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MeSH: proteiny hedgehog-genetika

3 záznamů v PubMed Filtry

Článek

The transcriptional landscape of Shh medulloblastoma

Skowron, Patryk
Autor Skowron, Patryk Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
Farooq, Hamza
Autor Farooq, Hamza Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
Cavalli, Florence M G
Autor Cavalli, Florence M G Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
Morrissy, A Sorana
Autor Morrissy, A Sorana Department of Biochemistry and Molecular Biology, Cumming School of Medicine, University of Calgary, Calgary, AB, Canada Alberta Children's Hospital Research Institute, Calgary, AB, Canada Charbonneau Cancer Institute, University of Calgary, Calgary, AB, Canada
Ly, Michelle
Autor Ly, Michelle Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, ON, Canada The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada
Hendrikse, Liam D
Autor Hendrikse, Liam D ORCID Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Wang, Evan Y
Autor Wang, Evan Y ORCID Developmental & Stem Cell Biology Program, The Hospital for Sick Children, Toronto, ON, Canada The Arthur and Sonia Labatt Brain Tumour Research Centre, The Hospital for Sick Children, Toronto, ON, Canada Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada
Djambazian, Haig
Autor Djambazian, Haig ORCID McGill University Genome Centre, McGill University, Montreal, QC, Canada Department of Human Genetics, McGill University, Montreal, QC, Canada
Zhu, Helen
Autor Zhu, Helen Department of Medical Biophysics, University of Toronto, Toronto, ON, Canada Computational Biology Program, Ontario Institute for Cancer Research, Toronto, ON, Canada
Mungall, Karen L
Autor Mungall, Karen L Canada's Michael Smith Genome Sciences Centre, BC Cancer Agency, Vancouver, BC, Canada

Nature communications. 2021 Mar 19 ; 12 (1) : 1749. [epub] 20210319

Nat Commun
ISSN 2041-1723
Zdroj

Sonic hedgehog medulloblastoma encompasses a clinically and molecularly diverse group of cancers of the developing central nervous system. Here, we use unbiased sequencing of the transcriptome across a large cohort of 250 tumors to reveal differences among molecular subtypes of the disease, and demonstrate the previously unappreciated importance of non-coding RNA transcripts. We identify alterations within the cAMP dependent pathway (GNAS, PRKAR1A) which converge on GLI2 activity and show that 18% of tumors have a genetic event that directly targets the abundance and/or stability of MYCN. Furthermore, we discover an extensive network of fusions in focally amplified regions encompassing GLI2, and several loss-of-function fusions in tumor suppressor genes PTCH1, SUFU and NCOR1. Molecular convergence on a subset of genes by nucleotide variants, copy number aberrations, and gene fusions highlight the key roles of specific pathways in the pathogenesis of Sonic hedgehog medulloblastoma and open up opportunities for therapeutic intervention.

MeSH
dítě MeSH
dospělí MeSH
genetická variace MeSH
genové regulační sítě MeSH
kojenec MeSH
lidé středního věku MeSH
lidé MeSH
meduloblastom genetika MeSH
mladiství MeSH
mladý dospělý MeSH
nádory mozečku genetika MeSH
předškolní dítě MeSH
proteiny hedgehog genetika MeSH
regulace genové exprese u nádorů * MeSH
signální transdukce genetika MeSH
transkriptom * MeSH
Check Tag
dítě MeSH
dospělí MeSH
kojenec MeSH
lidé středního věku MeSH
lidé MeSH
mladiství MeSH
mladý dospělý MeSH
mužské pohlaví MeSH
předškolní dítě MeSH
ženské pohlaví MeSH
Publikační typ
časopisecké články MeSH
práce podpořená grantem MeSH
Research Support, N.I.H., Extramural MeSH
Názvy látek
proteiny hedgehog MeSH
SHH protein, human MeSH Prohlížeč

Článek

An inactivating mutation in intestinal cell kinase, ICK, impairs hedgehog signalling and causes short rib-polydactyly syndrome

Human molecular genetics. 2016 Sep 15 ; 25 (18) : 3998-4011. [epub] 20160727

Hum Mol Genet
ISSN 1460-2083 | 0964-6906
Zdroj

The short rib polydactyly syndromes (SRPS) are a group of recessively inherited, perinatal-lethal skeletal disorders primarily characterized by short ribs, shortened long bones, varying types of polydactyly and concomitant visceral abnormalities. Mutations in several genes affecting cilia function cause SRPS, revealing a role for cilia function in skeletal development. To identify additional SRPS genes and discover novel ciliary molecules required for normal skeletogenesis, we performed exome sequencing in a cohort of patients and identified homozygosity for a missense mutation, p.E80K, in Intestinal Cell Kinase, ICK, in one SRPS family. The p.E80K mutation abolished serine/threonine kinase activity, resulting in altered ICK subcellular and ciliary localization, increased cilia length, aberrant cartilage growth plate structure, defective Hedgehog and altered ERK signalling. These data identify ICK as an SRPS-associated gene and reveal that abnormalities in signalling pathways contribute to defective skeletogenesis.

MeSH
cilie genetika patologie MeSH
exom genetika MeSH
kojenec MeSH
kostra abnormality růst a vývoj MeSH
lidé MeSH
MAP kinasový signální systém MeSH
mnohočetné abnormality genetika patofyziologie MeSH
protein-serin-threoninkinasy genetika MeSH
proteiny hedgehog genetika MeSH
rodokmen MeSH
sekvenční analýza DNA MeSH
signální transdukce MeSH
syndrom krátkého žebra a polydaktylie genetika patologie MeSH
těhotenství MeSH
Check Tag
kojenec MeSH
lidé MeSH
těhotenství MeSH
ženské pohlaví MeSH
Publikační typ
časopisecké články MeSH
Názvy látek
CILK1 protein, human MeSH Prohlížeč
protein-serin-threoninkinasy MeSH
proteiny hedgehog MeSH

Článek

Cytogenetic prognostication within medulloblastoma subgroups

Journal of clinical oncology. 2014 Mar 20 ; 32 (9) : 886-96. [epub] 20140203

J Clin Oncol
ISSN 1527-7755 | 0732-183X
Zdroj

PURPOSE: Medulloblastoma comprises four distinct molecular subgroups: WNT, SHH, Group 3, and Group 4. Current medulloblastoma protocols stratify patients based on clinical features: patient age, metastatic stage, extent of resection, and histologic variant. Stark prognostic and genetic differences among the four subgroups suggest that subgroup-specific molecular biomarkers could improve patient prognostication. PATIENTS AND METHODS: Molecular biomarkers were identified from a discovery set of 673 medulloblastomas from 43 cities around the world. Combined risk stratification models were designed based on clinical and cytogenetic biomarkers identified by multivariable Cox proportional hazards analyses. Identified biomarkers were tested using fluorescent in situ hybridization (FISH) on a nonoverlapping medulloblastoma tissue microarray (n = 453), with subsequent validation of the risk stratification models. RESULTS: Subgroup information improves the predictive accuracy of a multivariable survival model compared with clinical biomarkers alone. Most previously published cytogenetic biomarkers are only prognostic within a single medulloblastoma subgroup. Profiling six FISH biomarkers (GLI2, MYC, chromosome 11 [chr11], chr14, 17p, and 17q) on formalin-fixed paraffin-embedded tissues, we can reliably and reproducibly identify very low-risk and very high-risk patients within SHH, Group 3, and Group 4 medulloblastomas. CONCLUSION: Combining subgroup and cytogenetic biomarkers with established clinical biomarkers substantially improves patient prognostication, even in the context of heterogeneous clinical therapies. The prognostic significance of most molecular biomarkers is restricted to a specific subgroup. We have identified a small panel of cytogenetic biomarkers that reliably identifies very high-risk and very low-risk groups of patients, making it an excellent tool for selecting patients for therapy intensification and therapy de-escalation in future clinical trials.

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