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Background <p>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 <i>BRCA1/2</i> 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.</p> Methods <p>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.</p> Results <p><i>BRCA2</i> was the most frequently altered HRR gene, frequently co-occurring with <i>PTEN</i> loss. High GIS was associated with <i>BRCA2</i>/<i>RB1</i> 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.</p> Conclusions <p>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.</p>

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Functional footprints of homologous recombination deficiency in prostate cancer revealed by ctDNA fragmentation and transcription factor accessibility

  • 期刊论文

  • 出版模式：

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  • 发表日期：

    2026年1月9日

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  • Georgios Vlachos,
  • Tina Moser,
  • Isaac Lazzeri,
  • Matthias J. Moser,
  • Lisa Glawitch,
  • Emil Thomas Bauernhofer,
  • Anna Eberhard,
  • Christine Beichler,
  • Hanieh Sadeghi,
  • Jasmin Blatterer,
  • Stefan Kühberger,
  • Nina Monsberger,
  • Angelika Terbuch,
  • Karl Kashofer,
  • Jochen B. Geigl,
  • Thomas Bauernhofer,
  • Ellen Heitzer

摘要

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.