患者来源卵巢癌的整合基因组与转录分析揭示HRD相关特征及体内对PARP抑制的反应

Introduction Homologous recombination deficiency (HRD) and BRCA1/2 alterations are key biomarkers for PARP inhibitor sensitivity in ovarian cancer. Transcriptional features such as RB1 expression may further refine biologic subgroups and therapeutic hypotheses. We performed integrated DNA/RNA profiling of FFPE ovarian tumors to characterize histologic distribution, genomic alterations, genomic instability score (GIS), RB1 expression, and in vivo olaparib response in selected HRD-positive models. Methods Thirty-two patient-derived FFPE ovarian tumor blocks were prepared, and H&E sections were reviewed by an anatomic pathologist (SR) to confirm sufficient tumor content prior to next-generation sequencing. Comprehensive genomic, immune profiling, and HRD assessment were performed. RNA-seq quantified RB1 expression, with “RB1-low” defined as TPM ≤ 6.26 (study 25th percentile). Two HRD-positive models were subjected to in vivo testing of olaparib response in female NSG mice following subcutaneous implantation. Results The cohort consisted predominantly of serous adenocarcinomas (71.9%), followed by ovarian adenocarcinoma NOS (21.9%), mucinous adenocarcinoma (3.1%), and carcinosarcoma (3.1%). TP53 mutations were present in 93.8% of cases. BRCA1 alterations were identified in 37.5% of tumors and BRCA2 alterations in 25.0%. HRD status was positive in 34.4% of cases, negative in 43.8%, and indeterminate in 21.9%. GIS scores varied across HRD categories, with HRD-positive tumors showing a range of 12-61 (median 29, mean 32.9), HRD-negative tumors ranging from 3-41 (median 11.5, mean 17.2), and indeterminate tumors ranging from 7-32 (median 19, mean 18.1). RB1-low expression was observed in 21.9% of tumors overall, with enrichment in HRD-positive cases (45.5%) compared to HRD-negative (7.1%) and indeterminate (14.3%) groups. To assess translatability of HRD findings, two HRD-positive serous adenocarcinomas were tested for olaparib response in vivo. One BRCA2-mutated tumor (LCOV-2089, GIS=32) demonstrated a robust therapeutic effect, with a median tumor volume reduction of 68.1% and durable complete responses in 33.3% of treated mice. In contrast, a second BRCA2-mutated tumor (LCOV-2118, GIS=17) did not exhibit tumor regression but showed an increased time to progression of >85% compared to untreated controls. Conclusions Overall, these findings suggest a meaningful correlation between genomic HRD status and in vivo therapeutic response, supporting the translational relevance of integrated profiling and the use of patient-derived models for preclinical investigations.