c-Kit/PDGFRA Gene Status Alterations Possibly Related to Primary Imatinib Resistance in Gastrointestinal Stromal Tumors

• Published in: Clinical cancer research 2007-04, Vol.13 (8), p.2369-2377
• Main Authors: MISELLI, Francesca, CASIERI, Paola, PIEROTTI, Marco A, TAMBORINI, Elena, PILOTTI, Silvana, NEGRI, Tiziana, ORSENIGO, Marta, LAGONIGRO, M. Stefania, GRONCHI, Alessandro, FIORE, Marco, CASALI, Paolo G, BERTULLI, Rossella, CARBONE, Antonino
• Format: Article
• Language: English
• Subjects: Antineoplastic agents; Antineoplastic Agents - therapeutic use; Benzamides; Biological and medical sciences; Combined Modality Therapy; Drug Resistance, Neoplasm; Follow-Up Studies; Gastroenterology. Liver. Pancreas. Abdomen; Gastrointestinal stromal tumors (GIST); Gastrointestinal Stromal Tumors - drug therapy; Gastrointestinal Stromal Tumors - genetics; Gastrointestinal Stromal Tumors - pathology; Gastrointestinal Stromal Tumors - surgery; gene status; Humans; imatinib histologic response; Imatinib Mesylate; Immunophenotyping; In Situ Hybridization, Fluorescence; Kit/PDGFRA; Medical sciences; Mitosis; Mutation; Pharmacology. Drug treatments; Piperazines - therapeutic use; primary imatinib resistance; Proto-Oncogene Proteins c-kit - genetics; Pyrimidines - therapeutic use; Receptor, Platelet-Derived Growth Factor alpha - genetics; Stomach. Duodenum. Small intestine. Colon. Rectum. Anus; Tumors
• ISSN: 1078-0432; 1557-3265
• DOI: 10.1158/1078-0432.CCR-06-1745

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.