title: Classification of KIT/PDGFRA wild-type gastrointestinal stromal tumors: implications for therapy.
abstract: Gastrointestinal stromal tumors (GIST) are driven mostly by oncogenic KIT or PDGFRA mutations. However, in 10-15% of all GIST, no such activating mutations can be found and these tumors are classified as 'wild-type GIST' (KIT/PDGFRA wt-GIST). Subgroups of KIT/PDGFRA wt-GIST are driven by other sporadic mutations involving the RAS/RAF/MAP-kinase pathway, such as BRAF or KRAS mutations. Furthermore, KIT/PDGFRA wt-GIST are observed in the context of hereditary syndromes, such as neurofibromatosis Type 1, in which the lack of neurofibromin 1 also leads to the activation of the RAS/RAF/MAP-kinase pathway. Finally, the deficiency succinate dehydrogenase seems to play a major role in KIT/PDGFRA wt-GIST. In conclusion, KIT/PDGFRA wt-GIST belong to different subgroups defined by diverse underlying genetic alterations leading to different biological phenotypes. The vast majority of KIT/PDGFRA wt-GIST will not respond to imatinib. Further research to unravel the pathogenesis of KIT/PDGFRA wt-GIST is prerequisite to the development of effective treatment strategies.
authors.affiliation: Gerhard-Domagk-Institute of Pathology, University Hospital Münster, Building D17, Albert-Schweitzer-Campus 1, Münster 48149, Germany.
authors.forename: Sebastian
authors.initials: S
authors.lastname: Huss
authors.forename: Sandra
authors.initials: S
authors.lastname: Elges
authors.forename: Marcel
authors.initials: M
authors.lastname: Trautmann
authors.forename: Jan
authors.initials: J
authors.lastname: Sperveslage
authors.forename: Wolfgang
authors.initials: W
authors.lastname: Hartmann
authors.forename: Eva
authors.initials: E
authors.lastname: Wardelmann
mesh_terms: D000970:Antineoplastic Agents / Q000627:therapeutic use; D046152:Gastrointestinal Stromal Tumors / Q000235:genetics* / Q000473:pathology / Q000628:therapy; D006801:Humans; D000068877:Imatinib Mesylate / Q000627:therapeutic use; D009154:Mutation; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*; D013385:Succinate Dehydrogenase / Q000235:genetics
chemical_list: D000970:Antineoplastic Agents; D000068877:Imatinib Mesylate; D013385:Succinate Dehydrogenase; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha
keywords: BRAF; GIST; KIT; NF1; PDGFRA; SDHA; SDHB; imatinib; wild type