bg-szy HRD Analysis Agent
The HRD Analysis Agent provides comprehensive analysis of homologous recombination deficiency for predicting response to PARP inhibitors and platinum chemotherapy. It integrates genomic scarring signatures (LOH, TAI, LST), BRCA1/2 status, and HRD gene pathway analysis.
When to Use This Skill
- When determining HRD status for PARP inhibitor eligibility.
- To calculate genomic instability scores (GIS) from tumor sequencing.
- For analyzing BRCA1/2 and HRD gene mutations.
- When predicting response to PARP inhibitors or platinum chemotherapy.
- To identify "BRCAness" phenotype in BRCA wild-type tumors.
Core Capabilities
Genomic Scar Scoring: Calculate LOH, TAI, and LST scores from copy number data.
BRCA Pathway Analysis: Assess mutations in BRCA1, BRCA2, and 13 other HRD genes.
HRD Classification: Determine HRD-positive vs. HRD-negative status.
PARP Inhibitor Prediction: Predict response to olaparib, niraparib, rucaparib, talazoparib.
Platinum Sensitivity: Predict platinum chemotherapy sensitivity.
Reversion Detection: Identify BRCA reversion mutations restoring HR function.
HRD Scoring Components
| Score | Definition | Biological Basis |
|---|---|---|
| LOH | Loss of heterozygosity regions >15 Mb | Genomic scarring |
| TAI | Telomeric allelic imbalance | End-to-end fusions |
| LST | Large-scale state transitions | Break-induced repair |
| GIS | Combined LOH + TAI + LST | Overall HRD score |
HRD-Positive Threshold: GIS ≥ 42 (Myriad myChoice) or equivalent
HRD Gene Panel
| Gene | Function | HRD Contribution |
|---|---|---|
| BRCA1 | HR core component | Major |
| BRCA2 | RAD51 loading | Major |
| PALB2 | BRCA2 partner | Moderate-Major |
| RAD51C/D | HR mediators | Moderate |
| ATM | DNA damage sensing | Moderate |
| CHEK2 | Cell cycle checkpoint | Moderate |
| BARD1 | BRCA1 partner | Moderate |
| BRIP1 | Fanconi pathway | Moderate |
| CDK12 | Transcription | Variable |
| RAD51B | HR mediator | Low-Moderate |
Workflow
Input: Copy number segments, somatic mutations, germline variants.
Scar Calculation: Compute LOH, TAI, LST from segmented CNV data.
Gene Analysis: Assess pathogenic variants in HRD genes.
Score Integration: Calculate composite GIS score.
Classification: Determine HRD status.
Reversion Check: Screen for reversion mutations.
Output: HRD score, classification, gene mutations, treatment recommendations.
Example Usage
User: "Analyze HRD status for this ovarian cancer patient to guide PARP inhibitor selection."
Agent Action:
python3 Skills/Oncology/HRD_Analysis_Agent/hrd_analyzer.py \
--cnv_segments tumor_segments.tsv \
--mutations somatic_variants.maf \
--germline germline_variants.vcf \
--tumor_type ovarian \
--purity 0.65 \
--ploidy 2.1 \
--output hrd_report.json
Commercial HRD Tests
| Test | Components | Threshold | FDA Status |
|---|---|---|---|
| myChoice CDx | GIS + BRCA | ≥42 or BRCA+ | FDA approved |
| FoundationOne | LOH | ≥16% | FDA approved |
| SOPHiA DDM HRD | GIS + BRCA | ≥42 or BRCA+ | CE-IVD |
Clinical Indications
FDA-Approved PARP Inhibitor Indications:
- Ovarian: HRD+ or BRCA+ (maintenance, later-line)
- Breast: gBRCA+ (HER2-, metastatic)
- Pancreatic: gBRCA+ (maintenance)
- Prostate: HRR gene mutated (mCRPC)
Response Prediction
| Status | PARP Response | Platinum Response |
|---|---|---|
| BRCA mutated | Very high | High |
| HRD+ / BRCA WT | High | Moderate-High |
| HRD- / BRCA WT | Limited | Standard |
| Reversion+ | Poor | Poor |
AI/ML Components
GIS Calculation:
- ASCAT/FACETS for allele-specific CNV
- HRDetect algorithm integration
- ML refinement of thresholds
Reversion Detection:
- Frameshift restoration analysis
- Splice site reversion
- Secondary deletion removing stop
Response Prediction:
- Multi-feature model (GIS + genes + expression)
- HRDetect signature scoring
- Clinical outcome integration
Resistance Mechanisms
| Mechanism | Detection | Implication |
|---|---|---|
| BRCA reversion | Sequencing | Acquired resistance |
| 53BP1 loss | Expression/mutation | Rescued HR |
| ABCB1 upregulation | Expression | Drug efflux |
| PARP1 loss | Expression | Target loss |
Prerequisites
- Python 3.10+
- ASCAT/FACETS for CNV
- HRDetect implementation
- Germline/somatic variant callers
Related Skills
- Variant_Interpretation - For BRCA classification
- Liquid_Biopsy_Analytics_Agent - For ctDNA HRD monitoring
- Pan_Cancer_MultiOmics_Agent - For multi-omic context
Special Considerations
- Tumor Purity: Low purity affects scar detection
- Prior Therapy: Platinum may select resistant clones
- Germline Testing: Important for family counseling
- Reversion Monitoring: Serial testing recommended
Author
AI Group - Biomedical AI Platform