Xu Xinran, Gammon Marilie D, Zhang Yujing, Bestor Timothy H, Zeisel Steven H, Wetmur James G, Wallenstein Sylvan, Bradshaw Patrick T, Garbowski Gail, Teitelbaum Susan L, Neugut Alfred I, Santella Regina M, Chen Jia
Department of Community and Preventive Medicine, Mount Sinai School of Medicine, P.O. Box 1043, One Gustave L. Levy Place, New York, NY 10029, USA.
Breast Cancer Res Treat. 2009 May;115(2):397-404. doi: 10.1007/s10549-008-0075-5. Epub 2008 Jun 3.
Promoter-CpG island hypermethylation has been proposed as an alternative mechanism to inactivate BRCA1 in the breast where somatic mutations of BRCA1 are rare. To better understand breast cancer etiology and progression, we explored the association between BRCA1 promoter methylation status and prognostic factors as well as survival among women with breast cancer. Promoter methylation of BRCA1 was assessed in 851 archived tumor tissues collected from a population-based study of women diagnosed with invasive or in situ breast cancer in 1996-1997, and who were followed for vital status through the end of 2002. About 59% of the tumors were methylated at the promoter of BRCA1. The BRCA1 promoter methylation was more frequent in invasive cancers (P = 0.02) and among premenopausal cases (P = 0.05). BRCA1 promoter methylation was associated with increased risk of breast cancer-specific mortality (age-adjusted HR 1.71; 95% CI: 1.05-2.78) and all-cause mortality (age-adjusted HR 1.49; 95% CI: 1.02-2.18). Neither dietary methyl intakes in the year prior to the baseline interview nor the functional polymorphisms in one-carbon metabolism were associated with BRCA1 methylation status. Our study is the first epidemiological investigation on the prognostic value of BRCA1 promoter methylation in a large population-based cohort of breast cancer patients. Our results indicate that BRCA1 promoter methylation is an important factor to consider in predicting breast cancer survival.
启动子-CpG岛高甲基化被认为是一种使乳腺癌中BRCA1失活的替代机制,而BRCA1的体细胞突变在乳腺癌中较为罕见。为了更好地理解乳腺癌的病因和进展,我们探讨了BRCA1启动子甲基化状态与预后因素以及乳腺癌患者生存率之间的关联。对1996 - 1997年从一项基于人群的研究中收集的851份存档肿瘤组织进行了BRCA1启动子甲基化评估,这些组织来自被诊断为浸润性或原位乳腺癌的女性,并且随访至2002年底以了解其生命状态。约59%的肿瘤在BRCA1启动子处发生甲基化。BRCA1启动子甲基化在浸润性癌(P = 0.02)和绝经前病例中(P = 0.05)更为常见。BRCA1启动子甲基化与乳腺癌特异性死亡风险增加(年龄调整后HR 1.71;95% CI:1.05 - 2.78)和全因死亡风险增加(年龄调整后HR 1.49;95% CI:1.02 - 2.18)相关。基线访谈前一年的膳食甲基摄入量和一碳代谢中的功能多态性均与BRCA1甲基化状态无关。我们的研究是对一大群乳腺癌患者进行的关于BRCA1启动子甲基化预后价值的首次流行病学调查。我们的结果表明,BRCA1启动子甲基化是预测乳腺癌生存时需要考虑的一个重要因素。