PURPOSE: To correlate morphologic changes with molecular, biochemical, and cytogenetic profiles in gastrointestinal stromal tumor (GIST) patients before and after imatinib treatment. EXPERIMENTAL DESIGN: We investigated 132 tumor samples obtained from 35 patients with advanced disease who underwent resective surgery after imatinib treatment according to the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group protocol. On the basis of imaging findings, 27 patients were responders and 8 progressors, and retaining this radiological subdivision, we analyzed posttreatment morphologic changes correlating them with molecular, biochemical, and cytogenetic analyses. RESULTS: On the basis of morphology (residual viable cellularity/proliferation markers), three subgroups were identified showing high, moderate, or low response. All of the progressing cases clustered in the low-response subgroup, whereas the responding cases were distributed in all three subgroups. The correlation between morphology and the molecular findings showed that secondary mutations segregated with the low-response subgroup, whereas c-Kit primary resistance mutations were randomly distributed in the three subgroups. Fluorescence in situ hybridization analysis of c-Kit/PDGFRA genes showed that all of the progressing cases were disomic. Referring to morphology, among the responding cases, a disomic pattern was mainly restricted to the high responders, whereas the moderate and low responders were aneusomic. Comparison of post-imatinib genomic profiles with the 23 available primary tumors showed that 17 cases carried the same cytogenetic pattern. Overall, 12 of the 27 primary tumors presented a gain/loss of c-Kit/PDGFRA gene copy number. CONCLUSIONS: Our findings show that c-Kit/PDGFRA genomic alterations were present at disease onset in 1/3 of the examined cases. They therefore represent an early event possibly related to primary imatinib resistance in GISTs.
PURPOSE: To correlate morphologic changes with molecular, biochemical, and cytogenetic profiles in gastrointestinal stromal tumor (GIST) patients before and after imatinib treatment. EXPERIMENTAL DESIGN: We investigated 132 tumor samples obtained from 35 patients with advanced disease who underwent resective surgery after imatinib treatment according to the European Organization for Research and Treatment of Cancer-Soft Tissue and Bone Sarcoma Group protocol. On the basis of imaging findings, 27 patients were responders and 8 progressors, and retaining this radiological subdivision, we analyzed posttreatment morphologic changes correlating them with molecular, biochemical, and cytogenetic analyses. RESULTS: On the basis of morphology (residual viable cellularity/proliferation markers), three subgroups were identified showing high, moderate, or low response. All of the progressing cases clustered in the low-response subgroup, whereas the responding cases were distributed in all three subgroups. The correlation between morphology and the molecular findings showed that secondary mutations segregated with the low-response subgroup, whereas c-Kit primary resistance mutations were randomly distributed in the three subgroups. Fluorescence in situ hybridization analysis of c-Kit/PDGFRA genes showed that all of the progressing cases were disomic. Referring to morphology, among the responding cases, a disomic pattern was mainly restricted to the high responders, whereas the moderate and low responders were aneusomic. Comparison of post-imatinib genomic profiles with the 23 available primary tumors showed that 17 cases carried the same cytogenetic pattern. Overall, 12 of the 27 primary tumors presented a gain/loss of c-Kit/PDGFRA gene copy number. CONCLUSIONS: Our findings show that c-Kit/PDGFRA genomic alterations were present at disease onset in 1/3 of the examined cases. They therefore represent an early event possibly related to primary imatinib resistance in GISTs.
Authors: Kevin Kalinsky; Sandra Lee; Krista M Rubin; Donald P Lawrence; Anthony J Iafrarte; Darell R Borger; Kim A Margolin; Mario M Leitao; Ahmad A Tarhini; Henry B Koon; Andrew L Pecora; Anthony J Jaslowski; Gary I Cohen; Timothy M Kuzel; Christopher D Lao; John M Kirkwood Journal: Cancer Date: 2017-03-23 Impact factor: 6.860
Authors: Francesca Miselli; Tiziana Negri; Alessandro Gronchi; Marco Losa; Elena Conca; Silvia Brich; Elena Fumagalli; Marco Fiore; Paolo G Casali; Marco A Pierotti; Elena Tamborini; Silvana Pilotti Journal: Transl Oncol Date: 2008-12 Impact factor: 4.243
Authors: B Liegl; I Kepten; C Le; M Zhu; G D Demetri; M C Heinrich; C D M Fletcher; C L Corless; J A Fletcher Journal: J Pathol Date: 2008-09 Impact factor: 7.996
Authors: Narasimhan P Agaram; Michael P Laquaglia; Berrin Ustun; Tianhua Guo; Grace C Wong; Nicholas D Socci; Robert G Maki; Ronald P DeMatteo; Peter Besmer; Cristina R Antonescu Journal: Clin Cancer Res Date: 2008-05-15 Impact factor: 12.531