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Updated: Nov 22, 2025
Identifying the Effects of BRCA1 Mutations on Homologous Recombination using Cells that Express Endogenous Wild-type BRCA1
Published on: February 17, 2011
BRCA2, ATM, and CDK12 Defects Differentially Shape Prostate Tumor Driver Genomics and Clinical Aggression
Evan Warner1, Cameron Herberts1, Simon Fu2,3
1Vancouver Prostate Centre, Department of Urologic Sciences, University of British Columbia, Vancouver, British Columbia, Canada.
Purpose:
DNA damage repair (DDR) defects are common across cancer types and can indicate therapeutic vulnerability. Optimal exploitation of DDR defects in prostate cancer requires new diagnostic strategies and a better understanding of associated clinical genomic features.
Experimental Design:
We performed targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer. Depth-based copy-number calls and heterozygous SNP imbalance were leveraged to expose DDR-mutant allelic configuration and categorize mechanisms of biallelic loss. We used split-read structural variation analysis to characterize tumor suppressor rearrangements. Patient-matched archival primary tissue was analyzed identically.
Results:
BRCA2, ATM, and CDK12 were the most frequently disrupted DDR genes in circulating tumor DNA (ctDNA), collectively mutated in 15% of evaluable cases. Biallelic gene disruption via second somatic alteration or mutant allele-specific imbalance was identified in 79% of patients. A further 2% exhibited homozygous BRCA2 deletions. Tumor suppressors TP53, RB1, and PTEN were controlled via disruptive chromosomal rearrangements in BRCA2-defective samples, but via oncogene amplification in context of CDK12 defects. TP53 mutations were rare in cases with ATM defects. DDR mutations were re-detected across 94% of serial ctDNA samples and in all available archival primary tissues, indicating they arose prior to metastatic progression. Loss of BRCA2 and CDK12, but not ATM, was associated with poor clinical outcomes.
Conclusions:
BRCA2, ATM, and CDK12 defects are each linked to distinct prostate cancer driver genomics and aggression. The consistency of DDR status in longitudinal samples and resolution of allelic status underscores the potential for ctDNA as a diagnostic tool.
Insights
Defects in DNA damage repair (DDR) genes like BRCA2, ATM, and CDK12 are common in metastatic prostate cancer. These genetic alterations, detectable in circulating tumor DNA (ctDNA), offer potential diagnostic strategies and link to clinical outcomes.
Area of Science:
- Genomics
- Oncology
- Molecular Biology
Background:
- DNA damage repair (DDR) defects are prevalent in cancers and represent therapeutic vulnerabilities.
- Understanding these defects in prostate cancer is crucial for developing new diagnostic and therapeutic strategies.
Purpose of the Study:
- To investigate the genomic landscape of DDR defects in metastatic prostate cancer.
- To identify specific DDR gene alterations and their clinical genomic features.
- To evaluate the potential of circulating tumor DNA (ctDNA) as a diagnostic tool.
Main Methods:
- Targeted sequencing of 1,615 plasma cell-free DNA samples from 879 patients with metastatic prostate cancer.
- Analysis of copy-number alterations and single nucleotide polymorphism (SNP) imbalance to identify DDR-mutant allelic configurations and mechanisms of biallelic loss.
- Split-read structural variation analysis to characterize tumor suppressor rearrangements.
- Comparison with patient-matched archival primary tissue.
Main Results:
- BRCA2, ATM, and CDK12 were the most frequently mutated DDR genes in ctDNA (15% of cases).
- Biallelic gene disruption was observed in 79% of patients, with homozygous BRCA2 deletions in 2%.
- Distinct genomic alterations (chromosomal rearrangements vs. oncogene amplification) were associated with BRCA2 and CDK12 defects.
- DDR mutations were consistently detected in serial ctDNA samples and primary tissues, indicating early occurrence.
- Loss of BRCA2 and CDK12, but not ATM, correlated with poor clinical outcomes.
Conclusions:
- BRCA2, ATM, and CDK12 defects are associated with distinct prostate cancer genomic profiles and disease aggressiveness.
- The high consistency of DDR status in longitudinal ctDNA samples highlights its potential as a diagnostic biomarker.
- ctDNA analysis provides valuable insights into the allelic status and genomic alterations in metastatic prostate cancer.
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