The prognostic value of BRCA1 promoter methylation in early stage triple negative breast cancer.
The prognostic value of BRCA1 promoter methylation in early stage triple negative breast cancer.
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BRCA1启动子甲基化在早期三阴性乳腺癌中的预后价值。
DOI：
10.7243/2049-7962-3-2
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发表时间：
2014-03-19
期刊：
影响因子：
--
通讯作者：
Jensen RA
中科院分区：
文献类型：
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作者：
Sharma P;Stecklein SR;Kimler BF;Sethi G;Petroff BK;Phillips TA;Tawfik OW;Godwin AK;Jensen RA
BRCA1启动子甲基化在三阴性乳腺癌(TNBC)中很常见，导致的肿瘤表型类似于BRCA1突变的肿瘤。与传统的化疗药物相比，BRCA1突变相关的癌症对DNA损伤剂更敏感。目前尚不清楚在散发性TNBC中BRCA1启动子甲基化(PM)与化疗药物反应之间是否存在相互作用。我们试图研究在接受标准化疗的TNBC患者中BRCA1 PM的预后意义。对接受化疗的I-III期TNBC患者进行鉴定，并取回他们的福尔马林固定石蜡包埋(FFPE)肿瘤标本。提取基因组DNA，进行甲基化特异性聚合酶链式反应(MSPCR)。从39例患者的原发肿瘤中提取DNA。在30%的患者中检测到BRCA1 PM。BRCA1 PM的存在与较低的BRCA1转录水平相关，提示表观遗传的BRCA1沉默。所有患者均接受化疗(蒽环类药物：90%，紫杉烷：69%)。在数月的中位随访中，46%的患者复发，36%的患者死亡。在单变量分析中，非裔美国人种族、结节阳性、分期和BRCA1 PM与较差的RFS和OS相关。患有BRCA1 PM的患者5年OS为36%，而没有BRCA1 PM的患者为77%(p=0.004)。在多变量分析中，BRCA1 PM与显著更差的RFS和OS相关。我们发现BRCA1 PM在TNBC中很常见，并且有可能识别出标准化疗结果不佳的相当一部分TNBC患者。
Methylation of the BRCA1 promoter is frequent in triple negative breast cancers (TNBC) and results in a tumor phenotype similar to BRCA1-mutated tumors. BRCA1 mutation-associated cancers are more sensitive to DNA damaging agents as compared to conventional chemotherapy agents. It is not known if there is an interaction between the presence of BRCA1 promoter methylation (PM) and response to chemotherapy agents in sporadic TNBC. We sought to investigate the prognostic significance of BRCA1 PM in TNBC patients receiving standard chemotherapy. Subjects with stage I-III TNBC treated with chemotherapy were identified and their formalin-fixed paraffin-embedded (FFPE) tumor specimens retrieved. Genomic DNA was isolated and subjected to methylation-specific PCR (MSPCR). DNA was isolated from primary tumor of 39 subjects. BRCA1 PM was detected in 30% of patients. Presence of BRCA1 PM was associated with lower BRCA1 transcript levels, suggesting epigenetic BRCA1 silencing. All patients received chemotherapy (anthracycline:90%, taxane:69%). At a median follow-up of 64 months, 46% of patients have recurred and 36% have died. On univariate analysis, African-American race, node positivity, stage, and BRCA1 PM were associated with worse RFS and OS. Five year OS was 36% for patients with BRCA1 PM vs. 77% for patients without BRCA1 PM (p=0.004). On multivariable analysis, BRCA1 PM was associated with significantly worse RFS and OS. We show that BRCA1 PM is common in TNBC and has the potential to identify a significant fraction of TNBC patients who have suboptimal outcomes with standard chemotherapy.