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Gain-of-function mutations in DNMT3A in patients with paraganglioma
- Source :
- Genetics in Medicine, 20(12), 1644-1651. Lippincott Williams & Wilkins
- Publication Year :
- 2018
-
Abstract
- The high percentage of patients carrying germline mutations makes pheochromocytomas/paragangliomas the most heritable of all tumors. However, there are still cases unexplained by mutations in the known genes. We aimed to identify the genetic cause of disease in patients strongly suspected of having hereditary tumors. Whole-exome sequencing was applied to the germlines of a parent–proband trio. Genome-wide methylome analysis, RNA-seq, CRISPR/Cas9 gene editing, and targeted sequencing were also performed. We identified a novel de novo germline mutation in DNMT3A, affecting a highly conserved residue located close to the aromatic cage that binds to trimethylated histone H3. DNMT3A-mutated tumors exhibited significant hypermethylation of homeobox-containing genes, suggesting an activating role of the mutation. CRISPR/Cas9-mediated knock-in in HeLa cells led to global changes in methylation, providing evidence of the DNMT3A-altered function. Targeted sequencing revealed subclonal somatic mutations in six additional paragangliomas. Finally, a second germline DNMT3A mutation, also causing global tumor DNA hypermethylation, was found in a patient with a family history of pheochromocytoma. Our findings suggest that DNMT3A may be a susceptibility gene for paragangliomas and, if confirmed in future studies, would represent the first example of gain-of-function mutations affecting a DNA methyltransferase gene involved in cancer predisposition.
- Subjects :
- 0301 basic medicine
Adult
Male
Genotype
Adrenal Gland Neoplasms
Pheochromocytoma
Biology
medicine.disease_cause
Germline
DNA Methyltransferase 3A
Paraganglioma
03 medical and health sciences
Germline mutation
Exome Sequencing
medicine
CRISPR
Humans
Genetic Predisposition to Disease
DNA (Cytosine-5-)-Methyltransferases
Gene
Genetics (clinical)
Exome sequencing
Germ-Line Mutation
Genetics
Mutation
DNA Methylation
medicine.disease
hypermethylation
030104 developmental biology
Gain of Function Mutation
DNA methylation
DNMT3A
Female
CRISPR/Cas9 gene editing
CRISPR-Cas Systems
Subjects
Details
- ISSN :
- 10983600
- Volume :
- 20
- Issue :
- 12
- Database :
- OpenAIRE
- Journal :
- Genetics in Medicine
- Accession number :
- edsair.doi.dedup.....57ae6fa8670ae5496be6df7c9fe12f36