Abstract 3307: BRCA1 promoter methylation analyzed in 1032 primary breast cancers predicts favorable response to chemotherapy independently of p53 mutations
Authors: Olafur A. Stefansson, Holmfridur Hilmarsdottir, Kristrun Olafsdottir, Laufey Tryggvadottir, Asgerdur Sverrisdottir, Jon G. Jonasson, Jorunn E. Eyfjord, Stefan Sigurdsson
Journal: Cancer Research (2018)

Abstract Individuals with germline mutations in the breast cancer susceptibility gene, BRCA1, are at increased risk of developing breast- and ovarian cancer. BRCA1 is involved in DNA double strand break repair (DSB) by homologous recombination (HR), an error-free DNA repair pathway that uses an intact sister chromatid for the repair. BRCA1 mutated tumors are therefore HR deficient and sensitive to drugs that stall DNA replication forks, resulting in DSBs. Tumor cells lacking the protein are characterized by genomic instability and a pattern of specific genome-wide mutation signature as a consequence of dependence on alternative error prone repair pathways. BRCA1 can also be inactivated epigenetically by CpG promoter hypermethylation. These BRCA1 epigenetically silenced tumors are more likely to be of the basal-like subtype and are strongly associated with this pattern of mutational signature characteristic for individuals with germline mutations in BRCA1. This suggests that the tumorigenesis in the sporadic cancer cases is similar to tumors where germline mutations are present, highlighting the importance of epigenetic silencing of BRCA1. The aim of the study was to examine the clinical significance of epigenetic silencing of BRCA1 in primary breast cancer, focusing on the response to chemotherapy. DNA methylation analysis of the BRCA1 promoter was performed by pyrosequencing tumor samples from 1032 patients with primary breast cancer of which 966 were sporadic, 61 were BRCA2 germline mutation carriers and 5 were BRCA1 mutation carriers. The p53 mutational status was also studied in the same primary tumors by DNA sequencing. We analysed the methylation status of BRCA1 in tumors derived from 1032 patients and found BRCA1 to be promoter hypermethylated in 29 sporadic tumors (29 out of 966, 3.0 %) whereas none of the tumors derived from BRCA mutation carriers were BRCA1 promoter hypermethylated. Patients with BRCA1 promoter hypermethylation receiving chemotherapeutic drug treatment show significantly better breast cancer specific survival (P=0.0192). The trend is opposite in patients not receiving chemotherapeutic treatment, were patients with BRCA1 hypermethylated tumors show worse survival (P=0.074). The impact of BRCA1 methylation with respect to survival in chemotherapy treated patients was found to be independent of p53 mutational status, ER status, tumorsize, lymph node status, year- and age at diagnosis (HR = 0.108; 95% CI = 0.015-0.794; P = 0.0288). BRCA1 promoter hypermethylation predicts improved disease outcome in anti-cancer drug treated patients. Therefore, BRCA1 promoter methylation status in primary breast cancer is an important factor to be considered when deciding treatment options. Citation Format: Olafur A. Stefansson, Holmfridur Hilmarsdottir, Kristrun Olafsdottir, Laufey Tryggvadottir, Asgerdur Sverrisdottir, Jon G. Jonasson, Jorunn E. Eyfjord, Stefan Sigurdsson. BRCA1 promoter methylation analyzed in 1032 primary breast cancers predicts favorable response to chemotherapy independently of p53 mutations [abstract]. In: Proceedings of the American Association for Cancer Research Annual Meeting 2018; 2018 Apr 14-18; Chicago, IL. Philadelphia (PA): AACR; Cancer Res 2018;78(13 Suppl):Abstract nr 3307.