RNA-Based Homologous Recombination Deficiency Signature Detects Homologous Recombination Deficiency-RNA+ Patients...

Area of Science:

• Oncology
• Genetics
• Biomarker Discovery

Background:

• Homologous recombination deficiency (HRD) is a key phenotype in prostate cancer.
• Current HRD biomarkers are limited, often relying on single gene alterations.
• RNA signature-based methods offer a dynamic assessment of HRD but require validation against gene alterations.

Purpose of the Study:

• To evaluate an RNA signature assay for identifying HRD in prostate cancer.
• To assess the relationship between the RNA signature-based HRD (HRD-RNA+) and homologous recombination repair (HRR) gene alterations.
• To determine if the RNA signature expands the patient population benefiting from PARP inhibitors.

Main Methods:

• A retrospective cohort study of 985 prostate cancer patients was conducted.
• An RNA signature assay, linked to biallelic BRCA1/2 loss, was used to define HRD status.
• HRD status was determined using a binary threshold on a continuous RNA signature scale.

Main Results:

• 13% of patients (126/985) were HRD-RNA+; 79% of these had no coexisting HRR gene alteration.
• The HRD-RNA assay detected HRD in 78% of biallelic BRCA1/2 loss samples.
• HRD-RNA+ was significantly associated with increased TP53 and AR gene alterations.

Conclusions:

• An RNA-based HRD signature identifies a larger fraction of prostate cancer patients potentially benefiting from PARP inhibitors compared to HRR gene mutations alone.
• This RNA signature approach may improve selection of patients for PARPi therapy.
• Further research is needed to confirm the functional significance and predictive value of this HRD signature.