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MicroRNA-371-373 cluster and methylome analysis suggests that a subset of “somatic-type” malignancies arising in germ cell tumors may originate in yolk sac tumor components

ABSTRACT: Background: Somatic-type malignancies (SM) arising in germ cell tumors (GCTs) represent aggressive and chemoresistant neoplasms frequently occurring as metastases after chemotherapy. Historically, SM have been interpreted as originating in teratoma; however, recent observations suggest that a subset may derive from yolk sac tumor. In this study, we evaluate the relationship between conventional histologic types of GCT and SM of germ cell origin by assessing expression of miR-371~373 and genomic methylation. Methods: A cohort of 97 samples (41 SM and 38 conventional GCTs, including paired conventional GCT and SMs from individual tumors) were assessed for miR-371~373 expression (RT-qPCR) and genomic DNA methylation (clinically validated assay). Results: Expression of miR-371~373 was higher in conventional non-teratomatous GCT than in SM (considered as a single category containing all histologic subtypes). However, miR-371~373 expression was heterogeneous among the latter, with significantly higher levels in sarcomatoid yolk sac tumor (SYST) and glandular neoplasms than in other SMs. Genomic DNA methylation analysis showed that SMs (considered as a single category) did not form a discrete cluster. Instead, they grouped into subclusters that intercalated with conventional GCTs. Analysis of paired conventional GCT and SM or “SM-like” components (i.e., components with SM histology that did not meet size criteria) from individual tumors demonstrated a clear separation according to histology, suggesting that epigenetic processes play a significant role in the transformation of GCT to SM. Discussion: A subset of SMs shows molecular similarities to (and may derive from) yolk sac tumor, with SYST and glandular yolk sac tumor possibly representing intermediate phenotypes. The transformation of conventional GCT into SM seems to be driven largely by epigenetic mechanisms, suggesting that trials of targeted treatment with epidrugs may be beneficial in selected patients.

ORGANISM(S): Homo sapiens

PROVIDER: GSE281147 | GEO | 2025/04/04

REPOSITORIES: GEO

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Project description:Malignant germ-cell-tumours (GCTs) are characterised by microRNA (miRNA/miR-) dysregulation, with universal over-expression of miR-371~373 and miR-302/367 clusters regardless of patient age, tumour site, or subtype (seminoma/yolk-sac-tumour/embryonal carcinoma). These miRNAs are released into the bloodstream, presumed within extracellular-vesicles (EVs) and represent promising biomarkers. Here, we comprehensively examined the role of EVs, and their miRNA cargo, on (fibroblast/endothelial/macrophage) cells representative of the testicular GCT (TGCT) tumour microenvironment (TME). Small RNA next-generation-sequencing was performed on 34 samples, comprising representative malignant GCT cell lines/EVs and controls (testis fibroblast [Hs1.Tes] cell-line/EVs and testis/ovary samples). TME cells received TGCT co-culture, TGCT-derived EVs, and a miRNA overexpression system (miR-371a-OE) to assess functional relevance. TGCT cells secreted EVs into culture media. MiR-371~373 and miR-302/367 cluster miRNAs were overexpressed in all TGCT cells/subtypes compared with control cells and were highly abundant in TGCT-derived EVs, with miR-371a-3p/miR-371a-5p the most abundant. TGCT co-culture resulted in increased levels of miRNAs from the miR-371~373 and miR-302/367 clusters in TME (fibroblast) cells. Next, fluorescent labelling demonstrated TGCT-derived EVs were internalised by all TME (fibroblast/endothelial/macrophage) cells. TME (fibroblast/endothelial) cell treatment with EVs derived from different TGCT subtypes resulted in increased miR-371~373 and miR-302/367 miRNA levels, and other generic (eg, miR-205-5p/miR-148-3p) and subtype-specific (seminoma, eg, miR-203a-3p; yolk-sac-tumour, eg, miR-375-3p) miRNAs. MiR-371a-OE in TME cells resulted in increased collagen contraction (fibroblasts) and angiogenesis (endothelial cells), via direct mRNA downregulation and alteration of relevant pathways. TGCT cells communicate with nontumour stromal TME cells through release of EVs enriched in oncogenic miRNAs, potentially contributing to tumour progression.

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MicroRNA-371-373 cluster and methylome analysis suggests that a subset of “somatic-type” malignancies arising in germ cell tumors may originate in yolk sac tumor components

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