A Microregional Comparison of EGFR Amplification and MIB-1 Proliferative Index in High-Grade Astrocytomas
TS Kraus, RK Kraus, DJ Brat. Emory University, Atlanta, GA
Background: Amplification of the epidermal growth factor receptor (EGFR) gene is a genetic hallmark of glioblastoma (GBM), seen in approximately 40% of these biologically aggressive neoplasms. While it is widely assumed that EGFR amplification correlates with biologic activity, relationships with proliferation, invasiveness, and angiogenesis have not been clearly demonstrated in human tissue. In order to begin to address this issue, we examined the relationship between microregional EGFR amplification and MIB-1 proliferation indices in EGFR-amplified and non-amplified GBMs and non-amplified anaplastic astrocytomas (AA).
Design: Sections from 3 EGFR-amplified GBMs, 3 non-amplified GBMs, and 3 AAs were evaluated for regional variation in MIB-1 immunohistochemical staining indices. FISH was performed using dual color probes which hybridized to the EGFR gene and to the centromere of chromosome 7. Amplification was defined as a ratio of EGFR/centromere signal ratio of 2. EGFR/centromere ratios were obtained from selected regions of each GBM and AA specimen (average 6 regions per section, 25 cells per region). EGFR amplification status and degree were correlated with MIB-1 proliferation in each tumor region.
Results: The degree of EGFR amplification varied considerably among the 18 regions of 3 EGFR-amplified GBMs, and did not show overall correlation with proliferative index (rs= 0.11). Taken individually, one EGFR-amplified GBM showed a positive correlation between degree of amplification and MIB-1 index (rs= 0.61) and two showed a negative correlation (rs=-0.60 and -0.29). None of the correlations achieved statistical significance. The MIB-1 proliferation index was variable among the 18 selected regions in EGFR-amplified GBMs (mean +/- standard deviation = 24.9% +/- 17.6%, coefficient of variation = 73.1%), compared to non-amplified GBMs (14.4% +/- 9.4%, CV= 65.4%) and AAs (6.8% +/- 3.2%, CV=47.2%). The mean MIB-1 index and the CVs of EGFR-amplified GBMs were significantly higher than those of non-amplified GBMs (p<0.05).
Conclusions: From our limited data set, it appears that EGFR amplification in GBM is associated with an overall increase in MIB-1 proliferative index, but that the degree of amplification does not significantly correlate with the proliferative index within a given tumor microregion. High-grade astrocytomas show intratumoral heterogeneity of MIB-1 proliferation indices, and EGFR amplification appears to enhance this variability.
Tuesday, March 10, 2009 9:30 AM
Poster Session III # 187, Tuesday Morning