BRCA loss of function including BRCA1 - DNA-methylation, but not BRCA-unrelated homologous recombination deficiency, is associated with platinum hypersensitivity in high-grade ovarian cancer

Q: What hypothesis did the researchers test regarding BRCA LOF and HRD in high-grade ovarian cancer?

They tested whether BRCA loss of function due to epigenetic or genetic changes is a better predictor of clinical outcome than HRD for high-grade ovarian cancer patients.

Q: What did multivariate analysis show about the predictive value of BRCA-LOF versus HRD status?

BRCA-LOF independently predicted progression-free survival and overall survival, while HRD status showed no predictive value for either outcome.

Sep 21, 2026

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The study evaluates whether BRCA loss of function (LOF) driven by epigenetic or genetic aberrations predicts clinical outcomes more accurately than homologous recombination deficiency (HRD) in high-grade ovarian cancer. One hundred thirty-one tissue samples were analyzed for BRCA DNA-methylation, BRCA mutations, HRD status, and BRCA1 mRNA expression, followed by comprehensive survival analyses. Results show BRCA1 methylation in 11% of tumors and BRCA-LOF as an independent predictor of progression-free and overall survival, whereas HRD status lacked predictive value and HRD positivity without BRCA-wt-unmeth did not improve platinum sensitivity.

LanguageEnglish

CategoryResearch & Report

FormatPDF

Pages10

Reading Time25 min

AccessFree to download

Abstract

Background

Results

Conclusion

Keywords

Background

Fiegl et al. Clinical Epigenetics (2024) 16:171 [https://doi.org/10.1186/s13148-024-01781-0](https://doi.org/10.1186/s13148-024-01781-0) Clinical Epigenetics RESEARCH Open Access BRCA loss of function including BRCA1 DNA-methylation, but not BRCA‑unrelated homologous recombination deficiency, is associated with platinum hypersensitivity in high-grade ovarian cancer Heidelinde Fiegl 1*†, Simon Schnaiter2†, Daniel U. Reimer 1, Katharina Leitner 1, Petra Nardelli 1, Irina Tsibulak1, Verena Wieser1, Katharina Wimmer2, Esther Schamschula2, Christian Marth 1 and Alain G. Zeimet 1* Abstract Background In high-grade ovarian cancer (HGOC), determination of homologous recombination deficiency (HRD) status is commonly used in routine practice to predict response to platinum-based therapy or poly (ADP-ribose) polymerase inhibitors (PARPi) . Here we tested the hypothesis that BRCA loss of function (LOF) due to epigenetic or genetic aberrations is a better predictor for the clinical outcome than HRD. One hundred thirty-one HGOC tissues were tested for BRCA DNA-methylation, BRCA mutations, HRD and BRCA1 mRNA expression, followed by a comprehensive survival analysis. Results BRCA1-methylation was detected in 11% of the tumors, exclusively in BRCA1-wild-type (wt) HGOCs. BRCA1-methylated tumors (BRCA1-meth) had HRD-scores similar to those of BRCA-mutated (mut) tumors, and higher compared to unmethylated-BRCA-wt tumors (BRCA-wt-unmeth; P < 0. 001) . Platinum-refractory or-resistant HGOCs at first recurrence were all BRCA-unmeth cancers. Only one of the BRCA-mut cancers had a platinum-resistant recurrence. Thus, 99% of relapses in cancers with epigenetic or genetic BRCA-alterations were platinum-sensitive. Multivariate analysis confirmed BRCA-LOF as an independent predictor of progression-free survival (PFS) and overall survival (OS), whereas HRD-status had no predictive value for PFS and OS. Patients with BRCA-wt-unmeth cancers had the worst outcome compared to patients with cancers harboring epigenetic or genetic BRCA-alterations (PFS: P= 0 . 007; OS: P = 0 . 022) . Most importantly, the BRCA-wt-unmeth subfraction of HRD-positive HGOCs exhibited the same poor survival as the entire HRD-negative cohort. Conclusion In HGOC BRCA mutational status together with BRCA1-methylation exhibit the best predictive power for favorable clinical outcome and thus high sensitivity to platinum-based therapy, whereas BRCA-unrelated HRD positivity was not associated with improved platinum sensitivity. †Heidelinde Fiegl and Simon Schnaiter contributed equally. *Correspondence: Heidelinde Fiegl [Heidelinde.Fiegl@i-med.ac.at](Heidelinde.Fiegl@i-med.ac.at)[ ](Heidelinde.Fiegl@i-med.ac.at)Alain G. Zeimet [Alain.Zeimet@i-med.ac.at](Alain.Zeimet@i-med.ac.at) Full list of author information is available at the end of the article © The Author(s) 2024. Open Access This article is licensed under a Creative Commons Attribution-NonCommercial-NoDerivatives 4.0 International License, which permits any non-commercial use, sharing, distribution and reproduction in any medium or format, as long as you give appropriate credit to the original author(s) and the source, provide a link to the Creative Commons licence, and indicate if you modified the licensed material. You do not have permission under this licence to share adapted material derived from this article or parts of it. The images or other third party material in this article are included in the article’s Creative Commons licence, unless indicated otherwise in a credit line to the material. If material is not included in the article’s Creative Commons licence and your intended use is not permitted by statutory regulation or exceeds the permitted use, you will need to obtain permission directly from the copyright holder. To view a copy of this licence, visit [http://creativecommons.org/licenses/by-nc-nd/4.0/](http://creativecommons.org/licenses/by-nc-nd/4.0/.)[.](http://creativecommons.org/licenses

FAQs

What hypothesis did the researchers test regarding BRCA LOF and HRD in high-grade ovarian cancer?

They tested whether BRCA loss of function due to epigenetic or genetic changes is a better predictor of clinical outcome than HRD for high-grade ovarian cancer patients.

How was BRCA loss of function assessed in the study?

BRCA DNA-methylation, BRCA mutations, HRD status, and BRCA1 mRNA expression were measured in 131 high-grade ovarian cancer tissues.

What did multivariate analysis show about the predictive value of BRCA-LOF versus HRD status?

BRCA-LOF independently predicted progression-free survival and overall survival, while HRD status showed no predictive value for either outcome.

Sep 21, 2026

Uploaded by Seraphina