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Identification and validation of liquid biopsy-based methylation biomarkers: a germ cell tumor subtype-specific study [7]

ABSTRACT: Human germ cell tumors (GCTs) occur in infants, children, and adults, and present as germinomatous and/or non-germinomatous (embryonal carcinoma, teratoma, yolk sac tumor (YST), and choriocarcinoma) histologies at gonadal or extragonadal locations. Accurate subtyping is crucial for prognosis and treatment, but current clinical biomarkers lack sensitivity and specificity (serum proteins) or require a tissue biopsy (immunohistochemistry). Hence, less-invasive and improved subtype-specific biomarkers have potential for clinical utility. We conducted a meta-analysis of DNA methylation data (450K/EPIC array) from 15 (three original and 12 published) datasets including 713 GCTs, 109 healthy testis, and 221 healthy peripheral blood samples, revealing that GCT histology is the primary driver of methylation profiles, regardless of tumor location and patient’s age or sex. Per subtype, we identified differentially methylated regions as potential biomarkers. As proof of concept, we identified and validated two YST-specific biomarkers, i.e., APC and DPP7 promotor methylation, using methylation-sensitive restriction enzyme-based qPCR, of which DPP7 was also detectable in GCT serum-derived cell-free DNA. In conclusion, we present a novel method for in silico identification and in vitro and in vivo validation of YST subtype-specific liquid biopsy-based biomarkers. Our bioinformatic pipeline is also easily transferrable encouraging additional applications in pan(pediatric)-cancer studies beyond GCTs.

ORGANISM(S): Homo sapiens

PROVIDER: GSE303826 | GEO | 2026/03/13

REPOSITORIES: GEO

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Project description: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.

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Identification and validation of liquid biopsy-based methylation biomarkers: a germ cell tumor subtype-specific study [7]

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