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349 Dissecting the microenvironment of gestational trophoblastic disease through deconvolution of bulk RNA-seq data
  1. Alina Nicheperovich and
  2. Benjamin Schuster-Boeckler
  1. Ludwig Institute for Cancer Research, University of Oxford, Oxford, UK


Introduction/Background Gestational trophoblastic disease (GTD) describes a group of pre-malignant and cancerous lesions that arise from the trophoblast cells of the placenta. The drivers of GTD remain elusive. In its inherent state, the trophoblast exhibits certain similarities to cancer, such as angiogenesis and invasion of the surrounding tissues. To unveil the mechanisms underlying the transition from healthy placenta to malignant phenotype, this study utilises deconvolution of transcriptomic data to estimate cellular composition of GTD lesions.

Methodology BayesPrism was used to deconvolute transcriptome data from 4 pre-malignant complete hydatidiform moles (CHMs), 2 choriocarcinomas (CCs), 4 placental site trophoblast tumours (PSTTs), and 4 epithelioid trophoblast tumours (ETTs), using single-cell RNA-seq data from cells of the maternal-foetal interface as a reference. BayesPrism was also used to estimate sample-specific gene expression in extravillous trophoblast (EVT), a suspected cancer-initiating cell type. This data was then evaluated for differential gene expression and gene set enrichment analysis.

Results Epithelial glandular cell content increased with mortality rate, notably higher in PSTT and ETT versus control (p = 0.038 and p = 0.002, respectively). Immune cell content also rose with disease severity. Unlike healthy and molar samples, cancer subgroups exhibited innate lymphoid cells (ILCs), key in maternal-foetal immune tolerance and trophoblast invasion.

PTEN was significantly upregulated in molar EVT, and its role in hypoxic response in the placenta is further confirmed by the enrichment of the hallmark pathway in CHM. Upregulation of ASPSCR1 and SLC2A1 and downregulation of the oxidative phosphorylation pathway in CHM and PSTT suggest a glycolytic shift. Dysregulated expression of DNA methyltransferases across all disease groups supports the previously suggested role of epigenetics in GTD pathogenesis.

Conclusion This study is the first to consider both immune and non-immune microenvironment of GTD lesions. These findings can direct clinicians towards identifying novel diagnostic targets for developing personalised therapies against gestational neoplasms.

Disclosures The authors disclose no conflict of interest.

Abstract 349 Figure 1

The study workflow

Abstract 349 Figure 2

Overview of cellular composition of GTD lesions

Abstract 349 Figure 3

Gene expression in extravillous trophoblast of GTD lesions

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