Non-cell autonomous tumor promotion in DICER1 cancer predisposition
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ABSTRACT:
PROVIDER: PRJNA1103185 | ENA |
REPOSITORIES: ENA
Similar Datasets
Project description:This SuperSeries is composed of the SubSeries listed below.
2025-07-29 | GSE264583 | GEO
Project description:Background: MicroRNAs (miRNAs) are short non-coding RNA molecules that downregulate messenger RNA (mRNA) expression. Mature miRNAs (designated -5p or -3p) are produced by the endonuclease DICER1. Mature miRNAs are loaded into the AGO2-containing RNA-Induced Silencing Complex where they target mRNAs via a seed sequence in the mRNA’s 3’ untranslated region (3’ UTR). 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.
2026-07-02 | GSE299299 | GEO
Project description:The DICER1 gene is mutated in cancer, including in DICER1-related tumour predisposition. Cancer-associated hotspot mutations have been reported in both catalytic domains of DICER and are predicted to disrupt miRNA biogenesis. To understand how these hotspot mutations contribute to cancer development, we generate cell lines harbouring single amino acid substitutions within the catalytic RNase IIIa (S1344L) or RNase IIIb (D1709N) domains of the endogenous DICER1 gene. Here we show that both mutations result in a widespread loss of 5p miRNAs, and an increase in 3p passenger strands loading into AGO2. The shared similarities between both mutants can be attributed to the structural proximity of the S1344 residue to the RNase IIIb catalytic centre. Functionally, we find that changes in the repertoire of miRNAs loaded into AGO2 result in altered gene expression, impacting critical pathways for cancer development, including metastatic potential. Additionally, our results indicate that inactivating the processing activity of DICER does not result in genomic instability. Instead, mutations cause upregulation of transposable elements, including the human endogenous retrovirus H through miRNA-independent mechanisms. This suggests that both canonical and non-canonical DICER functions are important to understand DICER1-related tumour predisposition.
2026-06-22 | GSE328604 | GEO
Project description:Background: MicroRNAs (miRNAs) are short non-coding RNA molecules that downregulate messenger RNA (mRNA) expression. Mature miRNAs (designated -5p or -3p) are produced by the endonuclease DICER1. Mature miRNAs are loaded into the AGO2-containing RNA-Induced Silencing Complex where they target mRNAs via a seed sequence in the mRNA’s 3’ untranslated region (3’ UTR). 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.
2026-07-02 | GSE299033 | GEO
Project description:Identification of PEG10 as a biomarker for DICER1-related tumor predisposition syndrome
| PRJNA1273867 | ENA
Project description:Identification of PEG10 as a biomarker for DICER1-related tumor predisposition syndrome [RNA-Seq]
| PRJNA1272350 | ENA
Project description:The DICER1 gene is mutated in cancer, including Dicer1 syndrome, a rare tumour predisposition syndrome. Cancer-associated hotspots mutations have been reported in both catalytic domains of Dicer, and are predicted to disrupt miRNA processing activity. To understand these hotspot mutations in cancer development, we have generated cell lines harbouring single amino acid substitutions within either the RNAse IIIa (S1344L) and the RNAse IIIb (D1709N) domains of the endogenous Dicer1 gene. We show that both mutations result in a widespread loss of 5p miRNAs, but, unexpectedly, an increase in 3p passenger strands loading into Ago2. Similarities between both mutants can be explained as the S1344 residue is structurally also part of the RNase IIIb catalytical site. Functionally, we found that changes in the repertoire of miRNAs loaded into Ago2 result in altered gene expression, impacting critical pathways for cancer development, including metastatic potential. Our results indicate that inactivating the processing activity of Dicer does not result in genomic instability. Instead, mutations cause a specific upregulation of human endogenous retrovirus H (HERVH) and 3p miRNAs, which have the potential to be used as markers for Dicer1 syndrome tumours.
2026-06-23 | PXD072167 | Pride
Project description:PTEN restrains tumor expansion through cell autonomous and non-autonomous mechanisms
| PRJNA1256273 | ENA
Project description:DICER1 syndrome is a tumor predisposition syndrome caused by familial genetic mutations in DICER1. Pathogenic variants of DICER1 have been discovered in many rare cancers, including cystic liver tumors. However, the molecular mechanisms underlying liver lesions induced by these variants remain unclear. In the present study, we sought to gain a better understanding of the pathogenesis of these variants by generating a mouse model of liver-specific DICER1 syndrome. The mouse model developed bile duct hyperplasia with fibrosis, similar to congenital hepatic fibrosis, as well as cystic liver tumors resembling those in Caroli's syndrome, intrahepatic cholangiocarcinoma, and hepatocellular carcinoma. Interestingly, the mouse model of DICER1 syndrome showed abnormal formation of primary cilia in the bile duct epithelium, which is a known cause of bile duct hyperplasia and cyst formation. These results indicated that DICER1 mutations contribute to cystic liver tumors by inducing defective primary cilia. The mouse model generated in this study will be useful for elucidating the potential mechanisms of tumorigenesis induced by DICER1 variants and for obtaining a comprehensive understanding of DICER1 syndrome.
2024-05-02 | GSE231487 | GEO
Project description:DICER1-related tumor predisposition mutations lead to a gain of 3p-miRNA function, HERVH activity and increased metastatic potential
| PRJNA1455971 | ENA