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Gain-of-function mutations in DNMT3A in patients with paraganglioma

Authors :
Bruna Calsina
Maria Currás-Freixes
Juan María Roldan-Romero
Alberto Cascón
Rafael Torres-Pérez
Iñaki Comino-Méndez
Esther Korpershoek
Sandra Rodriguez-Perales
Cristina Rodríguez-Antona
Guillermo Pita
Maurizio Falcioni
Antonio Percesepe
Rocío Letón
Lucia Inglada Pérez
Cristina Montero-Conde
Susana Pedrinaci
Giuseppe Opocher
Mercedes Robledo
Benedicto Crespo-Facorro
Santiago Ramón-Maiques
Emiliano Honrado
Raúl Torres-Ruiz
María R Alonso
Francesca Schiavi
Laura Remacha
Maria José Santos
Pathology
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.

Details

ISSN :
10983600
Volume :
20
Issue :
12
Database :
OpenAIRE
Journal :
Genetics in Medicine
Accession number :
edsair.doi.dedup.....57ae6fa8670ae5496be6df7c9fe12f36