PEG10 is a candidate biomarker for malignant tumors occurring in DICER1-related tumor predisposition

Children with germline pathogenic variants of DICER1 have a highly elevated risk of cancers in many different organs, recognized as DICER1-related tumor predisposition (DRTP). DRTP tumors/lesions have one inactivated copy and one 'hotspot' mutated copy of DICER1. All 'hotspot' DICER1 mutations impair 5p microRNA (miRNA) production. MiRNAs are short non-coding RNA molecules that downregulate messenger RNA (mRNA) expression. Mature 5p or 3p miRNAs are produced by the endonuclease DICER1. Mature miRNAs are loaded into AGO2-containing RNA-induced silencing complex where they target mRNAs via a seed sequence in the mRNA's 3' untranslated region (3' UTR). Despite evidence of widespread dysregulation of gene expression in the presence of DICER1 'hotspot' mutations, there is no established immunohistochemistry (IHC) marker to complement sequencing-based strategies for identification of DRTP tumors. AGO2 miR-eCLIP and RNA-seq data from a mouse cell model of DRTP (Dicer1^E1705K, referred to here as E1705K cells) identified paternally expressed gene 10 (Peg10) as a diagnostic candidate. Peg10 mRNA and protein expression were tested in control and Dicer1-mutant cells, and de-repression of Peg10 3' UTR was tested using reporter assays. PEG10 IHC staining of a human tumor microarray (TMA, n = 63) was performed and the performance of the PEG10 H-score as a DICER1 classifier was evaluated using receiver operating characteristic (ROC) analysis. Peg10 mRNA and protein levels were elevated in E1705K cells. Expression of a reporter gene linked to the Peg10 3' UTR was elevated in mutant but not control cells, consistent with altered miRNA regulation of Peg10 in the mutant cells. A PEG10 H-score cutoff of 35 resulted in a sensitivity of 78.1% and specificity of 90.0% for presence of a DICER1 'hotspot' mutation. PEG10 is a biomarker that is elevated in many DRTP tumors from both sexes bearing a variety of DICER1 'hotspot' variants. PEG10 may act as a cancer-placental antigen/cancer-testis antigen, whose expression could create a possible target for cancer immunotherapies. © 2026 The Pathological Society of Great Britain and Ireland.