Identification of PEG10 as a biomarker for DICER1-related tumor predisposition syndrome

Children with pathogenic variants of DICER1 have a highly elevated risk of cancers in many different organs– recognized as DICER1-related tumour predisposition (DRTP). These tumours/lesions have one inactivated copy and one “hotspot” mutated copy of DICER1. All “hotspot” DICER1 mutations impair 5p miRNA production.

DICER1 DNA sequencing has become the diagnostic standard but an immunohistochemical (IHC) diagnostic method may improve patient care via faster return of results.

Methods

Using AGO2 miR-eCLIP and RNAseq data of a mouse cell model of DRTP (E1705K) I identified paternally expressed gene 10 (Peg10) as a diagnostic candidate. Validation of cell overexpression (mRNA and protein) and de-repression of Peg10 3’ UTR was assessed. Dependence on Peg10 for cell viability was measured (post 72-hour siRNA-mediated knockdown).

IHC staining of two tumour microarrays (TMAs) was performed and scored (H-score) to evaluate its use in the clinic (Area Under Curve, AUC). Results: In E1705K, Peg10 displayed elevated RNA and protein levels as well as de-repression of its 3’ UTR. Peg10 knockdown does not impact cell viability.

TMA1 (41 female samples) had an AUC of 0.80 (considered of good clinical utility) while TMA2 (95 male and female samples) had an AUC was 0.71 (fair clinical utility). Conclusion: E1705K identified Peg10 as a biomarker that is elevated in DRTP tumours from both sexes bearing a variety of DICER1 hotspot variants. Elevated Peg10 mRNA levels are in part due to lack of 5p-mediated interactions with its 3’ UTR.