| Summary: | <p>Abstract</p> <p>Background</p> <p>Oncogenic point mutations in <it>KIT </it>or <it>PDGFRA </it>are recognized as the primary events responsible for the pathogenesis of most gastrointestinal stromal tumors (GIST), but additional genomic alterations are frequent and presumably required for tumor progression. The relative contribution of such alterations for the biology and clinical behavior of GIST, however, remains elusive.</p> <p>Methods</p> <p>In the present study, somatic mutations in <it>KIT </it>and <it>PDGFRA </it>were evaluated by direct sequencing analysis in a consecutive series of 80 GIST patients. For a subset of 29 tumors, comparative genomic hybridization was additionally used to screen for chromosome copy number aberrations. Genotype and genomic findings were cross-tabulated and compared with available clinical and follow-up data.</p> <p>Results</p> <p>We report an overall mutation frequency of 87.5%, with 76.25% of the tumors showing alterations in <it>KIT </it>and 11.25% in <it>PDGFRA</it>. Secondary <it>KIT </it>mutations were additionally found in two of four samples obtained after imatinib treatment. Chromosomal imbalances were detected in 25 out of 29 tumors (86%), namely losses at 14q (88% of abnormal cases), 22q (44%), 1p (44%), and 15q (36%), and gains at 1q (16%) and 12q (20%). In addition to clinico-pathological high-risk groups, patients with <it>KIT </it>mutations, genomic complexity, genomic gains and deletions at either 1p or 22q showed a significantly shorter disease-free survival. Furthermore, genomic complexity was the best predictor of disease progression in multivariate analysis.</p> <p>Conclusions</p> <p>In addition to <it>KIT/PDGFRA </it>mutational status, our findings indicate that secondary chromosomal changes contribute significantly to tumor development and progression of GIST and that genomic complexity carries independent prognostic value that complements clinico-pathological and genotype information.</p>
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