[Translational research and diagnosis in GIST].

Gastrointestinal stromal tumors (GIST) are the most common mesenchymal tumors in the digestive tract. In up to 90% of cases, they are characterized by activating mutations in the KIT or the PDGFRA gene. GIST represent a paradigm for successful targeted treatment with tyrosine kinase inhibitors (TKI). Since the approval of the TKI imatinib in 2002 the survival of patients with metastatic GIST has tripled. The next logical step was the concept of using imatinib in an adjuvant approach, which was recently shown to increase overall survival significantly. In both settings, the mutational status has high predictive implications. In detail, GIST with KIT exon 11 mutations show the best response rates with partial remission rates of up to 80%. In KIT exon 9 mutations, a doubled daily dose of 800 mg imatinib is now standard. The PDGFRA exon 18 mutation D842V has been shown to lead to primary resistance. The treatment strategy in GIST is driven by their molecular characterisation. Further research has increased our knowledge on resistance mechanisms in solid tumors against TKI. The number of patients with secondary resistance due to acquired KIT mutations is increasing with treatment duration. Strategies to address this situation are the introduction of novel pathway inhibitors targeting different levels of signal transduction pathways, such as the mTOR/Akt pathway, the RAS/RAF pathway, histone deacetylation, among others. Among the GIST without mutations in the common hot spot regions of KIT and PDGFRA, the so-called wildtype GIST, further genomic subgroups have been identified. One such subgroup carries inactivating germline mutations in the genes encoding succinate dehydrogenase B, C, or D. They are associated with the occurrence of paragangliomas, so-called Carney-Stratakis syndrome. Most frequently, these GIST are located in the stomach, showing an epithelioid phenotype and a multinodular growth pattern. They preferentially occur in young females and often show lymph node metastases, the latter being very unusual in sporadic GIST. In sporadic Carney's triad additional pulmonary chondromas are observed and there are no SDH mutations. Another small subgroup of sporadic GIST present with BRAF mutations as an alternative genomic event. Finally, very rare kindreds with germline mutations in either KIT or PDGFRA have been described who develop multiple GIST and depending on the mutational subtype mastocytosis, hyperpigmentation and/or dysphagia. In summary, the molecular characterisation of GIST has revolutionized their treatment due to increasing knowledge about the high relevance of predictive molecular typing in solid tumors.