ATRX loss is an independent predictor of poor survival in pancreatic neuroendocrine tumors

Hum Pathol. 2018 Dec;82:249-257. doi: 10.1016/j.humpath.2018.07.032. Epub 2018 Aug 3.


Pancreatic neuroendocrine tumors (PanNETs) are rare neoplasms accounting for 1% to 2% of all pancreatic tumors. The biological behavior of PanNETs is heterogeneous and unpredictable, adding to the difficulties of clinical management. The DAXX (death domain associated protein) and ATRX (α-thalassemia/mental retardation syndrome X-linked) genes encode proteins involved in SWI/SNF-like chromatin remodeling. Somatic inactivating mutations in DAXX and ATRX are frequent in PanNETs, mutually exclusive, and associated with telomere dysfunction, resulting in genomic instability and alternate lengthening of telomeres. We sought to assess the clinical significance of the loss of the ATRX and DAXX proteins as determined by immunohistochemistry (IHC) in patients with PanNET. From an unselected cohort of 105 patients, we found ATRX loss in 10 tumors (9.5%) and DAXX loss in 16 (15.2%). DAXX and ATRX losses were confirmed mutually exclusive and associated with other adverse clinicopathological variables and poor survival in univariate analysis. In addition, ATRX loss was also associated with higher AJCC stage and infiltrative tumor borders. However, only ATRX loss, lymphovascular invasion, and perineural spread were independent predictors of poor overall survival in multivariate analysis. In conclusion, loss of expression of ATRX as determined by IHC is a useful independent predictor of poor overall survival in PanNETs. Given its relative availability, ATRX loss as determined by IHC may have a role in routine clinical practice to refine prognostication in patients with PanNET.

Keywords: ATRX; DAXX; PanNET; Pancreatic neuroendocrine tumor; Prognosis.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / analysis
  • Adolescent
  • Adult
  • Aged
  • Aged, 80 and over
  • Biomarkers, Tumor / analysis*
  • Co-Repressor Proteins
  • Down-Regulation
  • Female
  • Humans
  • Immunohistochemistry
  • Male
  • Middle Aged
  • Molecular Chaperones
  • Neoplasm Invasiveness
  • Neoplasm Staging
  • Neuroendocrine Tumors / chemistry*
  • Neuroendocrine Tumors / mortality
  • Neuroendocrine Tumors / pathology
  • Neuroendocrine Tumors / therapy
  • Nuclear Proteins / analysis
  • Pancreatic Neoplasms / chemistry*
  • Pancreatic Neoplasms / mortality
  • Pancreatic Neoplasms / pathology
  • Pancreatic Neoplasms / therapy
  • Risk Factors
  • Time Factors
  • Tissue Array Analysis
  • X-linked Nuclear Protein / analysis*
  • Young Adult


  • Adaptor Proteins, Signal Transducing
  • Biomarkers, Tumor
  • Co-Repressor Proteins
  • DAXX protein, human
  • Molecular Chaperones
  • Nuclear Proteins
  • ATRX protein, human
  • X-linked Nuclear Protein