Perry A et al., Cancer 92:701, 2001

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1 EMBOLIZED MENINGIOMAS Perry A et al., Cancer 92:71, 21 MENINGIOMA PREDISPOSITION Neurofibromatosis 2 () Prior Irradiation Trauma? Cowden s syndrome? Gorlin s nevoid basal cell syndrome? Li Fraumeni syndrome? Turcot s/gardener s syndrome? von Hippel-Lindau disease? Other Familial? WHO 27 GENETIC MODEL

2 PATHOLOGY-GENETIC GENETIC ASSOCIATIONS Location/Variant Histology Meningothelial at ant. base have less losses Transitional/Fibrous have more losses Hyperostosis (?alk. phosphatase, other OSF) Benign recurring meningiomas (-14q) Brain edema (?VEGF, tenascin) Brain invasion (?SPARC, MMP-9, tenascin, stromelysin-3) Anaplastic with worse survival (9p/p1 loss) l Survival Overall ANAPLASTIC MENINGIOMAS (N=23) Perry A et al., Brain Pathol 12:13-19, 22 p= Years p1 Deletion No Yes CEP9 9p21 BCR 4.1B C1 EMA MIB-1 PR PR BCR 1p32 14q32 Chip # Age Gender F F F F F M F F F M M F M F F M F Location PL FL FL FL PF SB SB SB SB FL FL BS Size L L L Recurrent Grade (B) 3 2 (B) NL NL NL 1 Variant T M M M M M T T M M T T T T F MI CNS Invasion Soft Tiss Invasion Rapid apdgo Growth + + Cellular Small Cells Nucleoli Sheeting Ne cr osis Atypia Mutation + + Elevated in NL Elevated in CA Elevated in Benign DYSREGULATED PATHWAYS Watson MA et al., Am J Pathol 11:-72, 22 Angiogenesis/Vascular Apoptotic Hypoxic/Stress-related Cytoskeletal/ECM/Invasion Growth Signaling Transcriptional Cell cycle Cellular differentiation

3 The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. The image cannot be displayed. Your computer may not have enough memory to open the image, or the image may have been corrupted. Restart your computer, and then open the file again. If the red x still appears, you may have to delete the image and then insert it again. Lusis EA, et al. Cancer Res :7121, 2 1,747, Signal Legend Present Absent NDRG2 (19,47,11-19,41,) 21,3,94 a b Chromosome 14 Chromosome ive expression tive expression relat 1. relat A I II III WHO grade. B indolent clinical behavior aggressive NDRG2 METHYLATION Discovery Set 1Set MAS. SAM BIRC CDC2 RRM2 PI3 AURKA KIF2A HMMR SOX11 TOP2A TPX2 DLG7 NUSAP1 NEK2 FANCI Validation Set 2Set MAS. SAM FC? 4 q < % grade I, grade III FC? 4 q < 2% grade I, grade III 9 TCEAL2 GPX3 PID1 NPY1R P2RY14 KCNMA1 TIMP3 SSPN LMOD1 Algorithm used to identify differentially expressed genes between grade I and grade III meningiomas. Set 1 included grade I and grade III meningiomas and set 2 included grade I and grade III meningiomas. Significance Analysis of Microarrays (SAM) was used to identify 14 genes that were overexpressed and 9 genes that were underexpressed in grade III meningiomas using a fold change (FC) >4 and a false discovery rate (q value) of <2% in set 1 and < % in set 2.

4 1 4 2 TPX RRM2 TOP2 A PI3 NUSAP1 BIRC DLG7 1 1 CDC2 SOX11 Differential RNA expression in human meningiomas as measured by real time reverse transcription PCR. Relative expression in 1 grade I and 1 grade III meningiomas. Relative gene expression was increased in grade III meningiomas as compared to grade I meningiomas for the genes (a i) and decreased in grade III meningiomas in the last two (j k). All were statistically significant with p values <. (Mann Whitney Test). When applied to an independent set of meningiomas from the Barrow Institute (A. Scheck), 1 of 11 markers validated. Survival of TTD Aggr Top2a:Survival proportions Percent survival P Clinical F/u (mos) Aggr Top2a neg Aggr Top2a pos P value TIMP KCNMA1 Survival rates of patients with meningioma stratified by Top2a expression and clinical behavior. Aggressive meningiomas stratified by TOP2a expression reveals TOP2a positive tumors having a shorter time to death... CELL LINES AND ANIMAL MODELS LTAg2B leptomeningeal cell line (viral transfection) Malignant meningioma cell lines Xenograft mouse models GENERATION OF IMMORTALIZED CELL LINES DERIVED FROM BENIGN BRAIN TUMORS BY htert TRANSDUCTION. 1. Püttmann S, et al., Lab Invest :113-71, 2 2. Baia GS, et al., J Neuro-Oncol 7:113-21, 2

5 PGDS Mouse Brain (c/o Marco Giovannini) WHAT CAN WE TELL CLINICAL TEAMS? Confirm the diagnosis of meningioma Assess margins (rare and controversial)? Suggest the possibility of Identify subsets at high risk of recurrence (i.e., grade II) IHC for MIB-1, PR, GFAP (performed on ~1% of our cases) Need for adjuvant radiotherapy vs. careful FU? Frequency of neuroimaging? Identify subsets at high risk of death (i.e., grade III) IHC and FISH for 9p21 deletions (<1% of our cases) Assess therapeutic efficacy? Help identify novel forms of adjuvant therapy MENINGIOMA COLLABORATORS WUSM David Gutmann Mark Watson Mike Chicoine DeWitte Cross Eriks Lusis Dan Cai (Metrohealth, Cleveland, OH) J. Philip Miller Mayo Clinic Bernd Scheithauer Scott Stafford Ed Shaw (Wake Forest) Bob Jenkins Christine Lohse C. David James U. Colorado Bette K. Kleinschmidt- DeMasters UT Southwestern Ravi Raghavan (Loma Linda) Cleveland Clinic Richard Prayson Massachusetts General Hospital Anat Stemmer-Rachamimov Emory University Dan Brat Heinrich-Heine-University, Düsseldorf, Germany Guido Reifenberger