DAXX/ATRX, MEN1, and mTOR pathway genes are frequently altered in pancreatic neuroendocrine tumors

Science. 2011 Mar 4;331(6021):1199-203. doi: 10.1126/science.1200609. Epub 2011 Jan 20.

Abstract

Pancreatic neuroendocrine tumors (PanNETs) are a rare but clinically important form of pancreatic neoplasia. To explore the genetic basis of PanNETs, we determined the exomic sequences of 10 nonfamilial PanNETs and then screened the most commonly mutated genes in 58 additional PanNETs. The most frequently mutated genes specify proteins implicated in chromatin remodeling: 44% of the tumors had somatic inactivating mutations in MEN1, which encodes menin, a component of a histone methyltransferase complex, and 43% had mutations in genes encoding either of the two subunits of a transcription/chromatin remodeling complex consisting of DAXX (death-domain-associated protein) and ATRX (α thalassemia/mental retardation syndrome X-linked). Clinically, mutations in the MEN1 and DAXX/ATRX genes were associated with better prognosis. We also found mutations in genes in the mTOR (mammalian target of rapamycin) pathway in 14% of the tumors, a finding that could potentially be used to stratify patients for treatment with mTOR inhibitors.

Publication types

  • Research Support, N.I.H., Extramural
  • Research Support, Non-U.S. Gov't

MeSH terms

  • Adaptor Proteins, Signal Transducing / genetics*
  • Carcinoma, Pancreatic Ductal / genetics
  • Chromatin Assembly and Disassembly / genetics
  • Class I Phosphatidylinositol 3-Kinases
  • DNA Helicases / genetics*
  • Genes, Tumor Suppressor
  • Humans
  • Mutation*
  • Neuroendocrine Tumors / genetics*
  • Neuroendocrine Tumors / metabolism
  • Nuclear Proteins / genetics*
  • PTEN Phosphohydrolase / genetics
  • Pancreatic Neoplasms / genetics*
  • Pancreatic Neoplasms / metabolism
  • Phosphatidylinositol 3-Kinases / genetics
  • Prognosis
  • Proto-Oncogene Proteins / genetics*
  • Sequence Analysis, DNA
  • Signal Transduction / genetics
  • TOR Serine-Threonine Kinases / genetics
  • TOR Serine-Threonine Kinases / metabolism*
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins / genetics
  • X-linked Nuclear Protein

Substances

  • Adaptor Proteins, Signal Transducing
  • DAXX protein, human
  • MEN1 protein, human
  • Nuclear Proteins
  • Proto-Oncogene Proteins
  • Tuberous Sclerosis Complex 2 Protein
  • Tumor Suppressor Proteins
  • Phosphatidylinositol 3-Kinases
  • MTOR protein, human
  • TOR Serine-Threonine Kinases
  • Class I Phosphatidylinositol 3-Kinases
  • PIK3CA protein, human
  • PTEN Phosphohydrolase
  • PTEN protein, human
  • DNA Helicases
  • ATRX protein, human
  • X-linked Nuclear Protein