Pyrosequencing quantified methylation level of BRCA1 promoter as prognostic factor for survival in breast cancer patient
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Feng-Feng Cai1,*, Su Chen2,*, Ming-Hong Wang3,*, Xiao-Yan Lin1, Lian Zhang1, Jia-Xin Zhang4, Lian-Xin Wang5, Jun Yang5, Jin-Hua Ding6, Xin Pan7, Zhi-Ming Shao8, Ewelina Biskup9
1Department of Breast Surgery, Yangpu Hospital, Tongji University School of Medicine, Shanghai, PR China
2Department of Molecular and Cellular Biology, School of Forensic Sciences, Xi’an Jiao Tong University Health Science Center, Xi’an, Shaanxi, PR China
3Department of General Practice, Yangpu Hospital, Tongji University School of Medicine, Shanghai, PR China
4Department of Breast Surgery, Fudan University Shanghai Cancer Center, Shanghai, PR China
5Department of General Surgery, Qidong Hospital, Jiangsu, PR China
6Department of Thyroid and Breast Surgery, Ningbo Medical Center Lihuili Eastern Hospital, Ningbo, Zhejiang, PR China
7Central Laboratory, Yangpu Hospital, Tongji University School of Medicine, Shanghai, PR China
8Department of Breast Surgery, Key Laboratory of Breast Cancer in Shanghai, Fudan University Shanghai Cancer Center, Department of Oncology, Shanghai Medical College, Fudan University, Shanghai, PR China
9Department of Oncology, University Hospital of Basel, Basel, Switzerland
*These authors have contributed equally to this work
Feng-Feng Cai, e-mail: [email protected]
Zhi-Ming Shao, e-mail: [email protected]
Xin Pan, e-mail: [email protected]
Keywords: breast cancer, BRCA1, methylation, pyrosequencing, prognosis
Received: February 21, 2016 Accepted: March 16, 2016 Published: March 25, 2016
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.
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