c-Kit/PDGFRA gene status alterations possibly related to primary imatinib resistance in gastrointestinal stromal tumors.
OBJECTIVE
To correlate morphologic changes with molecular, biochemical, and cytogenetic profiles in gastrointestinal stromal tumor (GIST) patients before and after imatinib treatment.


METHODS
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.
Miselli
Francesca C
FC
Experimental Molecular Pathology, Fondazione IRCCS, Istituto Nazionale dei Tumori, Milan, Italy.
Casieri
Paola
P
Negri
Tiziana
T
Orsenigo
Marta
M
Lagonigro
M Stefania
MS
Gronchi
Alessandro
A
Fiore
Marco
M
Casali
Paolo G
PG
Bertulli
Rossella
R
Carbone
Antonino
A
Pierotti
Marco A
MA
Tamborini
Elena
E
Pilotti
Silvana
S
D000970:Antineoplastic Agents / Q000627:therapeutic use*; D001549:Benzamides; D003131:Combined Modality Therapy; D019008:Drug Resistance, Neoplasm; D005500:Follow-Up Studies; D046152:Gastrointestinal Stromal Tumors / Q000188:drug therapy* / Q000235:genetics* / Q000473:pathology / Q000601:surgery; D006801:Humans; D000068877:Imatinib Mesylate; D016130:Immunophenotyping; D017404:In Situ Hybridization, Fluorescence; D008938:Mitosis; D009154:Mutation; D010879:Piperazines / Q000627:therapeutic use*; D019009:Proto-Oncogene Proteins c-kit / Q000235:genetics*; D011743:Pyrimidines / Q000627:therapeutic use*; D020796:Receptor, Platelet-Derived Growth Factor alpha / Q000235:genetics*
D000970:Antineoplastic Agents; D001549:Benzamides; D010879:Piperazines; D011743:Pyrimidines; D000068877:Imatinib Mesylate; D019009:Proto-Oncogene Proteins c-kit; D020796:Receptor, Platelet-Derived Growth Factor alpha