MAX inactivation is an early event in GIST development that regulates p16 and cell proliferation

Nat Commun. 2017 Mar 8;8:14674. doi: 10.1038/ncomms14674.

Abstract

KIT, PDGFRA, NF1 and SDH mutations are alternate initiating events, fostering hyperplasia in gastrointestinal stromal tumours (GISTs), and additional genetic alterations are required for progression to malignancy. The most frequent secondary alteration, demonstrated in ∼70% of GISTs, is chromosome 14q deletion. Here we report hemizygous or homozygous inactivating mutations of the chromosome 14q MAX gene in 16 of 76 GISTs (21%). We find MAX mutations in 17% and 50% of sporadic and NF1-syndromic GISTs, respectively, and we find loss of MAX protein expression in 48% and 90% of sporadic and NF1-syndromic GISTs, respectively, and in three of eight micro-GISTs, which are early GISTs. MAX genomic inactivation is associated with p16 silencing in the absence of p16 coding sequence deletion and MAX induction restores p16 expression and inhibits GIST proliferation. Hence, MAX inactivation is a common event in GIST progression, fostering cell cycle activity in early GISTs.

Publication types

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

MeSH terms

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors / genetics*
  • Cell Cycle / genetics
  • Cell Proliferation / genetics*
  • Chromosome Deletion
  • Chromosomes, Human, Pair 14 / genetics
  • Cyclin-Dependent Kinase Inhibitor p16 / genetics*
  • DNA Mutational Analysis
  • Disease Progression
  • Female
  • Gastrointestinal Neoplasms / genetics*
  • Gastrointestinal Stromal Tumors / genetics*
  • Gene Silencing
  • Humans
  • Loss of Function Mutation
  • Male
  • Neurofibromin 1 / genetics
  • Proto-Oncogene Proteins c-kit / genetics
  • Receptor, Platelet-Derived Growth Factor alpha / genetics
  • Succinate Dehydrogenase / genetics

Substances

  • Basic Helix-Loop-Helix Leucine Zipper Transcription Factors
  • CDKN2A protein, human
  • Cyclin-Dependent Kinase Inhibitor p16
  • MAX protein, human
  • Neurofibromin 1
  • Succinate Dehydrogenase
  • Proto-Oncogene Proteins c-kit
  • Receptor, Platelet-Derived Growth Factor alpha