Somatic mutations in DROSHA and DICER1 impair microRNA biogenesis in Wilms tumors
Ontology highlight
ABSTRACT:
ORGANISM(S): Homo sapiens
PROVIDER: GSE56955 | GEO | 2015/04/21
SECONDARY ACCESSION(S): PRJNA245069
REPOSITORIES: GEO
Similar Datasets
Project description:Through whole-exome sequencing we identified somatic missense mutations in DICER1 and DROSHA in Wilms tumor, a childhood kidney cancer. DICER1 and DROSHA are key enzymes in the microRNA biogenesis pathway. To determine the effect of these mutations on microRNA expression, we prepared small RNAs from Wilms tumors and used next-generation sequencing to determine the expression levels of microRNAs in the tumors. Comparison of miRNA expression in tumors with and without mutations in DICER1 or DROSHA.
2015-04-21 | E-GEOD-56955 | biostudies-arrayexpress
Project description:Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find novel therapeutic leads for this subgroup of patients, we analyzed 58 blastemal-type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large independent replication cohort. Recurrent mutations identified either somatically or in the germline included a hotspot mutation (Q177R) in the homeodomain of SIX1 and SIX2 in tumors with high proliferative potential, mutations in microprocessor genes like DROSHA, DGCR8, DICER1 and DIS3L2, and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations had a strong effect on miRNA expression patterns in tumors, which was functionally validated in cell lines transfected with mutant DROSHA. total samples analyzed are 16, each done as technical replicate
2015-02-18 | E-GEOD-60081 | biostudies-arrayexpress
Project description:Blastemal histology in chemotherapy-treated pediatric Wilms tumors (nephroblastoma) is associated with adverse prognosis. To uncover the underlying tumor biology and find novel therapeutic leads for this subgroup of patients, we analyzed 58 blastemal-type Wilms tumors by exome and transcriptome sequencing and validated our findings in a large independent replication cohort. Recurrent mutations identified either somatically or in the germline included a hotspot mutation (Q177R) in the homeodomain of SIX1 and SIX2 in tumors with high proliferative potential, mutations in microprocessor genes like DROSHA, DGCR8, DICER1 and DIS3L2, and alterations in IGF2, MYCN, and TP53, the latter being strongly associated with dismal outcome. DROSHA and DGCR8 mutations had a strong effect on miRNA expression patterns in tumors, which was functionally validated in cell lines transfected with mutant DROSHA.
2015-02-18 | GSE60081 | GEO
Project description:Mutations in the microRNA processing genes DICER1 and DROSHA drive childhood cancers such as pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. To understand how microRNAs regulate proliferation of these progenitors, we developed a mouse model of pineoblastoma by ablating Drosha or Dicer1 in the developing pineal gland. The tumors that arise in these models resemble proliferative, undifferentiated embryonic progenitors. They are marked by loss of microRNAs, including the let-7 family, and de-repression of let-7 target genes. One upregulated let-7 target gene is the oncofetal transcription factor Plagl2, which activates expression of key pro-growth genes Igf2 and Ccnd2, and we show that small molecules targeting these two drivers block tumor growth. Thus, our results demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.
2024-10-03 | GSE278579 | GEO
Project description:RNAi-mediated knockdown of DICER1 and DROSHA, enzymes critically involved in miRNA biogenesis, has been postulated to affect the homeostasis and the angiogenic capacity of human endothelial cells. To re-evaluate this issue, we reduced the expression of DICER1 or DROSHA by RNAi-mediated knockdown and subsequently investigated the effect of these interventions on the angiogenic capacity of human umbilical vein endothelial cells (HUVEC) in vitro (proliferation, migration, tube formation, endothelial cell spheroid sprouting) and in a HUVEC xenograft assay in immune incompetent NSGTM mice in vivo. In contrast to previous reports, neither knockdown of DICER1 nor knockdown of DROSHA profoundly affected migration or tube formation of HUVEC or the angiogenic capacity of HUVEC in vivo. Furthermore, knockdown of DICER1 and the combined knockdown of DICER1 and DROSHA tended to increase VEGF-induced BrdU incorporation and induced angiogenic sprouting from HUVEC spheroids. Consistent with these observations, global proteomic analyses showed that knockdown of DICER1 or DROSHA only moderately altered HUVEC protein expression profiles but additively reduced, for example, expression of the angiogenesis inhibitor thrombospondin-1. In conclusion, global reduction of miRNA biogenesis by knockdown of DICER1 or DROSHA does not inhibit the angiogenic capacity of HUVEC. Further studies are therefore needed to elucidate the influence of these enzymes in the context of human endothelial cell-related angiogenesis.
2022-02-17 | PXD027923 | Pride
Project description:Mutations in the microRNA processing genes DICER1 and DROSHA drive childhood cancers such as pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. To understand how microRNAs regulate proliferation of these progenitors, we developed a mouse model of pineoblastoma by ablating Drosha or Dicer1 in the developing pineal gland. The tumors that arise in these models resemble proliferative, undifferentiated embryonic progenitors. They are marked by loss of microRNAs, including the let-7 family, and de-repression of let-7 target genes. One upregulated let-7 target gene is the oncofetal transcription factor Plagl2, which activates expression of key pro-growth genes Igf2 and Ccnd2, and we show that small molecules targeting these two drivers block tumor growth. Thus, our results demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.
2024-10-03 | GSE255913 | GEO
Project description:Mutations in the microRNA processing genes DICER1 and DROSHA drive childhood cancers such as pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. To understand how microRNAs regulate proliferation of these progenitors, we developed a mouse model of pineoblastoma by ablating Drosha or Dicer1 in the developing pineal gland. The tumors that arise in these models resemble proliferative, undifferentiated embryonic progenitors. They are marked by loss of microRNAs, including the let-7 family, and de-repression of let-7 target genes. One upregulated let-7 target gene is the oncofetal transcription factor Plagl2, which activates expression of key pro-growth genes Igf2 and Ccnd2, and we show that small molecules targeting these two drivers block tumor growth. Thus, our results demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.
2024-10-03 | GSE255911 | GEO
Project description:Mutations in the microRNA processing genes DICER1 and DROSHA drive childhood cancers such as pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. To understand how microRNAs regulate proliferation of these progenitors, we developed a mouse model of pineoblastoma by ablating Drosha or Dicer1 in the developing pineal gland. The tumors that arise in these models resemble proliferative, undifferentiated embryonic progenitors. They are marked by loss of microRNAs, including the let-7 family, and de-repression of let-7 target genes. One upregulated let-7 target gene is the oncofetal transcription factor Plagl2, which activates expression of key pro-growth genes Igf2 and Ccnd2, and we show that small molecules targeting these two drivers block tumor growth. Thus, our results demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.
2024-10-03 | GSE255906 | GEO
Project description:Mutations in the microRNA processing genes DICER1 and DROSHA drive childhood cancers such as pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. To understand how microRNAs regulate proliferation of these progenitors, we developed a mouse model of pineoblastoma by ablating Drosha or Dicer1 in the developing pineal gland. The tumors that arise in these models resemble proliferative, undifferentiated embryonic progenitors. They are marked by loss of microRNAs, including the let-7 family, and de-repression of let-7 target genes. One upregulated let-7 target gene is the oncofetal transcription factor Plagl2, which activates expression of key pro-growth genes Igf2 and Ccnd2, and we show that small molecules targeting these two drivers block tumor growth. Thus, our results demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.
2024-10-03 | GSE255912 | GEO
Project description:Mutations in the microRNA processing genes DICER1 and DROSHA drive childhood cancers such as pineoblastoma, a brain tumor that resembles undifferentiated precursors of the pineal gland. To understand how microRNAs regulate proliferation of these progenitors, we developed a mouse model of pineoblastoma by ablating Drosha or Dicer1 in the developing pineal gland. The tumors that arise in these models resemble proliferative, undifferentiated embryonic progenitors. They are marked by loss of microRNAs, including the let-7 family, and de-repression of let-7 target genes. One upregulated let-7 target gene is the oncofetal transcription factor Plagl2, which activates expression of key pro-growth genes Igf2 and Ccnd2, and we show that small molecules targeting these two drivers block tumor growth. Thus, our results demonstrate that tumors driven by loss of microRNA processing may be therapeutically targeted by inhibiting downstream drivers of proliferation.
2024-10-03 | GSE255909 | GEO