KIT, PDGFRA, VEGFR2 and EGFR gene amplifications in primary and recurrent astrocytic brain tumors. M. Puputti¹, H. Sihto¹, O. Tynninen², T. Blom³, H. Mäenpää¹, J. Isola⁴, A. Paetau², N. Nupponen³, H. Joensuu¹. 1) Department of Oncology, Helsinki University Central Hospital, Finland; 2) Department of Pathology, Helsinki University Central Hospital (HUSLAB) and University of Helsinki, Finland; 3) Molecular Cancer Biology Program, University of Helsinki, Biomedicum Helsinki, Finland; 4) Institute of Medical Technology, University of Tampere, Finland. MP and HS equally contributed to the work.
   Histological biopsies taken from 87 primary brain tumors and their recurrent tumors were analyzed for the presence of KIT, PDGFRA, VEGFR2 and EGFR gene amplifications using either chromogenic in situ hybridization (CISH) or fluorescence in situ hybridization (FISH). KIT, PDGFRA and VEGFR2 receptor tyrosine kinase genes are located adjacent to each other on chromosome 4q12, whereas EGFR is located on chromosome 7p12. CISH analyses were performed from a representative tumor tissue microarray. The primary tumors consisted of oligodendroglioma grade II-III (n=20), oligoastrocytoma grade II-III (n=11), astrocytoma (n=38) and anaplastic astrocytoma (N=18). The histological diagnoses of the corresponding recurrent tumors were oligodendroglioma grade II-III (n=17), oligoastrocytoma grade II-III (n=16), astrocytoma (n=17), anaplastic astrocytoma (n=21) and glioblastoma (n=16). KIT, PDGFRA, VEGFR2 and EGFR gene amplification were detected in 8 (10%), 6 (8%), 10 (12%) and 3 (4%) of the primary neoplasms, respectively. In the recurrent tumors the same genes were amplified in 19 (27%), 13 (18%), 10 (14%) and 6 (8%) of the cases, respectively. KIT amplifications were associated with PDGFRA and VEGFR2 amplifications both in primary and secondary gliomas, and with VEGFR2 amplifications in recurrent gliomas. Aneuploid (3 to 5) KIT, PDGFRA, VEGFR2 and EGFR gene copy numbers were commonly present in both primary gliomas and in their recurrent tumors. Strong KIT, EGFR and VEGFR2 expression were infrequently found in immunohistochemistry of the tumor tissue. The results suggest that KIT and PDGFRA amplifications may have a role in the genesis of some human gliomas.