title: Hypo-methylation mediates chromosomal instability in pancreatic NET.
abstract: DAXX and or ATRX loss occur in 40% of pancreatic neuroendocrine tumors (PanNETs). PanNETs negative for DAXX or ATRX show an increased risk of relapse. The tumor-associated pathways activated upon DAXX or ATRX loss and how this event may induce chromosomal instability (CIN) and alternative lengthening telomeres (ALT) are still unknown. Both DAXX and ATRX are involved in DNA methylation regulation. DNA methylation of heterochromatin and of non-coding sequences is extremely important for the maintenance of genomic stability. We analyzed the association of DAXX and/or ATRX loss and CIN with global DNA methylation in human PanNET samples and the effect of DAXX knock-down on methylation and cell proliferation. We assessedLINE1as well as global DNA methylation in 167 PanNETs, and we found that DAXX and or ATRX-negative tumors and tumors with CIN were hypomethylated. DAXX knock-down in PanNET cell lines blocked cells in G1/G0 phase and seemed to increase CIN in QGP-1 cells. However, no direct changes in DNA methylation were observed after DAXX knock-downin vitroIn conclusion, our data indicate that epigenetic changes are crucial steps in the progression of PanNETs loss and suggest that DNA methylation is the mechanism via which CIN is induced, allowing clonal expansion and selection.
authors.affiliation: Institute of PathologyUniversity of Bern, Bern, Switzerland Ilaria.marinoni@pathology.unibe.ch.
authors.forename: I
authors.initials: I
authors.lastname: Marinoni
authors.affiliation: Institute of PathologyUniversity of Bern, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Wiederkeher
authors.affiliation: Institute of PathologyUniversity of Bern, Bern, Switzerland.|GCB Graduate School BernBern, Switzerland.
authors.forename: T
authors.initials: T
authors.lastname: Wiedmer
authors.affiliation: Institute of PathologyUniversity of Bern, Bern, Switzerland.
authors.forename: S
authors.initials: S
authors.lastname: Pantasis
authors.affiliation: Institute of PathologyUniversity of Bern, Bern, Switzerland.|GCB Graduate School BernBern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Di Domenico
authors.affiliation: Institute of PathologyUniversity of Bern, Bern, Switzerland.
authors.forename: R
authors.initials: R
authors.lastname: Frank
authors.affiliation: Institute of PathologyUniversity of Bern, Bern, Switzerland.
authors.forename: E
authors.initials: E
authors.lastname: Vassella
authors.affiliation: Institute of PathologyUniversity of Bern, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Schmitt
authors.affiliation: Institute of PathologyUniversity of Bern, Bern, Switzerland.
authors.forename: A
authors.initials: A
authors.lastname: Perren
mesh_terms: D048868:Adaptor Proteins, Signal Transducing / Q000235:genetics / Q000378:metabolism; D045744:Cell Line, Tumor; D002470:Cell Survival; D043171:Chromosomal Instability / Q000235:genetics*; D056970:Co-Repressor Proteins; D019175:DNA Methylation; D005260:Female; D006801:Humans; D008297:Male; D008875:Middle Aged; D018832:Molecular Chaperones; D018358:Neuroendocrine Tumors / Q000235:genetics* / Q000378:metabolism; D009687:Nuclear Proteins / Q000235:genetics / Q000378:metabolism; D010190:Pancreatic Neoplasms / Q000235:genetics* / Q000378:metabolism; D000075924:X-linked Nuclear Protein / Q000235:genetics / Q000378:metabolism
chemical_list: D048868:Adaptor Proteins, Signal Transducing; D056970:Co-Repressor Proteins; C106985:DAXX protein, human; D018832:Molecular Chaperones; D009687:Nuclear Proteins; C092332:ATRX protein, human; D000075924:X-linked Nuclear Protein
keywords: DAXX and ATRX; DNA methylation; chromosomal instability; pancreatic neuroendocrine tumors