Journal Article

BRCA1 Promoter Methylation in Ovarian Cancer: Clinical Relevance and a Novel Diagnostic Approach Using Fragment Analysis

Miyamoto, Yuichiro, Fukaya, Sayuri, Osuga, Yutaka, Sone, Kenbun, Yoshimoto, Daisuke, Taguchi, Ayumi, Tsuchimochi, Saki, Nishijima, Akira, Hirota, Yasushi, Ushiku, Tetsuo, Ishizaka, Aya, Hiraike, Osamu, Kawazu, Masahito, Tamai, Kana, Oda, Katsutoshi, Ikemura, Masako, Kitamura, Shuhei, Yamamoto, Yoko, Mori, Mayuyo, Hasegawa, Kosei, Quynh, Anh Duong

2025

Overview

Homologous recombination deficiency (HRD) tests, including MyChoice CDx, are companion diagnostics for poly (ADP‐ribose) polymerase (PARP) inhibitors. BRCA1 promoter hypermethylation, a major HRD cause, may correlate with poorer prognosis. This study aimed to develop a simple, accurate method for detecting BRCA1 promoter hypermethylation and elucidate the characteristics of such cases. BRCA1 promoter methylation was analyzed using bisulfite sequencing (BIS‐seq) in high‐grade serous ovarian carcinoma specimens. We developed a newly developed BRCA1 methylation assay, BRCA1‐Fragment Analysis of Methylation (BRCA1‐FAM), which combines restriction enzyme digestion with fragment analysis. The accuracy of this assay was compared to the results of BIS‐seq. We evaluated the relationship between BRCA1 promoter hypermethylation and prognosis and examined its association with BRCA1 expression and loss of heterozygosity. BRCA1 mutations and promoter methylation were mutually exclusive in the analyzed cases, with methylation observed in 28.9% (22/76) of primary debulking surgery cases. The BRCA1‐FAM showed high sensitivity (91.3%) and specificity (100%) for detecting BRCA1 promoter hypermethylation, comparable to BIS‐seq. Cases with BRCA1 promoter hypermethylation had significantly poorer progression‐free survival (log‐rank test, p = 0.048). Among these cases, 86.4% displayed abnormal BRCA1 immunostaining, with lower frequencies of BRCA1 loss of heterozygosity compared to those of other groups. BRCA1 promoter hypermethylation is associated with poor prognosis, underscoring the importance of its identification for HRD stratification. BRCA1‐FAM is a simple and highly accurate method for evaluating BRCA1 promoter methylation. This approach may potentially enhance the precision of personalized therapies for ovarian cancer. With the aim of clinical applications, we established a simplified evaluation method for BRCA1 methylation using fragment analysis, called BRCA1‐FAM. We confirmed that high‐grade serous ovarian cancer patients with BRCA1 methylation had poor prognosis. The introduction of BRCA1 methylation testing is expected to contribute to the stratification of prognosis and drug selection for HRD tumors.

• Publisher: John Wiley & Sons, Inc,John Wiley and Sons Inc
• Subject: Adult / Aged / Biomarkers, Tumor - genetics / Bisulfite / BRCA1 / BRCA1 protein / BRCA1 Protein - genetics / Breast cancer / Cancer therapies / Clinical Relevance / DNA fragmentation / DNA Methylation / Enzymes / Female / Genes / Genetic testing / Genetics / Heterozygosity / Homologous recombination / homologous recombination deficiency / Humans / Loss of Heterozygosity / Medical prognosis / Medical records / Middle Aged / Mutation / Original / ORIGINAL ARTICLE / Ovarian cancer / Ovarian carcinoma / Ovarian Neoplasms - diagnosis / Ovarian Neoplasms - genetics / Ovarian Neoplasms - pathology / Polymerase chain reaction / Prognosis / Promoter Regions, Genetic - genetics / Surgical outcomes / Tumors