CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer
Abstract Homologous recombination deficiency (HRD) is a predictive biomarker for PARP inhibition and platinum-based chemotherapy. While copy number alteration-based scores such as HRDsum = LST + TAI + LOH are included in therapy approvals, single base substitutions (SBS) are underinvestigated as pre...
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| Format: | Article |
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Nature Portfolio
2025-07-01
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| Series: | Communications Biology |
| Online Access: | https://doi.org/10.1038/s42003-025-08529-3 |
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| author | Eva Romanovsky Michael Menzel Klaus Kluck Susanne Beck Markus Ball Peter Schirmacher Daniel Kazdal Albrecht Stenzinger Jan Budczies |
| author_facet | Eva Romanovsky Michael Menzel Klaus Kluck Susanne Beck Markus Ball Peter Schirmacher Daniel Kazdal Albrecht Stenzinger Jan Budczies |
| author_sort | Eva Romanovsky |
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| description | Abstract Homologous recombination deficiency (HRD) is a predictive biomarker for PARP inhibition and platinum-based chemotherapy. While copy number alteration-based scores such as HRDsum = LST + TAI + LOH are included in therapy approvals, single base substitutions (SBS) are underinvestigated as predictors of HRD. WES data of the TCGA pan-cancer cohort and an in-house ovarian cancer cohort were annotated by alterations in BRCA1/2 and additional genes causative of HRD. Using this reference, the new biomarker fdeam defined as frequency of C > T transitions at CpG sites in relation to all SBS and HRDsum were compared for the detection of HRD. In the TCGA ovarian cancer, the in-house, and the TCGA breast cancer cohorts, fdeam performed non-inferior to HRDsum (AUC = 0.84, AUC = 0.85, and AUC = 0.88). The cutpoint fdeam = 13.1% maximized the balanced accuracy in the TCGA ovarian cancer cohort and resulted in sensitivity = 89% and specificity = 77% in the in-house cohort. In a simulation study, fdeam retained high sensitivity for HRD detection and outperformed HRDsum in tumors of purity 40%, 20%, and 10%. Overcoming the limited robustness against low tumor purity, the new biomarker can contribute to a more sensitive detection of HRD in clinical samples. Further studies are warranted to confirm its clinical validity and utility and explore its potential for liquid biopsies. |
| format | Article |
| id | doaj-art-0c9ecb16a7c9418a8c6ddec9fcbedd72 |
| institution | Kabale University |
| issn | 2399-3642 |
| language | English |
| publishDate | 2025-07-01 |
| publisher | Nature Portfolio |
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| series | Communications Biology |
| spelling | doaj-art-0c9ecb16a7c9418a8c6ddec9fcbedd722025-08-20T03:42:52ZengNature PortfolioCommunications Biology2399-36422025-07-018111310.1038/s42003-025-08529-3CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancerEva Romanovsky0Michael Menzel1Klaus Kluck2Susanne Beck3Markus Ball4Peter Schirmacher5Daniel Kazdal6Albrecht Stenzinger7Jan Budczies8Institute of Pathology, Heidelberg University HospitalInstitute of Pathology, Heidelberg University HospitalInstitute of Pathology, Heidelberg University HospitalInstitute of Pathology, Heidelberg University HospitalInstitute of Pathology, Heidelberg University HospitalInstitute of Pathology, Heidelberg University HospitalInstitute of Pathology, Heidelberg University HospitalInstitute of Pathology, Heidelberg University HospitalInstitute of Pathology, Heidelberg University HospitalAbstract Homologous recombination deficiency (HRD) is a predictive biomarker for PARP inhibition and platinum-based chemotherapy. While copy number alteration-based scores such as HRDsum = LST + TAI + LOH are included in therapy approvals, single base substitutions (SBS) are underinvestigated as predictors of HRD. WES data of the TCGA pan-cancer cohort and an in-house ovarian cancer cohort were annotated by alterations in BRCA1/2 and additional genes causative of HRD. Using this reference, the new biomarker fdeam defined as frequency of C > T transitions at CpG sites in relation to all SBS and HRDsum were compared for the detection of HRD. In the TCGA ovarian cancer, the in-house, and the TCGA breast cancer cohorts, fdeam performed non-inferior to HRDsum (AUC = 0.84, AUC = 0.85, and AUC = 0.88). The cutpoint fdeam = 13.1% maximized the balanced accuracy in the TCGA ovarian cancer cohort and resulted in sensitivity = 89% and specificity = 77% in the in-house cohort. In a simulation study, fdeam retained high sensitivity for HRD detection and outperformed HRDsum in tumors of purity 40%, 20%, and 10%. Overcoming the limited robustness against low tumor purity, the new biomarker can contribute to a more sensitive detection of HRD in clinical samples. Further studies are warranted to confirm its clinical validity and utility and explore its potential for liquid biopsies.https://doi.org/10.1038/s42003-025-08529-3 |
| spellingShingle | Eva Romanovsky Michael Menzel Klaus Kluck Susanne Beck Markus Ball Peter Schirmacher Daniel Kazdal Albrecht Stenzinger Jan Budczies CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer Communications Biology |
| title | CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer |
| title_full | CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer |
| title_fullStr | CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer |
| title_full_unstemmed | CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer |
| title_short | CG>TG mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer |
| title_sort | cg tg mutation frequency as negative predictor of homologous recombination deficiency in ovarian and breast cancer |
| url | https://doi.org/10.1038/s42003-025-08529-3 |
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