Identification of biomarkers complementary to homologous recombination deficiency for improving the clinical outcome of ovarian serous cystadenocarcinoma

Abstract Background: Ovarian cancer patients with tumors positive for homologous recombination deficiency (HRD) would benefit from PAPR inhibitor (PAPRi)therapy. However, patients with HRD-positive tumors account for less than 50% of the whole cohort. So new biomarkers still need to be developed. The aim of this study was to identify biomarkers complementary to HRD for improving the clinical outcome of ovarian serous cystadenocarcinoma (OSC).Methods: The HRD score was established from SNP array data of OSC cohort from TCGA. The genomic landscape and transcriptome data of patients with different HRD scores were analyzed in order to identify biomarkers complementary to HRD. The candidate biomarker was validated in vivo and in vitro experiments.Results: Based on the data from the SNP array and somatic mutation profiles in the OSC patients’ genome, we found that high frequency of actionable mutations existed in NF1 and CDK12 in patients with HRD-negative tumors. We then leveraged the gene expression profiles to screen out CXCL11 expression that was associated with the HRD score and could be used as a predictor of survival outcome. Further comprehensive analysis of the tumor immune microenvironment (TIME) revealed that CXCL11 expression was closely correlated with cytotoxic cells, neoantigen load and immune checkpoint blockade (ICB). Finally, in vivo and in vitro experiments showed that PAPRi increased the expression of CXCL11. Conclusions: Collectively, our study not only provides biomarkers of ovarian cancer complementary to the HRD score but also introduced a potential new perspective for identifying cancer biomarkers associated with genomic instability.