Mutational and low-coverage whole genome sequencing identifies actionable DNA repair alterations in prostate cancer...

Area of Science:

• Oncology
• Genetics
• Molecular Biology

Background:

• PARP inhibitors (PARPi) are emerging treatments for metastatic castration-resistant prostate cancer (mCRPC).
• Molecular profiling of homologous recombination DNA repair (HRR) genes is crucial for mCRPC patient selection.
• Liquid biopsy presents a non-invasive alternative to tumor tissue for genetic analysis.

Purpose of the Study:

• To evaluate the feasibility and utility of combining mutational panel sequencing with shallow whole genome sequencing (sWGS) for HRR status determination in prostate cancer (PCa) patients using plasma.
• To assess the concordance between liquid biopsy and tumor tissue for identifying single nucleotide variants (SNVs) and copy number variations (CNVs).

Main Methods:

• Assessed mutational profiles of 16 HRR genes in 63 PCa patients via plasma.
• Integrated sWGS data to identify non-informative plasma samples and determine mutation origin (germline/somatic).
• Compared plasma-derived SNV and CNV profiles with matched tumor tissue from 41 patients.

Main Results:

• 28.6% of patients had putative pathogenic variants in HRR genes; 15.8% were defined as HRR-mutant.
• Plasma-based mutational analysis showed an 85.7% concordance rate with matched tumor tissue.
• sWGS identified CNV profiles consistent with known PCa profiles.
• Concordance was influenced by circulating tumor DNA (ctDNA) levels and clonal hematopoiesis.

Conclusions:

• Plasma ctDNA analysis is a dependable method for detecting SNVs and CNVs in PCa patients.
• Integrating sWGS with targeted sequencing enhances comprehensive molecular profiling of PCa.
• Liquid biopsy, especially when combined with sWGS, offers a valuable tool for guiding mCRPC treatment decisions.