Altered ATRX/DAXX Expression and Telomere Length of Pancreatic Neuroendocrine Tumors in MEN-1 Syndrome
Roeland F de Wilde, Christopher M Heaphy, Anirban Maitra, Alan K Meeker, Barish H Edil, Christopher L Wolfgang, Trevor Ellison, Richard D Schulick, I Quintus Molenaar, Gerlof D Valk, Menno R Vriens, Inne H M Borel Rinkes, G Johan A Offerhaus, Ralph H Hruban, Karen E Matsukuma. Johns Hopkins Medical Institutions, Baltimore, MD; University Medical Center Utrecht, Utrecht, Netherlands; University Medical Center Utrecht, Utrecht, Netherlands
Background: Approximately 45% of well-differentiated large sporadic pancreatic neuroendocrine tumors (PanNETs) harbor mutations in either the ATRX (α-thalassemia/mental retardation syndrome X-linked) or DAXX (death-domain associated protein) gene. These mutations are associated with loss of protein expression as determined by immunolabeling and correlate with the alternative lengthening of telomeres (ALT) phenotype. Patients with multiple endocrine neoplasia type 1 (MEN-1) syndrome, genetically defined by a germ line mutation in the MEN1 gene, are predisposed to developing PanNETs and thus represent a unique model for studying the timing of ATRX and DAXX inactivation in the development of PanNETs.
Design: We characterized ATRX and DAXX protein expression and the ALT status of 109 well-differentiated pancreatic neuroendocrine lesions in 28 MEN-1 patients. The study set consisted of 47 neuroendocrine microadenomas (< 0.5 cm), 50 PanNETs (≥ 0.5 cm), and 12 PanNET lymph node metastases. ATRX and DAXX were evaluated by immunohistochemistry, and ALT was assessed by telomere-specific fluorescence in situ hybridization (FISH).
Results: ATRX and DAXX expression was intact in all 47 microadenomas, and none showed the ALT phenotype. ATRX and/or DAXX expression was lost or aberrant in 3 of 50 (6%) PanNETs. In all 3 of these cases, the tumor was ≥ 3 cm, and loss of ATRX and/or DAXX expression correlated with the presence of the ALT phenotype. In 2 of the 3 cases, defective ATRX/DAXX expression and ALT were also present in the corresponding lymph node metastases.
Conclusions: These findings establish the existence of ATRX/DAXX defects and the ALT phenotype in the context of MEN-1 syndrome. Overall, these alterations were relatively uncommon. The finding that ATRX/DAXX defects and the ALT phenotype occurred only in tumors ≥ 3 cm and their lymph node metastases suggests that these changes are a late event in the development of PanNETs.
Wednesday, March 21, 2012 9:30 AM
Poster Session V # 254, Wednesday Morning