RT Journal Article
T1 Gain-of-function mutations in DNMT3A in patients with paraganglioma.
A1 Remacha, Laura
A1 Currás-Freixes, Maria
A1 Torres-Ruiz, Raúl
A1 Schiavi, Francesca
A1 Torres-Pérez, Rafael
A1 Calsina, Bruna
A1 Letón, Rocío
A1 Comino-Méndez, Iñaki
A1 Roldán-Romero, Juan M
A1 Montero-Conde, Cristina
A1 Santos, María
A1 Pérez, Lucía Inglada
A1 Pita, Guillermo
A1 Alonso, María R
A1 Honrado, Emiliano
A1 Pedrinaci, Susana
A1 Crespo-Facorro, Benedicto
A1 Percesepe, Antonio
A1 Falcioni, Maurizio
A1 Rodríguez-Perales, Sandra
A1 Korpershoek, Esther
A1 Ramón-Maiques, Santiago
A1 Opocher, Giuseppe
A1 Rodríguez-Antona, Cristina
A1 Robledo, Mercedes
A1 Cascón, Alberto
K1 CRISPR/Cas9 gene editing
K1 DNMT3A
K1 exome sequencing
K1 hypermethylation
K1 paraganglioma
AB 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.
YR 2018
FD 2018-05-08
LK http://hdl.handle.net/10668/12435
UL http://hdl.handle.net/10668/12435
LA en
DS RISalud
RD Mar 14, 2025