Original ResearchFull Report: Clinical—PancreasLoss of DAXX and ATRX Are Associated With Chromosome Instability and Reduced Survival of Patients With Pancreatic Neuroendocrine Tumors
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Tissues, Patient Characteristics, and Follow-Up Data
pNETs of 142 patients (collective I, University of Zurich) were formalin-fixed and paraffin-embedded. A subset of collected tissues additionally was snap-frozen. Clinical follow-up data of 113 patients were obtained by contacting the patients' general practitioners and Cancer Registry Zurich. The tumors were reclassified into 3 groups according to the 2010 World Health Organization classification.13 In addition, 101 patients with follow-up data were selected from the Department of Pathology of
DAXX and ATRX Protein Loss in pNETs
We performed IHC for DAXX and ATRX on a TMA with 142 pNETs (patient characteristics are shown in Table 1). Only nuclear labeling for DAXX and ATRX were scored as positive and only samples with positive internal control were considered negative (Figure 1).7 Results were obtained for 92 pNETs (24 tumors had no positive internal control and no tumor tissue was evaluable in another 26 samples). We observed a loss of DAXX in 23 samples (25%) and a loss of ATRX in 20 samples (18%). Altogether, 39
Discussion
We provide evidence that pNETs with loss of either DAXX or ATRX expression show ALT activation and CIN. No specific genetic background has been associated previously with CIN in pNETs. The significant association of loss of DAXX or ATRX protein with ALT and CIN provides strong evidence for a causal relationship between these factors. Several arguments support this interpretation. ALT activation has been linked to CIN in several tumor types and in glioblastoma with DAXX or ATRX loss.20, 21, 22,
Acknowledgments
The authors thank Cornelia Schlup and Caroline Hammer for technical assistance, Iria Gonzalez Vasconcellos for the fluorescence in situ hybridization protocol and scientific support, Prof. P. Komminoth for helpful discussions, and Inti Zlobec for careful reading of the manuscript. The tissues were provided with support of the Tissue Bank Bern.
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Conflicts of interest The authors disclose no conflicts.
Funding The study was supported by a Swiss National Foundation grant (310030_144236 to A.P.); and supported in part by the Dutch Digestion Foundation (E.-J.S.).