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Selected Publication:
SHR Neuro Cancer Cardio Lipid Metab Microb
Vlachos, G; Moser, T; Lazzeri, I; Moser, MJ; Glawitch, L; Bauernhofer, ET; Eberhard, A; Beichler, C; Sadeghi, H; Blatterer, J; Kühberger, S; Monsberger, N; Terbuch, A; Kashofer, K; Geigl, JB; Bauernhofer, T; Heitzer, E.
Functional footprints of homologous recombination deficiency in prostate cancer revealed by ctDNA fragmentation and transcription factor accessibility.
Br J Cancer. 2026;
Doi: 10.1038/s41416-025-03301-0
PubMed
FullText
FullText_MUG
- Leading authors Med Uni Graz
- Heitzer Ellen
- Vlachos Georgios
- Co-authors Med Uni Graz
- Bauernhofer Thomas
- Beichler Christine
- Blatterer Jasmin
- Eberhard Anna
- Geigl Jochen Bernd
- Kashofer Karl
- Kühberger Stefan
- Lazzeri Isaac
- Monsberger Nina
- Moser Tina
- Sadeghi Hanieh
- Terbuch Angelika
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- Abstract:
- BACKGROUND: Homologous recombination deficiency (HRD) is a predictive biomarker for response to PARP inhibitors and platinum-based therapies in prostate cancer (PCa). However, current diagnostic approaches, often limited to BRCA1/2 mutation testing or genomic scars, fail to capture the full spectrum of HRD. Tissue-based testing is further hampered by tumour heterogeneity and biopsy limitations in patients with metastatic bone disease. This study aimed to develop a noninvasive, multimodal ctDNA-based strategy for comprehensive HRD profiling in advanced PCa. METHODS: We analysed plasma-derived ctDNA from 106 patients with metastatic PCa. The approach integrated targeted sequencing of homologous recombination repair (HRR) genes, low-pass whole genome sequencing for genomic instability scores (GIS), whole-exome sequencing for mutational signature analysis, and cfDNA fragmentomics, including chromatin accessibility profiling. RESULTS: BRCA2 was the most frequently altered HRR gene, frequently co-occurring with PTEN loss. High GIS was associated with BRCA2/RB1 loss, increased somatic copy number alterations, and poor overall survival. HRD tumours were enriched for mutational signatures SBS3 and ID6, displayed increased dinucleosome-length fragments, and showed reduced accessibility at zinc finger transcription factor binding sites. A fragmentomics-based classifier identified HRD-positive cases with high accuracy. CONCLUSIONS: Our findings support the use of multimodal ctDNA profiling as a non-invasive approach to identify HRD in prostate cancer. The integration of mutation, genomic instability, and fragmentomic features provides a broader functional view of HRD and may enhance patient stratification for targeted therapies.