KIT Mutation and Loss of 14q May Be Sufficient for the Development of Clinically Symptomatic Very Low-Risk GIST

PLoS One. 2015 Jun 23;10(6):e0130149. doi: 10.1371/journal.pone.0130149. eCollection 2015.


The aim of this study was to determine the minimal set of genetic alterations required for the development of a very low risk clinically symptomatic gastro-intestinal stromal tumour within the stomach wall. We studied the genome of a very low-risk gastric gastro-intestinal stromal tumour by whole-genome sequencing, comparative genomic hybridisation and methylation profiling. The studied tumour harboured two typical genomic lesions: loss of the long arm of chromosome 14 and an activating mutation in exon 11 of KIT. Besides these genetic lesions, only two point mutations that may affect tumour progression were identified: A frame-shift deletion in RNF146 and a missense mutation in a zinc finger of ZNF407. Whilst the frameshift deletion in RNF146 seemed to be restricted to this particular tumour, a similar yet germline mutation in ZNF407 was found in a panel of 52 gastro-intestinal stromal tumours from different anatomical sites and different categories. Germline polymorphisms in the mitotic checkpoint proteins Aurora kinase A and BUB1 kinase B may have furthered tumour growth. The epigenetic profile of the tumour matches that of other KIT-mutant tumours. We have identified mutations in three genes and loss of the long arm of chromosome 14 as the so far minimal set of genetic abnormalities sufficient for the development of a very low risk clinically symptomatic gastric stromal tumour.

Publication types

  • Research Support, Non-U.S. Gov't

MeSH terms

  • Chromosome Deletion*
  • Chromosomes, Human, Pair 14*
  • DNA Methylation
  • Gastrointestinal Stromal Tumors / genetics*
  • Gastrointestinal Stromal Tumors / pathology
  • Humans
  • Mutation*
  • Polymorphism, Single Nucleotide
  • Proto-Oncogene Proteins c-kit / genetics*


  • Proto-Oncogene Proteins c-kit

Grants and funding

The authors gratefully acknowledge the contribution to this study made by the University of Birmingham’s Human Biomaterials Resource Centre, which has been supported through Birmingham Science City - Experimental Medicine Network of Excellence project. HJD is the director of Inserm unit U1074,