焦磷酸测序定量BRCA1启动子甲基化水平可作为乳腺癌患者生存预后因素
乳腺癌易感基因1（BRCA1）是一种遗传性乳腺癌有关的抑癌基因。最近研究发现启动子高甲基化是抑癌基因失活的又一重要机制，而且在某些情况下是唯一机制。焦磷酸测序是一种基于聚合原理的基因测序（确定基因中核苷酸的顺序）技术，可以用于定量检测BRCA1启动子区甲基化水平。
2016年3月25日，同济大学医学院附属杨浦医院、西安交通大学医学部法医学院、复旦大学附属肿瘤医院及上海医学院、启东市人民医院、宁波市医疗中心李惠利医院东院、瑞士巴塞尔大学医院在《Oncotarget》联合发表的研究发现：焦磷酸测序技术定量检测BRCA1启动子区甲基化水平可作为乳腺癌患者生存预后因素。
Oncotarget. 2016 Mar 25. [Epub ahead of print]
Pyrosequencing quantified methylation level of BRCA1 promoter as prognostic factor for survival in breast cancer patient.
Cai FF, Chen S, Wang MH, Lin XY, Zhang L, Zhang JX, Wang LX, Yang J, Ding JH, Pan X, Shao ZM, Biskup E.
Yangpu Hospital, Tongji University School of Medicine, Shanghai, PR China.
School of Forensic Sciences, Xi'an Jiao Tong University Health Science Center, Xi'an, Shaanxi, PR China.
Fudan University Shanghai Cancer Center, Shanghai, PR China.
Qidong Hospital, Jiangsu, PR China.
Ningbo Medical Center Lihuili Eastern Hospital, Ningbo, Zhejiang, PR China.
Shanghai Medical College, Fudan University, Shanghai, PR China.
University Hospital of Basel, Basel, Switzerland.
BRCA1 promoter methylation is an essential epigenetic transcriptional silencing mechanism, related to breast cancer (BC) occurrence and progression. We quantified the methylation level of BRCA1 promoter and evaluated its significance as prognostic and predictive factor. BRCA1 promoter methylation level was quantified by pyrosequencing in surgical cancerous and adjacent normal specimens from 154 BC patients. A follow up of 98 months was conducted to assess the correlation between BRCA1-methylation level vs. overall survival (OS) and disease free survival (DFS). The mean methylation level in BC tissues was significantly higher (mean 32.6%; median 31.9%) than in adjacent normal samples (mean 16.2%; median 13.0%) (P < 0.0001). Tumor stage (R = 0.6165, P < 0.0001) and size (R = 0.7328, P < 0.0001) were significantly correlated with the methylation level. Patients with unmethylated BRCA1 had a better OS and DFS compared to the methylated group (each P < 0.0001). BRCA1 promoter methylation level has a statistically significance on survival in BC patients (HazR = 1.465, P = 0.000) and is an independent prognostic factor for OS in BC patients (HazR = 2.042, P = 0.000). Patients with ductal type, HER2 negative, lymph node negative stage 1+2 tumors had a better OS and DFS. Classification of grades and molecular subtypes did not show any prognostic significance. Pyrosequencing is a precise and efficient method to quantify BRCA1 promoter methylation level, with a high potential for future clinical implication, as it identifies subgroups of patients with poorer prognosis.
KEYWORDS: BRCA1; breast cancer; methylation; prognosis; pyrosequencing
PMID: 27027444
DOI: 10.18632/oncotarget.8355