Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors

Marinoni, Ilaria; Schmitt Kurrer, Anja; Vassella, Erik; Dettmer, Matthias; Rudolph, Thomas; Banz, Vanessa Martine; Hunger, Fabio; Pasquinelli, Silvan; Speel, Ernst-Jan; Perren, Aurel (2014). Loss of DAXX and ATRX are associated with chromosome instability and reduced survival of patients with pancreatic neuroendocrine tumors. Gastroenterology, 146(2), 453-460.e5. Elsevier 10.1053/j.gastro.2013.10.020

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BACKGROUND & AIMS Sporadic pancreatic neuroendocrine tumors (pNETs) are rare and genetically heterogeneous. Chromosome instability (CIN) has been detected in pNETs from patients with poor outcomes, but no specific genetic factors have been associated with CIN. Mutations in death domain-associated protein gene (DAXX) or ATR-X gene (ATRX) (which both encode proteins involved in chromatin remodeling) have been detected in 40% of pNETs, in association with activation of alternative lengthening of telomeres. We investigated whether loss of DAXX or ATRX, and consequent alternative lengthening of telomeres, are related to CIN in pNETs. We also assessed whether loss of DAXX or ATRX is associated with specific phenotypes of pNETs. METHODS We collected well-differentiated primary pNET samples from 142 patients at the University Hospital Zurich and from 101 patients at the University Hospital Bern (both located in Switzerland). Clinical follow-up data were obtained for 149 patients from general practitioners and tumor registries. The tumors were reclassified into 3 groups according to the 2010 World Health Organization classification. Samples were analyzed by immunohistochemistry and telomeric fluorescence in situ hybridization. We correlated loss of DAXX, or ATRX, expression, and activation of alternative lengthening of telomeres with data from comparative genomic hybridization array studies, as well as with clinical and pathological features of the tumors and relapse and survival data. RESULTS Loss of DAXX or ATRX protein and alternative lengthening of telomeres were associated with CIN in pNETs. Furthermore, loss of DAXX or ATRX correlated with tumor stage and metastasis, reduced time of relapse-free survival, and decreased time of tumor-associated survival. CONCLUSIONS Loss of DAXX or ATRX is associated with CIN in pNETs and shorter survival times of patients. These results support the hypothesis that DAXX- and ATRX-negative tumors are a more aggressive subtype of pNET, and could lead to identification of strategies to target CIN in pancreatic tumors.

Item Type:

Journal Article (Original Article)

Division/Institute:

04 Faculty of Medicine > Pre-clinic Human Medicine > Institute of Anatomy
04 Faculty of Medicine > Department of Gastro-intestinal, Liver and Lung Disorders (DMLL) > Clinic of Visceral Surgery and Medicine > Visceral Surgery
04 Faculty of Medicine > Service Sector > Institute of Pathology

UniBE Contributor:

Marinoni, Ilaria; Schmitt Kurrer, Anja; Vassella, Erik; Dettmer, Matthias; Rudolph, Thomas; Banz, Vanessa Martine; Hunger, Fabio and Perren, Aurel

Subjects:

600 Technology > 610 Medicine & health
500 Science > 570 Life sciences; biology

ISSN:

0016-5085

Publisher:

Elsevier

Language:

English

Submitter:

Andrea Arnold

Date Deposited:

02 Apr 2014 14:49

Last Modified:

10 Sep 2015 09:32

Publisher DOI:

10.1053/j.gastro.2013.10.020

PubMed ID:

24148618

Uncontrolled Keywords:

Pancreas, Neoplasm ALT, Prognosis, Human

BORIS DOI:

10.7892/boris.46100

URI:

https://boris.unibe.ch/id/eprint/46100

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