Discovering a qualitative transcriptional signature of homologous recombination defectiveness for prostate cancer.

The discovery of homologous recombination deficiency (HRD) biomarkers in prostate cancer is important for patients who will benefit from poly ADP-ribose polymerase inhibitor (PARPi). Here, we developed a transcriptional homologous recombination defectiveness (HRDness) signature, comprising 16 gene pairs (16-GPS), for prostate cancer by a relative expression ordering (REO)-based discovery procedure. Subsequently, two newly subtypes classified by 16-GPS showed a higher significance level in various clinicopathological and HRD features than subtypes obtained by other methods, such as HRDetect. HRDness subtype also displayed more aggressive features and higher genomics scores than non-HRDness in three independent datasets. HRDness prostate cancer cells were more sensitive to PARPi than non-HRDness. Moreover, the HRDness samples showed distinct multi-omics characteristics related to homologous recombination repair function loss. Overall, the newly proposed qualitative signature can robustly determine the HRD status for prostate cancer at the personalized level, and especially be an auxiliary tool for PARPi treatment strategy.