Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors

Roeland F. De Wilde, Christopher M. Heaphy, Anirban Maitra, Alan K. Meeker, Barish H. Edil, Christopher L. Wolfgang, Trevor A. 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 Matsukuma

Research output: Contribution to journalArticle

100 Scopus citations

Abstract

Approximately 45% of sporadic well-differentiated pancreatic neuroendocrine tumors harbor mutations in either ATRX (alpha thalassemia/mental retardation X-linked) or DAXX (death domain-associated protein). These novel tumor suppressor genes encode nuclear proteins that interact with one another and function in chromatin remodeling at telomeric and peri-centromeric regions. Mutations in these genes are associated with loss of their protein expression and correlate with the alternative lengthening of telomeres phenotype. Patients with multiple endocrine neoplasia-1 (MEN-1) syndrome, genetically defined by a germ line mutation in the MEN1 gene, are predisposed to developing pancreatic neuroendocrine tumors and thus represent a unique model for studying the timing of ATRX and DAXX inactivation in pancreatic neuroendocrine tumor development. We characterized ATRX and DAXX protein expression by immunohistochemistry and telomere status by telomere-specific fluorescence in situ hybridization in 109 well-differentiated pancreatic neuroendocrine lesions from 28 MEN-1 syndrome patients. The study consisted of 47 neuroendocrine microadenomas (0.5 cm), 50 pancreatic neuroendocrine tumors (0.5 cm), and 12 pancreatic neuroendocrine tumor lymph node metastases. Expression of ATRX and DAXX was intact in all 47 microadenomas, and none showed the alternative lengthening of telomeres phenotype. ATRX and/or DAXX expression was lost in 3 of 50 (6%) pancreatic neuroendocrine tumors. In all three of these, tumor size was 3 cm, and loss of ATRX and/or DAXX expression correlated with the alternative lengthening of telomeres phenotype. Concurrent lymph node metastases were present for two of the three tumors, and each metastasis displayed the same changes as the primary tumor. These findings establish the existence of ATRX and DAXX defects and the alternative lengthening of telomeres phenotype in pancreatic neuroendocrine tumors in the context of MEN-1 syndrome. The observation that ATRX and DAXX defects and the alternative lengthening of telomeres phenotype occurred only in pancreatic neuroendocrine tumors measuring 3 cm and their lymph node metastases suggests that these changes are late events in pancreatic neuroendocrine tumor development.

Original languageEnglish (US)
Pages (from-to)1033-1039
Number of pages7
JournalModern Pathology
Volume25
Issue number7
DOIs
StatePublished - Jul 1 2012
Externally publishedYes

Keywords

  • alternative lengthening of telomeres
  • ATRX
  • DAXX
  • MEN-1
  • multiple endocrine neoplasia-1
  • pancreatic neuroendocrine tumor

ASJC Scopus subject areas

  • Pathology and Forensic Medicine

Fingerprint Dive into the research topics of 'Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors'. Together they form a unique fingerprint.

  • Cite this

    De Wilde, R. F., Heaphy, C. M., Maitra, A., Meeker, A. K., Edil, B. H., Wolfgang, C. L., Ellison, T. A., Schulick, R. D., Molenaar, I. Q., Valk, G. D., Vriens, M. R., Rinkes, I. H. M. B., Offerhaus, G. J. A., Hruban, R. H., & Matsukuma, K. (2012). Loss of ATRX or DAXX expression and concomitant acquisition of the alternative lengthening of telomeres phenotype are late events in a small subset of MEN-1 syndrome pancreatic neuroendocrine tumors. Modern Pathology, 25(7), 1033-1039. https://doi.org/10.1038/modpathol.2012.53