Molecular characterization of DICER1-mutated pituitary blastoma.

Adolescent Adult Aged Aged, 80 and over Antigens, Neoplasm / genetics Child Child, Preschool DEAD-box RNA Helicases / genetics Enhancer of Zeste Homolog 2 Protein / genetics Female Fetus Humans Ki-67 Antigen / genetics Male Methylation MicroRNAs / genetics Middle Aged Mutation Phosphatidylinositol 3-Kinases / genetics Pituitary Neoplasms / genetics Ribonuclease III / genetics Sequence Analysis, RNA Signal Transduction Tissue Array Analysis Whole Genome Sequencing
DICER1 DICER1 syndrome Differentiation Methylation PI3K PRAME Pituitary blastoma Pre-miRNA Whole genome sequencing mRNA-sequencing miRNA miRNA-sequencing

Journal

Acta neuropathologica
ISSN: 1432-0533
Titre abrégé: Acta Neuropathol
Pays: Germany
ID NLM: 0412041

Informations de publication

Date de publication:
06 2021
Historique:
received: 22 12 2020
accepted: 09 02 2021
revised: 08 02 2021
pubmed: 2 3 2021
medline: 16 2 2022
entrez: 1 3 2021
Statut: ppublish

Résumé

Pituitary blastoma (PitB) has recently been identified as a rare and potentially lethal pediatric intracranial tumor. All cases that have been studied molecularly possess at least one DICER1 pathogenic variant. Here, we characterized nine pituitary samples, including three fresh frozen PitBs, three normal fetal pituitary glands and three normal postnatal pituitary glands using small-RNA-Seq, RNA-Seq, methylation profiling, whole genome sequencing and Nanostring® miRNA analyses; an extended series of 21 pituitary samples was used for validation purposes. These analyses demonstrated that DICER1 RNase IIIb hotspot mutations in PitBs induced improper processing of miRNA precursors, resulting in aberrant 5p-derived miRNA products and a skewed distribution of miRNAs favoring mature 3p over 5p miRNAs. This led to dysregulation of hundreds of 5p and 3p miRNAs and concomitant dysregulation of numerous mRNA targets. Gene expression analysis revealed PRAME as the most significantly upregulated gene (500-fold increase). PRAME is a member of the Retinoic Acid Receptor (RAR) signaling pathway and in PitBs, the RAR, WNT and NOTCH pathways are dysregulated. Cancer Hallmarks analysis showed that PI3K pathway is activated in the tumors. Whole genome sequencing demonstrated a quiet genome with very few somatic alterations. The comparison of methylation profiles to publicly available data from ~ 3000 other central nervous system tumors revealed that PitBs have a distinct methylation profile compared to all other tumors, including pituitary adenomas. In conclusion, this comprehensive characterization of DICER1-related PitB revealed key molecular underpinnings of PitB and identified pathways that could potentially be exploited in the treatment of this tumor.

Identifiants

DOI: 10.1007/s00401-021-02283-6 PMID: 33644822
pubmed: 33644822
doi: 10.1007/s00401-021-02283-6
pii: 10.1007/s00401-021-02283-6
doi:

Substances chimiques

Antigens, Neoplasm 0
Ki-67 Antigen 0
MKI67 protein, human 0
MicroRNAs 0
PRAME protein, human 0
EZH2 protein, human EC 2.1.1.43
Enhancer of Zeste Homolog 2 Protein EC 2.1.1.43
DICER1 protein, human EC 3.1.26.3
Ribonuclease III EC 3.1.26.3
DEAD-box RNA Helicases EC 3.6.4.13

Types de publication

Journal Article Research Support, Non-U.S. Gov't

Langues

eng

Sous-ensembles de citation

IM

Pagination

929-944

Subventions

Organisme : Medical Research Council
ID : MR/M018539/1
Pays : United Kingdom
Organisme : CIHR
ID : FDN-148390
Pays : Canada

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Auteurs

Javad Nadaf (J)

Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada.
Department of Human Genetics, McGill University, Montreal, QC, Canada.
McGill University Genome Centre, Montreal, QC, Canada.

Leanne de Kock (L)

Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada.
Department of Human Genetics, McGill University, Montreal, QC, Canada.
Children's Hospital of Eastern Ontario Research Institute, Ottawa, ON, Canada.
ORCID: 0000-0001-7314-1371

Anne-Sophie Chong (AS)

Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada.
Department of Human Genetics, McGill University, Montreal, QC, Canada.

Márta Korbonits (M)

Centre for Endocrinology, William Harvey Research Institute, Barts and the London School of Medicine, Queen Mary University of London, London, UK.
ORCID: 0000-0002-4101-9432

Paul Thorner (P)

Department of Laboratory Medicine and Pathobiology, University of Toronto, Toronto, Canada.

Naciba Benlimame (N)

Research Pathology Facility, Lady Davis Institute, Jewish General Hospital, Montreal, QC, Canada.

Lili Fu (L)

Department of Pathology, McGill University Health Centre, Montreal, QC, Canada.

Andrew Peet (A)

Birmingham Children's NHS Foundation Trust, Birmingham, UK.
Institute of Cancer and Genomic Sciences, University of Birmingham, Birmingham, UK.

Justin Warner (J)

Department of Child Health, University Hospital of Wales, Heath Park, Cardiff, UK.

Oswald Ploner (O)

Diakonie-Klinikum, Stuttgart, Germany.

Shanop Shuangshoti (S)

Department of Pathology and Chulalongkorn GenePRO Center, Faculty of Medicine, Chulalongkorn University, Bangkok, 10330, Thailand.

Steffen Albrecht (S)

Department of Pathology, McGill University Health Centre, Montreal, QC, Canada.

Nancy Hamel (N)

Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada.

John R Priest (JR)

, Minneapolis, MN, USA.

Barbara Rivera (B)

Program in Molecular Mechanisms and Experimental Therapy in Oncology (Oncobell), IDIBELL, Hospitalet de Llobregat, Barcelona, Spain.
Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada.

Jiannis Ragoussis (J)

Department of Human Genetics, McGill University, Montreal, QC, Canada.
McGill University Genome Centre, Montreal, QC, Canada.

William D Foulkes (WD)

Department of Medical Genetics, The Lady Davis Institute, Jewish General Hospital, 3755 Cote St. Catherine Road, Montreal, QC, H3T 1E2, Canada. william.foulkes@mcgill.ca.
Department of Human Genetics, McGill University, Montreal, QC, Canada. william.foulkes@mcgill.ca.
Cancer Research Program, Research Institute of the McGill University Health Centre, Montreal, QC, Canada. william.foulkes@mcgill.ca.
Gerald Bronfman Department of Oncology, McGill University, Montreal, Canada. william.foulkes@mcgill.ca.
ORCID: 0000-0001-7427-4651

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Classifications MeSH

questionsmedicales.fr › Personnes › Tranches d'âge › Adolescent › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Sujet âgé › Sujet âgé de 80 ans ou plus › Molecular characterization of DICER1-mutated...
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questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Personnes › Tranches d'âge › Enfant › Enfant d'âge préscolaire › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Transferases › Phosphotransferases › Nucleotidyltransferases › RNA nucleotidyltransferases › RNA helicases › DEAD-box RNA helicases › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Facteurs de transcription › Protéines de répression › Protéines du groupe Polycomb › Complexe répresseur Polycomb-2 › Protéine-2 homologue de l'activateur de Zeste › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Structures de l'embryon › Foetus › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Eucaryotes › Animaux › Chordés › Vertébrés › Mammifères › Eutheria › Primates › Haplorhini › Catarrhini › Hominidae › Humains › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Facteurs biologiques › Marqueurs biologiques › Marqueurs biologiques tumoraux › Antigène KI-67 › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Métabolisme › Alkylation › Méthylation › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Acides nucléiques, nucléotides et nucléosides › Acides nucléiques › ARN › ARN non traduit › Petit ARN non traduit › microARN › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Personnes › Tranches d'âge › Adulte › Adulte d'âge moyen › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Phénomènes génétiques › Variation génétique › Mutation › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Acides aminés, peptides et protéines › Protéines › Protéines et peptides de signalisation intracellulaire › Phosphatidylinositol 3-kinases › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Maladies endocriniennes › Maladies de l'hypophyse › Tumeurs de l'hypophyse › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Enzymes et coenzymes › Enzymes › Hydrolases › Esterases › Ribonucléases › Endoribonucleases › Ribonuclease III › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ARN › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Phénomènes physiologiques cellulaires › Transduction du signal › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Techniques d'investigation › Procédures d'analyse sur micropuce › Analyse sur microréseau › Analyse sur puce à tissus › Molecular characterization of DICER1-mutated...
questionsmedicales.fr › Techniques d'investigation › Techniques génétiques › Analyse de séquence › Analyse de séquence d'ADN › Séquençage du génome entier › Molecular characterization of DICER1-mutated...