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

Olaf Karl Klinke,Olaf Karl Klinke,Katrin Hinderhofer,Pierre-Paul Bringuier,Gouri Baldwin,Tuba Mizani,Brigitte Bancel,Regina Feederle,Regina Feederle,Mojgan Devouassoux-Shisheboran,Tuba Mizani,Jean-Yves Scoazec,Philippe Taniere,Henri-Jacques Delecluse,Henri-Jacques Delecluse,Anna Jauch,Gouri Baldwin

doi:10.1371/journal.pone.0130149

Abstract

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.

Highlights

GISTs are the most frequent mesenchymal tumours of the gastrointestinal tract
The majority of GISTs carry an activating mutation in either the mast cell growth factor receptor KIT or the platelet-derived growth factor receptor α (PDGFRA) tyrosine kinases; an event that is considered as crucial for tumourigenesis [1]. (We shall refer to this kind of GIST as kinase mutant .) transgenic mice that carry similar KIT mutations develop multiple GIST along the GI tract, they more frequently succumb of ileus caused by a massive hyperplasia of Cajal cells rather than from neoplastic infiltration [3]
The aim of this study was to identify molecular events that are sufficient for the development of a very low risk gastric GIST

Summary

Introduction

GISTs are the most frequent mesenchymal tumours of the gastrointestinal tract They are thought to develop from Cajal cells of the myenteric plexus [1, 2]. The clinical behaviour of GIST with identical KIT mutations can widely vary from clinically silent small tumours incidentally discovered at autopsy in elderly patients to locally invasive tumours, some of which metastasise, in particular to the liver [5, 6]. This suggests that additional genetic events condition the variable behaviour of these tumours. In patients with non-metastatic clear-cell renal cell carcinoma 14q loss is associated with decreased survival [18]

Objectives

Methods

Results

Conclusion