Background: The incidence of venous thromboembolism (VTE) in patients with ovarian cancer is higher than most solid tumors, ranging between 10–30%, and a diagnosis of VTE in this patient population is associated with worse oncologic outcomes. The tumor-specific molecular factors that may lead to the development of VTE are not well understood. Objectives: The aim of this study was to identify molecular features present in ovarian tumors of patients with VTE compared to those without. Methods: We performed a multiplatform omics analysis incorporating RNA and DNA sequencing, quantitative proteomics, as well as immune cell profiling of high-grade serous ovarian carcinoma (HGSC) samples from a cohort of 32 patients with or without VTE. Results: Pathway analyses revealed upregulation of both inflammatory and coagulation pathways in the VTE group. While DNA whole-exome sequencing failed to identify significant coding alterations between the groups, the results of an integrated proteomic and RNA sequencing analysis indicated that there is a relationship between VTE and the expression of platelet-derived growth factor subunit B (PDGFB) and extracellular proteins in tumor cells, namely collagens, that are correlated with the formation of thrombosis. Conclusions: In this comprehensive analysis of HGSC tumor tissues from patients with and without VTE, we identified markers unique to the VTE group that could contribute to development of thrombosis. Our findings provide additional insights into the molecular alterations underlying the development of VTE in ovarian cancer patients and invite further investigation into potential predictive biomarkers of VTE in ovarian cancer.

Patients with high-grade serous ovarian cancer (HGSC) who have no visible residual disease (R0) after primary surgery have the best clinical outcomes, followed by patients who undergo neoadjuvant chemotherapy (NACT) and have a response enabling interval cytoreductive surgery. Clinically useful biomarkers for predicting these outcomes are still lacking. Extracellular vesicles (EVs) have been recognized as liquid biopsy-based biomarkers for early cancer detection and disease surveillance in other disease settings. In this study, we performed extensive molecular characterization of serum-derived EVs and correlated the findings with therapeutic outcomes in patients with HGSC. Using EV-DNA whole-genome sequencing and EV-RNA sequencing, we identified distinct somatic EV-DNA alterations in cancer-hallmark genes and in ovarian cancer genes, as well as significantly altered oncogenic pathways between the R0 group and NACT groups. We also found significantly altered EV-RNA transcriptomic variations and enriched pathways between the groups. Taken together, our data suggest that the molecular characteristics of EVs could enable prediction of patients with HGSC who could undergo R0 surgery or respond to chemotherapy.

In patients with high-grade serous ovarian cancer (HGSC), it is unclear which genomic features are related to complete gross resection (R0), which is typically associated with better clinical outcomes, or response to neoadjuvant chemotherapy (NACT). In this study, we evaluated T cell receptor (TCR) repertoire diversity in primary and metastatic tumor samples (n = 90) from clinically well-annotated patients with HGSC who achieved R0 or received NACT with excellent or poor response based on a laparoscopic triage algorithm. TCR sequencing followed by an integrative analysis with comprehensive multi-omics data identified higher TCR diversity (e.g., higher number of unique productive sequences and less clonal relatedness) in the R0 than NACT groups. We found enrichment of specific TCRβ genes usage, distinct mutual exclusiveness and co-occurrence pattern of TCRβ genes among the groups. We also found significantly positive correlations between clonal relatedness and neoantigens, copy number variations, and mutation load in the groups.

Background: The impact of chemotherapy response score (CRS) on prognosis has varied among studies. We addressed the prognostic significance of CRS and the prognostic value of previously undescribed histologic features using a cohort of 245 patients. Methods: Retrospective study in patients with advanced extrauterine high-grade serous carcinomas treated with neoadjuvant chemotherapy followed by interval tumor reductive surgery from 1990 to 2018 in our hospital. Gynecologic pathologists assessed tumor CRS and other histologic features. Clinical information was collected, and multivariate analyses were conducted. Results: A modified 2 tier CRS (CRS 1/2 versus CRS 3) was significantly associated, independent of scoring site (omental versus adnexal), with overall survival (OS) (omentum, p = 0.018; adnexa, p = 0.042; entire cohort, p = 0.002) and progression-free survival (PFS) (p = 0.021, p = 0.035, and p = 0.001, respectively). On multivariate survival analysis, 2 tier CRS, oncocytic change, inflammation, and desmoplasia were significant for OS (p = 0.034, p = 0.020, p = 0.007, and p = 0.010, respectively). Likewise, 2 tier CRS, inflammation, and desmoplasia were significant for PFS (p = 0.012, p = 0.003, p = 0.011, respectively). Conclusions: The modified 2 tier CRS was significantly associated with survival, independent of scoring site. Additional histologic features including oncocytic change, inflammation, and desmoplasia can also predict patient outcomes.

Introduction: Clonal hematopoiesis (CH) is characterized by the presence of hematopoietic stem cells (HSCs) with the potential of clonally expanding and giving rise to hematological malignancies. Clonal hematopoiesis of indeterminate potential (CHIP) is the outgrowth of a single HSC clone with an acquired somatic mutation in the absence of hematological abnormalities. CHIP variants occur with a variant allele frequency (VAF) of at least 2% in peripheral blood. This definition does not account for less frequent mutations that give rise to hematopoietic clones. Previous studies indicate an association between CH and secondary hematologic malignancies in cancer patients who receive chemotherapy.Methods: To discover novel candidate CHIP mutations, including those with extremely low VAFs, we performed an in-depth characterization of low-frequency CHIP variants in a highly selected group of patients with high-grade serous ovarian cancer (HGSC) before and after neoadjuvant chemotherapy (NACT). We performed comprehensive ultra-high-depth whole-exome sequencing of circulating free DNA (cfDNA) and matched white blood cell (WBC) DNA from pre- (n=9) and post-NACT (n=9) samples from HGSC patients who had excellent response (ER; n=4) or poor response (PR; n=5) to NACT.Results: Variants present in both the WBC DNA and cfDNA from a patient were considered candidate CHIP variants. We identified 93,088 candidate CHIP variants in 13,780 genes. Compared with pre-NACT samples, post-NACT samples tended to have fewer CHIP mutations with VAFs of less than 5%, which may reflect the negative selective pressure of chemotherapy on rare hematopoietic clones. Finally, we identified CHIP variants in tumor samples matched to the liquid biopsies.Discussion: Our innovative sequencing approach enabled the discovery of a large number of novel low-frequency candidate CHIP mutations, whose frequency and composition are affected by chemotherapy, in the cfDNA of patients with HGSC. The CHIP variants that were enriched after chemotherapy, if validated, might become essential predictive markers for therapy-related myeloid neoplasia.