title: KIT Mutation and Loss of 14q May Be Sufficient for the Development of Clinically Symptomatic Very Low-Risk GIST.
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.
authors.affiliation: German Cancer Research Centre (DKFZ) Unit F100, Heidelberg, Germany; Inserm unit U1074, Heidelberg, Germany.
authors.forename: Olaf Karl
authors.initials: OK
authors.lastname: Klinke
authors.affiliation: German Cancer Research Centre (DKFZ) Unit F100, Heidelberg, Germany; Inserm unit U1074, Heidelberg, Germany.
authors.forename: Tuba
authors.initials: T
authors.lastname: Mizani
authors.affiliation: Histopathology Cellular Pathology-University Hospitals Birmingham, NHS Foundation, Trust Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston Birmingham, B15 2WB, England.
authors.forename: Gouri
authors.initials: G
authors.lastname: Baldwin
authors.affiliation: Service d'Anatomie et Cytologie pathologiques, Hôpital de la Croix Rousse, 103 Grande-Rue-de-la-Croix-Rousse, Lyon cedex 04, France.
authors.forename: Brigitte
authors.initials: B
authors.lastname: Bancel
authors.affiliation: Service d'Anatomie et Cytologie pathologiques, Hôpital de la Croix Rousse, 103 Grande-Rue-de-la-Croix-Rousse, Lyon cedex 04, France.
authors.forename: Mojgan
authors.initials: M
authors.lastname: Devouassoux-Shisheboran
authors.affiliation: Service d'Anatomie Pathologique, Hôpital Édouard-Herriot, 5, place d'Arsonval, 69437 Lyon cedex 03, France.
authors.forename: Jean-Yves
authors.initials: JY
authors.lastname: Scoazec
authors.affiliation: Service d'Anatomie Pathologique, Hôpital Édouard-Herriot, 5, place d'Arsonval, 69437 Lyon cedex 03, France.
authors.forename: Pierre-Paul
authors.initials: PP
authors.lastname: Bringuier
authors.affiliation: German Cancer Research Centre (DKFZ) Unit F100, Heidelberg, Germany; Inserm unit U1074, Heidelberg, Germany.
authors.forename: Regina
authors.initials: R
authors.lastname: Feederle
authors.affiliation: Institute of Human Genetics, University Heidelberg, Heidelberg, Germany.
authors.forename: Anna
authors.initials: A
authors.lastname: Jauch
authors.affiliation: Institute of Human Genetics, University Heidelberg, Heidelberg, Germany.
authors.forename: Katrin
authors.initials: K
authors.lastname: Hinderhofer
authors.affiliation: Histopathology Cellular Pathology-University Hospitals Birmingham, NHS Foundation, Trust Queen Elizabeth Hospital Birmingham, Mindelsohn Way, Edgbaston Birmingham, B15 2WB, England.
authors.forename: Philippe
authors.initials: P
authors.lastname: Taniere
authors.affiliation: German Cancer Research Centre (DKFZ) Unit F100, Heidelberg, Germany; Inserm unit U1074, Heidelberg, Germany.
authors.forename: Henri-Jacques
authors.initials: HJ
authors.lastname: Delecluse
mesh_terms: D002872:Chromosome Deletion; D002883:Chromosomes, Human, Pair 14; D019175:DNA Methylation; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology; D006801:Humans; D009154:Mutation; D020641:Polymorphism, Single Nucleotide; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*
chemical_list: D019009:Proto-Oncogene Proteins c-kit