Jirtle Randy, Weaver Valerie M, Seewaldt Victoria L
Department of Medicine, Duke University Medical Center, Box 2628, Durham, NC 27710, USA.
Cancer Epidemiol Biomarkers Prev. 2009 Mar;18(3):901-14. doi: 10.1158/1055-9965.EPI-08-0875. Epub 2009 Mar 3.
Only 5% of all breast cancers are the result of BRCA1/2 mutations. Methylation silencing of tumor suppressor genes is well described in sporadic breast cancer; however, its role in familial breast cancer is not known.
CpG island promoter methylation was tested in the initial random periareolar fine-needle aspiration sample from 109 asymptomatic women at high risk for breast cancer. Promoter methylation targets included RARB (M3 and M4), ESR1, INK4a/ARF, BRCA1, PRA, PRB, RASSF1A, HIN-1, and CRBP1.
Although the overall frequency of CpG island promoter methylation events increased with age (P<0.0001), no specific methylation event was associated with age. In contrast, CpG island methylation of RARB M4 (P=0.051), INK4a/ARF (P=0.042), HIN-1 (P=0.044), and PRA (P=0.032), as well as the overall frequency of methylation events (P=0.004), was associated with abnormal Masood cytology. The association between promoter methylation and familial breast cancer was tested in 40 unaffected premenopausal women in our cohort who underwent BRCA1/2 mutation testing. Women with BRCA1/2 mutations had a low frequency of CpG island promoter methylation (15 of 15 women had <or=4 methylation events), whereas women without a mutation showed a high frequency of promoter methylation events (24 of 25 women had 5-8 methylation events; P<0.0001). Of women with a BRCA1/2 mutation, none showed methylation of HIN-1 and only 1 of 15 women showed CpG island methylation of RARB M4, INK4a/ARF, or PRB promoters.
This is the first evidence of CpG island methylation of tumor suppressor gene promoters in non-BRCA1/2 familial breast cancer.
所有乳腺癌中只有5%是由BRCA1/2突变引起的。肿瘤抑制基因的甲基化沉默在散发性乳腺癌中已有充分描述；然而，其在家族性乳腺癌中的作用尚不清楚。
对109名无症状的乳腺癌高危女性最初随机采集的乳晕周围细针穿刺样本进行CpG岛启动子甲基化检测。启动子甲基化靶点包括RARB（M3和M4）、ESR1、INK4a/ARF、BRCA1、PRA、PRB、RASSF1A、HIN-1和CRBP1。
尽管CpG岛启动子甲基化事件的总体频率随年龄增加而升高（P<0.0001），但没有特定的甲基化事件与年龄相关。相比之下，RARB M4（P=0.051）、INK4a/ARF（P=0.042）、HIN-1（P=0.044）和PRA（P=0.032）的CpG岛甲基化，以及甲基化事件的总体频率（P=0.004）与异常的马苏德细胞学检查相关。在我们队列中40名接受BRCA1/2突变检测的未受影响的绝经前女性中，检测了启动子甲基化与家族性乳腺癌之间的关联。携带BRCA1/2突变的女性CpG岛启动子甲基化频率较低（15名女性中有15名甲基化事件≤4次），而未发生突变的女性启动子甲基化事件频率较高（25名女性中有24名甲基化事件为5 - 8次；P<0.0001）。在携带BRCA1/2突变的女性中，没有发现HIN-1甲基化，15名女性中只有1名显示RARB M4、INK4a/ARF或PRB启动子的CpG岛甲基化。
这是首次在非BRCA1/2家族性乳腺癌中发现肿瘤抑制基因启动子CpG岛甲基化的证据。
