DNA methylation of the immediate upstream region of BRCA1 major transcription start sites is an independent favorable prognostic factor in patients with high-grade serous ovarian cancer

Takahiro Ebata; Satoshi Yamashita; Hideyuki Takeshima; Hiroshi Yoshida; Yoshiko Kawata; Nao Kino; Toshiharu Yasugi; Yasuhisa Terao; Kan Yonemori; Tomoyasu Kato; Toshikazu Ushijima

doi:10.1016/j.ygyno.2022.10.008

DNA methylation of the immediate upstream region of BRCA1 major transcription start sites is an independent favorable prognostic factor in patients with high-grade serous ovarian cancer

Gynecol Oncol. 2022 Dec;167(3):513-518. doi: 10.1016/j.ygyno.2022.10.008. Epub 2022 Oct 15.

Authors

Affiliations

¹ Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan; Department of Epigenomics, Life Science Tokyo Advanced Research Center, Hoshi University, Tokyo, Japan.
² Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan.
³ Department of Diagnostic Pathology, National Cancer Center Hospital, Tokyo, Japan.
⁴ Department of Gynecology, Tokyo Metropolitan Cancer and Infectious Diseases Center Komagome Hospital, Tokyo, Japan.
⁵ Department of Obstetrics and Gynecology, Juntendo University, Tokyo, Japan.
⁶ Department of Medical Oncology, National Cancer Center Hospital, Tokyo, Japan.
⁷ Department of Gynecology, National Cancer Center Hospital, Tokyo, Japan.
⁸ Division of Epigenomics, National Cancer Center Research Institute, Tokyo, Japan; Department of Epigenomics, Life Science Tokyo Advanced Research Center, Hoshi University, Tokyo, Japan. Electronic address: tushijim@ncc.go.jp.

PMID: 36253303
DOI: 10.1016/j.ygyno.2022.10.008

Abstract

Objective: To establish a quantitative method to evaluate the DNA methylation level of an immediate upstream region of major BRCA1 transcriptional start sites (TSSs), and to investigate whether methylation of the region is a prognostic factor in high-grade serous ovarian cancer patients after neoadjuvant chemotherapy.

Methods: Ninety-two FFPE samples of advanced high-grade serous ovarian cancers after neoadjuvant chemotherapy between 2011 and 2018 were used for mutation and methylation analysis. DNA methylation levels were assessed by pyrosequencing and DNA methylation microarray. An association between methylation level (or a mutation) and progression-free survival was assessed by Kaplan-Meier analysis.

Result: Major BRCA1 transcripts and CpG sites immediately upstream of their TSSs were identified, and a pyrosequencing method was developed. BRCA1 methylation, BRCA1/2 mutations, and a RAD51C mutation were detected in 17/79 (21.5%), 17/92 (18.5%), and 1/92 (1.1%) high-grade serious ovarian cancer samples. In univariate analysis, BRCA1 methylation and no residual tumor were associated with progression-free survival (BRCA1 methylation: P = 0.025, no residual tumor: P = 0.0026). Multivariate analysis showed that both BRCA1 methylation (P = 0.038, HR = 0.47, 95% CI: 0.21-0.96) and no residual tumor (P = 0.012, HR = 0.49, 95% CI: 0.28-0.85) were significant favorable prognostic factors.

Conclusion: A quantitative method to estimate the methylation level of the immediate upstream region of major BRCA1 TSSs was established. Methylation of the region of was an independent favorable prognostic factor in high-grade serous ovarian cancer patients.

Keywords: BRCA1; Biomarker; DNA methylation; High-grade serous ovarian cancer; Transcriptional start site.

MeSH terms

BRCA1 Protein / genetics
DNA Methylation*
Female
Germ-Line Mutation
Humans
Ovarian Neoplasms* / pathology
Prognosis
Transcription Initiation Site

Substances

BRCA1 protein, human
BRCA1 Protein