PDGFRA, KIT, and KDR Gene Amplification in Glioblastoma: Heterogeneity and Clinical Significance

Abstract

Glioblastoma (GBM) is the most frequent tumor of the central nervous system, and its heterogeneity is a challenge in treatment. This study examined tumoral heterogeneity involving PDGFRA, KIT, and KDR gene amplification (GA) in 4q12 and its association with clinical parameters. Specimens from 22 GBM cases with GA for the 4q12 amplicon detected by FISH were investigated for homogeneous or heterogeneous coamplification patterns, diffuse or focal distribution of cells harboring GA throughout tumor sections, and pattern of clustering of fluorescence signals. Sixteen cases had homogenously amplification for all three genes (45.5%), for PDGFRA and KDR (22.7%), or only for PDGFRA (4.6%); six cases had heterogeneous GA patterns, with subpopulations including GA for all three genes and for two genes - PDGFRA and KDR (13.6%), or GA for all three and for only one gene - PDGFRA (9.1%) or KIT (4.6%). In 6 tumors (27.3%), GA was observed in focal tumor areas, while in the remaining 16 tumors (72.7%) it was diffusely distributed throughout the pathological specimen. Amplification was universally expressed as double minutes and homogenously stained regions. Coamplification of all three genes PDGFRA, KIT, and KDR, age ≥ 60 years, and total tumor resection were statistically associated with poor prognosis. FISH proved effective for detailed interpretation of molecular heterogeneity. The study uncovered an even more diverse range of amplification patterns involving the 4q12 oncogenes in GBM than previously described, thus highlighting a complex tumoral heterogeneity to be considered when devising more effective therapies.

Keywords: FISH; Genetic heterogeneity; Glioblastoma; KDR; KIT; PDGFRA.

Fig. 1

Case 12 - Segmented images of a microscope field (100x) showing coamplification of the three investigated genes, all presented as DM and HSR. A CEP4 (aqua signals) corresponded to a control probe recognizing centromere sequences of chromosome 4. B Copies of PDGFRA shown as green signals. C Copies of KIT shown as red signals. D Copies of KDR shown as yellow signals

Fig. 2

Cumulative survival estimated by the Kaplan–Meier method. A According to age group (HR = 13.9; 95% CI 2.82–68.3: p = 0.001). B According to the presence of homogeneous coamplification of the PDGFRA/KIT/KDR genes (HR = 10.5; 95% CI 1.24–89.5: p = 0.031). C According to resection type (HR = 9.30; 95% CI 1.62–53.3: p = 0.012)