Nami Yamashita1, Eriko Tokunaga2, Hiroyuki Kitao3, Megan Hitchins4, Yuka Inoue1, Kimihiro Tanaka1, Yuichi Hisamatsu1, Kenji Taketani1, Sayuri Akiyoshi1, Satoko Okada1, Yoshinao Oda5, Hiroshi Saeki1, Eiji Oki1, Yoshihiko Maehara1. 1. Department of Surgery and Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 2. Department of Comprehensive Clinical Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. Electronic address: eriko@surg2.med.kyushu-u.ac.jp. 3. Department of Molecular Oncology, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan. 4. Division of Oncology, Stanford University School of Medicine, Stanford, CA. 5. Department of Anatomic Pathology, Pathological Science, Graduate School of Medical Sciences, Kyushu University, Fukuoka, Japan.
Abstract
BACKGROUND: Triple-negative breast cancer (TNBC) has many similarities with basal-like breast cancer. Additionally, TNBCs are associated with Breast cancer susceptibility gene I (BRCA1) functional loss, which leads to impaired homologous recombination-mediated DNA repair. Although somatic mutations in BRCA1 rarely occur in sporadic breast cancer, lower than normal rates of expression of BRCA1 is reported to be an important factor that contributes to tumorigenesis in sporadic tumors. The epigenetic inactivation of BRCA1 expression might thus play an important role in sporadic breast cancer cases. PATIENTS AND METHODS: Breast cancer specimens were obtained from 69 TNBC and 161 non-TNBC patients who underwent surgery without neoadjuvant systemic therapy. BRCA1 promoter methylation status was investigated using combined bisulfite and restriction analysis. BRCA1 mRNA expression was evaluated using quantitative reverse transcriptase polymerase chain reaction and BRCA1 protein expression was assessed using immunohistochemistry. RESULTS: BRCA1 promoter methylation was found in 11 tumors and all of these were in TNBC cases (P < .0001). BRCA1 promoter methylation was significantly associated with lymphovessel invasion (P = .02), high nuclear grade (P = .05), low BRCA1 mRNA expression (P < .0001), and loss of BRCA1 protein expression (P = .0015). BRCA1 promoter methylation was significantly associated with shorter overall survival (P = .038). CONCLUSION: BRCA1 promotor methylation was found only in TNBC cases and the methylated cases account for 16% of TNBC. BRCA1 promoter methylation was significantly associated with reduced BRCA1 expression, aggressive phenotype, and poor prognosis. BRCA1 promoter methylation is an important mechanism that leads to functional loss of BRCA1.
BACKGROUND: Triple-negative breast cancer (TNBC) has many similarities with basal-like breast cancer. Additionally, TNBCs are associated with Breast cancer susceptibility gene I (BRCA1) functional loss, which leads to impaired homologous recombination-mediated DNA repair. Although somatic mutations in BRCA1 rarely occur in sporadic breast cancer, lower than normal rates of expression of BRCA1 is reported to be an important factor that contributes to tumorigenesis in sporadic tumors. The epigenetic inactivation of BRCA1 expression might thus play an important role in sporadic breast cancer cases. PATIENTS AND METHODS: Breast cancer specimens were obtained from 69 TNBC and 161 non-TNBC patients who underwent surgery without neoadjuvant systemic therapy. BRCA1 promoter methylation status was investigated using combined bisulfite and restriction analysis. BRCA1 mRNA expression was evaluated using quantitative reverse transcriptase polymerase chain reaction and BRCA1 protein expression was assessed using immunohistochemistry. RESULTS:BRCA1 promoter methylation was found in 11 tumors and all of these were in TNBC cases (P < .0001). BRCA1 promoter methylation was significantly associated with lymphovessel invasion (P = .02), high nuclear grade (P = .05), low BRCA1 mRNA expression (P < .0001), and loss of BRCA1 protein expression (P = .0015). BRCA1 promoter methylation was significantly associated with shorter overall survival (P = .038). CONCLUSION:BRCA1 promotor methylation was found only in TNBC cases and the methylated cases account for 16% of TNBC. BRCA1 promoter methylation was significantly associated with reduced BRCA1 expression, aggressive phenotype, and poor prognosis. BRCA1 promoter methylation is an important mechanism that leads to functional loss of BRCA1.
Authors: Shari E Smith; Paul Mellor; Alison K Ward; Stephanie Kendall; Megan McDonald; Frederick S Vizeacoumar; Franco J Vizeacoumar; Scott Napper; Deborah H Anderson Journal: Breast Cancer Res Date: 2017-06-05 Impact factor: 6.466