18,29,30 In the first phase, the presence of activating mutations seemed to be related prompt delivery to a malignant behaviour.31,32 Subsequently, it was shown that most GISTs, even the tumours <1 cm in size that were found incidentally, do harbour KIT mutations.24,33,34,35 The meaning of KIT activation is highlighted by the recent introduction of an inhibitor of RTKs, STI�\571 (Imatinib, Gleevec, Novartis, Switzerland), which can induce regression of GISTs. Even advanced disease has been stabilised, with a return of quality of life.36,37,38,39,40,41,42 The proper application of STI�\571 is currently being investigated to identify the patients most likely to benefit from the treatment. So far, it is indicated for the treatment of metastatic inoperable disease or for cytoreduction in cases not amenable to macroscopically complete resection.

43 Many trials are in course which are, however, considering the possibility of using the drug in an adjuvant or neoadjuvant setting.44 Figure 1A simplified scheme of the signal transduction pathways activated by KIT or platelet�\derived growth factor receptor ��(PDGFR��) (PI3K/AKT, Ras/mitogen activated protein kinase, JAK/STAT, sarcoma inducing gene with … Another member of the RTK family, PDGFR��, is associated with the pathogenesis of GIST and mutations in c�\kit are mutually exclusive with those in pdgfra.45 Interestingly, these two genes are located in the same chromosomal region (4q12).46,47 The most frequent mutations in pdgfra are observed in exons 18 (second tyrosine kinase domain), 12 (regulatory juxtamembrane domain) or 14 (tyrosine kinase domain) (fig.

11).). Both in vitro48 and in vivo49 studies have shown that the type of mutation in c�\kit or pgdfra genes may predict the response to treatment with imatinib. It is now well known that a mutation in exon 11 of kit is associated with a better response to treatment with inhibitors of RTK, with a decreasing response for mutation in exons 9, 13, 17 and wild�\type tumours. Depending on the mutation, some cells expressing the PDGFR�� exon 18 mutant were sensitive to imatinib, whereas others were resistant. Mutants in exons 14 and 12 are sensitive to the drug .14,49,50 Moreover, tumours with mutations in the pdgfra gene are prevalently epithelioid.51 Some specific RTK mutations are also correlated with GSK-3 clinicopathological parameters, such as histological type, overall survival, localisation and risk classification.48,49,52,53 Table 33 shows a brief summary of this correlation. Table 3Summary of most frequent kit and pdgfra mutations in sporadic gastrointestinal stromal tumours Mutations of the kit gene Exon 11 (juxtamembrane domain) The juxtamembrane region of KIT inhibits receptor dimerisation in the absence of stem cell factor.