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A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del)
About 10–15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha (PDGFRA) (wt-GISTs). These tumors are currently defined by having no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and...
Autores principales: | , , , , , , , , , , |
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Formato: | Online Artículo Texto |
Lenguaje: | English |
Publicado: |
Nature Publishing Group
2013
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Materias: | |
Acceso en línea: | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701292/ https://www.ncbi.nlm.nih.gov/pubmed/23599150 http://dx.doi.org/10.1038/modpathol.2013.47 |
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author | Huss, Sebastian Künstlinger, Helen Wardelmann, Eva Kleine, Michaela A Binot, Elke Merkelbach-Bruse, Sabine Rüdiger, Thomas Mittler, Jens Hartmann, Wolfgang Büttner, Reinhard Schildhaus, Hans-Ulrich |
author_facet | Huss, Sebastian Künstlinger, Helen Wardelmann, Eva Kleine, Michaela A Binot, Elke Merkelbach-Bruse, Sabine Rüdiger, Thomas Mittler, Jens Hartmann, Wolfgang Büttner, Reinhard Schildhaus, Hans-Ulrich |
author_sort | Huss, Sebastian |
collection | PubMed |
description | About 10–15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha (PDGFRA) (wt-GISTs). These tumors are currently defined by having no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene. Until now, the analysis of further exons is not recommended. However, we have previously published a report on a KIT exon 8 germline mutation, which was associated with familial GIST and mastocytosis. We therefore investigated whether KIT exon 8 mutations might also occur in sporadic GIST. We screened a cohort of 145 wt-GISTs from a total of 1351 cases from our registry for somatic mutations in KIT exon 8. Two primary GISTs with an identical exon 8 mutation (p.D419del) were detected, representing 1.4% of all the cases analyzed. Based on all GISTs from our registry, the overall frequency of KIT exon 8 mutations was 0.15%. The first tumor originating in the small bowel of a 53-year-old male patient had mostly a biphasic spindled-epithelioid pattern with a high proliferative activity (14 mitoses/50 HPF) combined with a second low proliferative spindle cell pattern (4/50 HPF). The patient developed multiple peritoneal metastases 29 months later. The second case represented a jejunal GIST in a 67-year old woman who is relapse-free under adjuvant imatinib treatment. We conclude that about 1–2% of GISTs being classified as ‘wild type' so far might, in fact, carry KIT mutations in exon 8. Moreover, this mutational subtype was shown to be activating and imatinib sensitive in vitro. We therefore propose that screening for KIT exon 8 mutations should become a routine in the diagnostic work-up of GIST and that patients with an exon 8 mutation and a significant risk for tumor progression should be treated with imatinib. |
format | Online Article Text |
id | pubmed-3701292 |
institution | National Center for Biotechnology Information |
language | English |
publishDate | 2013 |
publisher | Nature Publishing Group |
record_format | MEDLINE/PubMed |
spelling | pubmed-37012922013-07-05 A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del) Huss, Sebastian Künstlinger, Helen Wardelmann, Eva Kleine, Michaela A Binot, Elke Merkelbach-Bruse, Sabine Rüdiger, Thomas Mittler, Jens Hartmann, Wolfgang Büttner, Reinhard Schildhaus, Hans-Ulrich Mod Pathol Original Article About 10–15% of gastrointestinal stromal tumors (GISTs) carry wild-type sequences in all hot spots of KIT and platelet-derived growth factor receptor alpha (PDGFRA) (wt-GISTs). These tumors are currently defined by having no mutations in exons 9, 11, 13, and 17 of the KIT gene and exons 12, 14, and 18 of the PDGFRA gene. Until now, the analysis of further exons is not recommended. However, we have previously published a report on a KIT exon 8 germline mutation, which was associated with familial GIST and mastocytosis. We therefore investigated whether KIT exon 8 mutations might also occur in sporadic GIST. We screened a cohort of 145 wt-GISTs from a total of 1351 cases from our registry for somatic mutations in KIT exon 8. Two primary GISTs with an identical exon 8 mutation (p.D419del) were detected, representing 1.4% of all the cases analyzed. Based on all GISTs from our registry, the overall frequency of KIT exon 8 mutations was 0.15%. The first tumor originating in the small bowel of a 53-year-old male patient had mostly a biphasic spindled-epithelioid pattern with a high proliferative activity (14 mitoses/50 HPF) combined with a second low proliferative spindle cell pattern (4/50 HPF). The patient developed multiple peritoneal metastases 29 months later. The second case represented a jejunal GIST in a 67-year old woman who is relapse-free under adjuvant imatinib treatment. We conclude that about 1–2% of GISTs being classified as ‘wild type' so far might, in fact, carry KIT mutations in exon 8. Moreover, this mutational subtype was shown to be activating and imatinib sensitive in vitro. We therefore propose that screening for KIT exon 8 mutations should become a routine in the diagnostic work-up of GIST and that patients with an exon 8 mutation and a significant risk for tumor progression should be treated with imatinib. Nature Publishing Group 2013-07 2013-04-19 /pmc/articles/PMC3701292/ /pubmed/23599150 http://dx.doi.org/10.1038/modpathol.2013.47 Text en Copyright © 2013 United States & Canadian Academy of Pathology http://creativecommons.org/licenses/by-nc-nd/3.0/ This work is licensed under a Creative Commons Attribution-NonCommercial-NoDerivs 3.0 Unported License. To view a copy of this license, visit http://creativecommons.org/licenses/by-nc-nd/3.0/ |
spellingShingle | Original Article Huss, Sebastian Künstlinger, Helen Wardelmann, Eva Kleine, Michaela A Binot, Elke Merkelbach-Bruse, Sabine Rüdiger, Thomas Mittler, Jens Hartmann, Wolfgang Büttner, Reinhard Schildhaus, Hans-Ulrich A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del) |
title | A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del) |
title_full | A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del) |
title_fullStr | A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del) |
title_full_unstemmed | A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del) |
title_short | A subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in KIT exon 8 (p.D419del) |
title_sort | subset of gastrointestinal stromal tumors previously regarded as wild-type tumors carries somatic activating mutations in kit exon 8 (p.d419del) |
topic | Original Article |
url | https://www.ncbi.nlm.nih.gov/pmc/articles/PMC3701292/ https://www.ncbi.nlm.nih.gov/pubmed/23599150 http://dx.doi.org/10.1038/modpathol.2013.47 |
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