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
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 lo...
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BMC
2024-11-01
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| Series: | Clinical Epigenetics |
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| Online Access: | https://doi.org/10.1186/s13148-024-01781-0 |
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| author | Heidelinde Fiegl Simon Schnaiter Daniel U. Reimer Katharina Leitner Petra Nardelli Irina Tsibulak Verena Wieser Katharina Wimmer Esther Schamschula Christian Marth Alain G. Zeimet |
| author_facet | Heidelinde Fiegl Simon Schnaiter Daniel U. Reimer Katharina Leitner Petra Nardelli Irina Tsibulak Verena Wieser Katharina Wimmer Esther Schamschula Christian Marth Alain G. Zeimet |
| author_sort | Heidelinde Fiegl |
| collection | DOAJ |
| description | 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. |
| format | Article |
| id | doaj-art-0bdf725b0b91401bac844e6c5607a2b3 |
| institution | Kabale University |
| issn | 1868-7083 |
| language | English |
| publishDate | 2024-11-01 |
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| series | Clinical Epigenetics |
| spelling | doaj-art-0bdf725b0b91401bac844e6c5607a2b32024-12-01T12:31:48ZengBMCClinical Epigenetics1868-70832024-11-0116111010.1186/s13148-024-01781-0BRCA loss of function including BRCA1 DNA-methylation, but not BRCA-unrelated homologous recombination deficiency, is associated with platinum hypersensitivity in high-grade ovarian cancerHeidelinde Fiegl0Simon Schnaiter1Daniel U. Reimer2Katharina Leitner3Petra Nardelli4Irina Tsibulak5Verena Wieser6Katharina Wimmer7Esther Schamschula8Christian Marth9Alain G. Zeimet10Department of Obstetrics and Gynecology, Medical University of InnsbruckInstitute of Human Genetics, Medical University of InnsbruckDepartment of Obstetrics and Gynecology, Medical University of InnsbruckDepartment of Obstetrics and Gynecology, Medical University of InnsbruckDepartment of Obstetrics and Gynecology, Medical University of InnsbruckDepartment of Obstetrics and Gynecology, Medical University of InnsbruckDepartment of Obstetrics and Gynecology, Medical University of InnsbruckInstitute of Human Genetics, Medical University of InnsbruckInstitute of Human Genetics, Medical University of InnsbruckDepartment of Obstetrics and Gynecology, Medical University of InnsbruckDepartment of Obstetrics and Gynecology, Medical University of InnsbruckAbstract 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.https://doi.org/10.1186/s13148-024-01781-0Ovarian cancerBRCA1BRCA2DNA-methylationHomologous recombination deficiency (HRD)Platinum sensitivity |
| spellingShingle | Heidelinde Fiegl Simon Schnaiter Daniel U. Reimer Katharina Leitner Petra Nardelli Irina Tsibulak Verena Wieser Katharina Wimmer Esther Schamschula Christian Marth Alain G. Zeimet 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 Clinical Epigenetics Ovarian cancer BRCA1 BRCA2 DNA-methylation Homologous recombination deficiency (HRD) Platinum sensitivity |
| title | 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 |
| title_full | 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 |
| title_fullStr | 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 |
| title_full_unstemmed | 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 |
| title_short | 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 |
| title_sort | 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 |
| topic | Ovarian cancer BRCA1 BRCA2 DNA-methylation Homologous recombination deficiency (HRD) Platinum sensitivity |
| url | https://doi.org/10.1186/s13148-024-01781-0 |
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