Related Experiment Video
Updated: Jul 10, 2026
Sequencing Small Non-coding RNA from Formalin-fixed Tissues and Serum-derived Exosomes from Castration-resistant Prostate Cancer Patients
Published on: November 19, 2019
Shallow Whole-Genome Sequencing to Assess Genomic Instability and Predict Treatment Response in Metastatic
Peter H J Slootbeek1, Yarah M Quint2, Julian J R Kokke1
1Department of Medical Oncology, Radboud University Medical Center, Nijmegen, the Netherlands.
Purpose:
Patients with metastatic castration-resistant prostate cancer (mCRPC) and homologous recombination deficiency (HRD) benefit from poly (ADP-ribose) polymerase (PARP) inhibitors (PARPis) or platinum-based chemotherapy (PlCh). Pathogenic variants in homologous recombination repair genes are used as a proxy for the phenotype. Genomic Instability Score (GIS) is a metric for the effect of HRD. This study used shallow whole-genome sequencing (sWGS), a cost-effective alternative to full-depth WGS, to calculate GIS and evaluate its predictive value for PARPi or PlCh response.
Patients And Methods:
We analyzed 288 tumor samples from 266 patients with mCRPC, consisting of 120 whole-genome samples from formalin-fixed paraffin-embedded material newly profiled at a sequencing depth of 2× and 168 from fresh frozen material downsampled in silico from 106× to 2×. The GIS was defined as the sum of large-scale transitions, telomeric-allelic imbalances, and genomic loss of heterozygosity.
Results:
The median GIS was 26 (IQR, 19-37). Samples with pathogenic variants in BRCA1, BRCA2, or PALB2 (BRCA complex) had a significantly higher median GIS (38 v 26, P < .0005). The median GIS increased significantly with tumor ploidy. Patients showing ≥50% prostate-specific antigen (PSA) declines had higher GIS on both PARPi (median 40 v 28, P = .0003) and PlCh (41 v 26, P = .0113). Similarly, patients with a partial response by RECIST1.1 had higher GIS than those with progressive disease (PARPi: 39 v 26, P = .0356; PlCh: 44 v 25, P = .0046). Adding GIS to BRCA-complex status improved PSA response prediction in logistic models (AUC PARPi: 0.849 v 0.781, P = .0308; PlCh: 0.731 v 0.658, P = .1888).
Conclusion:
GIS assessment by sWGS is feasible and associated with response to PARPis and PlCh. The combination of BRCA-complex status and GIS is superior to BRCA-complex status alone in predicting PSA response to PARPis but not to PlCh.
Insights
Genomic Instability Score (GIS) calculated via shallow whole-genome sequencing (sWGS) predicts treatment response in metastatic castration-resistant prostate cancer (mCRPC). Combining GIS with BRCA-complex status improves prediction of prostate-specific antigen (PSA) decline for poly (ADP-ribose) polymerase inhibitors (PARPis).
Area of Science:
- Oncology
- Genomics
- Cancer Therapeutics
Background:
- Metastatic castration-resistant prostate cancer (mCRPC) patients with homologous recombination deficiency (HRD) benefit from PARP inhibitors (PARPis) or platinum chemotherapy (PlCh).
- Pathogenic variants in homologous recombination repair genes are commonly used as a proxy for HRD.
- Genomic Instability Score (GIS) quantifies the genomic effect of HRD.
Purpose of the Study:
- To evaluate the predictive value of GIS, calculated using cost-effective shallow whole-genome sequencing (sWGS), for treatment response to PARPis or PlCh in mCRPC.
- To assess if GIS can serve as a more comprehensive biomarker for HRD-related treatment sensitivity.
Main Methods:
- Shallow whole-genome sequencing (sWGS) was performed on 288 mCRPC tumor samples.
- Genomic Instability Score (GIS) was calculated as the sum of large-scale transitions, telomeric-allelic imbalances, and genomic loss of heterozygosity.
- GIS was correlated with treatment response (PSA decline, RECIST1.1) and BRCA-complex pathogenic variants.
Main Results:
- Median GIS was 26; samples with BRCA-complex variants had significantly higher GIS (median 38).
- Higher GIS was associated with significant PSA declines (≥50%) and partial responses by RECIST1.1 for both PARPi and PlCh.
- Combining GIS with BRCA-complex status improved prediction of PSA response to PARPis (AUC 0.849 vs 0.781).
Conclusions:
- Genomic Instability Score (GIS) assessment by sWGS is a feasible method for evaluating HRD.
- GIS is associated with treatment response to PARPis and PlCh in mCRPC patients.
- The combination of GIS and BRCA-complex status offers superior prediction of PSA response to PARPis compared to BRCA-complex status alone.
