Molecular Correlates of Venous Thromboembolism (VTE) in Ovarian Cancer

Abstract

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.

Keywords: genetic markers; genomics; ovarian cancer; proteomics; venous thromboembolism.

Figure 1

Schema of multi-omics analysis in HGSC patients with and without concurrent VTE. In this analysis, a total of 32 samples (n = 16 for both control and VTE groups) were obtained from the MD Anderson Cancer Center Ovarian Cancer Moon Shot database and subjected to a multi-platform omics analysis including whole exome sequencing (WES), quantitative mass spectrometry-based proteomics, and transcriptomics with RNA sequencing and a full integrated analysis incorporating clinical data and outcomes from the electronic medical record. Figure created with BioRender (https://app.biorender.com/illustrations/612d1ad2a3e2c500a5b6b6c3, accessed on 23 October 2021).

Figure 2

Differentially expressed genes and metabolic pathways in HGSC patients in VTE and control groups. (A) Heat map of the top 40 altered transcripts in HGSC tumor tissue in patients with and without venous thromboembolism (VTE). Abbreviations: Fallopian_T, fallopian tube; Post_cul_de_sac, posterior cul de sac; ROV, right ovary; MS, moonshot cancer database; non-MS, non-moonshot cancer database. (B) Gene set enrichment analysis (GSEA) identifying enriched pathways for VTE compared to non-VTE controls. Red indicates enhanced enrichment; blue indicates decreased enrichment.

Figure 3

Significantly altered proteins in HGSC tumor tissues between VTE and control groups. (A) Supervised hierarchical cluster analysis of 255 significantly altered proteins between VTE and control tumors, including VTE timing metadata. (B) Cellular localization of 255 proteins that were significantly altered between VTE and control tumors (LIMMA, p < 0.01).

Figure 4

Co-altered proteins and transcripts between the VTE and control groups. (A) Comparison of co-quantified protein and transcript alterations in VTE vs. control tissue (LIMMA, p < 0.05, FC ± 1.5). (B) Differential protein expression matrix in collagen 1A1 between control (blue) and VTE (red); the X-axis represents log-fold change, p = 0.00093. (C) Differential protein expression matrix in collagen 3A1 between the control (blue) and VTE (red) groups, p = 0.00032.