Eriks A. Lusis

Integrative Genomic Analysis Identifies NDRG2 as a Candidate Tumor Suppressor Gene Frequently Inactivated in Clinically Aggressive Meningioma

Although meningiomas are common central nervous system tumors, little is known about the genetic events responsible for malignant progression. In this study, we employed gene expression profiling to identify transcripts whose expression was lost in anaplastic (WHO grade III) versus benign (WHO grade I) meningioma. Approximately 40% of genes down-regulated in anaplastic meningioma were localized to chromosomes 1p and 14q. One specific gene located at 14q11.2, NDRG2, was consistently down-regulated in grade III meningioma, a finding which we validated at both the transcript and protein levels in independent sets of clinically and pathologically diverse meningiomas. Loss of NDRG2 expression was also seen in a subset of lower-grade meningiomas, including atypical meningiomas (WHO grade II) with clinically aggressive behavior. Furthermore, we found that the loss of NDRG2 expression was significantly associated with hypermethylation of the NDRG2 promoter. Collectively, these data identify NDRG2 as the first specific candidate tumor suppressor gene on chromosome 14q that is inactivated during meningioma progression. In addition, these findings highlight the utility of combining genomic, epigenetic, and expression data to identify clinically significant tumor biomarkers, and suggest that NDRG2 expression will be a useful and functionally relevant biomarker to predict aggressive behavior in patients with meningioma.

Meningioma: an update.

Purpose of reviewRecent clinical and molecular research has shed new light on the biology of meningiomas - a common but understudied CNS neoplasm. This review will focus on recent advances and their significance for future research and treatment. Recent findingsMeningiomas represent the second most common brain tumor in adults, and while improved diagnostic modalities are available, these tumors remain underreported. Radiosurgery is an effective adjuvant therapy against meningioma; however, no effective chemotherapy exists. In addition to histologic grading and estimates of the extent of resection, biomarkers, such as progesterone receptor, cyclooxygenase 2, S100A5 and ornithine decarboxylase may be useful in predicting tumor recurrence and/or progression potential in patients with meningioma. On the genetic level, cytogenetic losses on chromosomes 1, 7, 10 and 14 and telomerase activation are observed in clinically aggressive meningioma, whereas monosomy 22 is a common early molecular event in tumor formation. Several candidate growth regulatory genes have been identified, including the Neurofibromatosis 2 (NF2), Tumor Suppressor in Lung Cancer-1 (TSLC1), Protein 4.1B, p53/MDM2 and S6-Kinase genes. The roles of these genes in meningioma formation and progression, as well as the clinical implications of these genetic changes, are discussed. SummaryThe recent insights into the molecular biology and genetics of meningioma provide new avenues for basic science research aimed at understanding the mechanisms underlying meningioma formation and malignant progression. These advances may be useful in improving our ability to predict clinical outcome and developing targeted therapies to improve outcomes in patients with clinically aggressive meningiomas.

High throughput screening of meningioma biomarkers using a tissue microarray

SummaryMeningiomas are histologically and clinically diverse CNS neoplasms with few available immunohistochemical markers of differentiation and progression. Therefore, we investigated a panel of potentially useful meningioma-associated biomarkers using high throughput tissue microarray immunohistochemistry (TMA-IHC) with a TMA that includes 9 hemangiopericytomas (HPCs) and 41 meningiomas spanning all grades, as well as two subsets of atypical meningiomas, stratified according to clinical behavior. Antibodies utilized were progesterone receptor (PR), epithelial membrane antigen (EMA), cathepsin D, E-cadherin, platelet derived growth factor (PDGF) receptor β, PDGF BB ligand, survivin, epithelial growth factor receptor (EGFR), and vascular endothelial growth factor (VEGF). In most cases, frequencies of tumor positivity were similar to those previously reported using whole section IHC. EMA, E-cadherin, and PDGFR-β staining patterns distinguished the anaplastic meningiomas from the HPCs (P < 0.001, P = 0.02, P = 0.015, respectively). As in prior studies, PR and cathepsin D expression were inversely proportional to tumor grade. However, PR and EGFR were also differentially expressed between symptomatic, surgically resected benign meningiomas and incidental meningiomas found at autopsy. We conclude that (1) TMA-IHC is an accurate and efficient way to rapidly assess biomarkers in meningeal tumors, (2) EMA, E-cadherin, and PDGFR-β are useful in distinguishing anaplastic meningiomas from HPCs, and (3) the expression patterns for incidental meningiomas differ slightly from their surgically resected symptomatic counterparts.

Meningiomas in Pregnancy: A Clinicopathologic Study of 17 Cases

BACKGROUND Dramatic growth of meningiomas is occasionally encountered during pregnancy. While cell proliferation is often assumed, hemodynamic changes have also been touted as a cause. OBJECTIVE We identified 17 meningiomas resected during pregnancy or within 3 weeks post-partum and characterized them to determine the cause of occasional rapid growth in pregnancy. METHODS Seventeen tumors were identified from searches at 4 university centers. All available clinical records, radiology images, and tissue specimens were reviewed, with immunohistochemical studies performed as needed. RESULTS Sixteen patients underwent tumor resection and 1 died of complications prior to surgery. Average patient age was 32 years. Nine experienced onset of symptoms in the third trimester or within 8 days post-partum. Principle physical findings included visual complaints (59%) and cranial nerve palsies (29%). Ten tumors (59%) were located in the skull base region. The Ki-67 labeling index was low (0.5-3.6%) in 11 of 13 benign (grade I) tumors and elevated (11-23.2%) in 3 of 4 atypical (grade II) meningiomas. Eight (50%) tumors featured hypervascularity with at least focal CD34-positive hemangioma-like microvasculature. Fourteen (82%) showed evidence of intra- and/or extracellular edema, 1 so extensive that its meningothelial nature was not apparent. Five tumors (29%) exhibited intratumoral hemorrhage and/or necrosis. CONCLUSION Our series suggests that pregnancy-associated meningiomas located in the skull base are likely to require surgical intervention for visual complaints and cranial nerve palsies. The rapid tumor growth is more often due to potentially reversible hemodynamic changes rather than hormone-induced cellular proliferation.

Combined surgical resection and stereotactic radiosurgery for treatment of cerebral metastases

BACKGROUND Patients with limited intracranial metastatic disease traditionally have been treated with surgery followed by WBRT. However, there is growing concern for the debilitating cognitive effects after WBRT in long-term survivors. We present a series of patients treated with surgery followed by SRS, while reserving WBRT as a salvage therapy for disease progression. METHODS Medical records from 15 patients with 1 to 2 cerebral metastases who underwent both resection and SRS were reviewed. Outcome measures included overall survival, survival by RPA class, EOR, local tumor control, progression of intracranial disease, need for WBRT salvage therapy, and COD. RESULTS Fifteen patients with cerebral metastases were treated with the combined surgery-SRS paradigm. Eight of the 15 patients (53.3%) were designated RPA class 1, with 6 of 15 (40.0%) in class 2 and 1 of 15 (6.7%) in class 3. Gross total resection was achieved in 12 cases (80.0%). Overall median survival was 20.0 months, with values of 22.0 and 13.0 months for RPA classes 1 and 2, respectively. Local recurrence occurred in 16.7% of those patients with GTR. Six patients (40.0%) went on to receive WBRT at a median of 8.0 months from initial presentation. Twelve patients (80.0%) had died at the completion of the study, and the COD was CNS progression in 33.3%. CONCLUSIONS Surgical resection combined with SRS is an effective treatment for selected patients with limited cerebral metastatic disease. Survival using this combined treatment was equivalent to or greater than that reported by other studies using surgery + WBRT or SRS + WBRT.

Identification of Gene Markers Associated with Aggressive Meningioma by Filtering across Multiple Sets of Gene Expression Arrays

Meningiomas are common intracranial tumors, but relatively little is known about the genetic events responsible for their clinical diversity. Although recent genomic studies have provided clues, the genes identified often differ among publications. We used microarray expression profiling to identify genes that are differentially expressed, with at least a 4-fold change, between grade I and grade III meningiomas. We filtered this initial set of potential biomarkers through a second cohort of meningiomas and then verified the remaining genes by quantitative polymerase chain reaction followed by examination using a third microarray expression cohort. Using this approach, we identified 9 overexpressed (TPX2, RRM2, TOP2A, PI3, BIRC5, CDC2, NUSAP1, DLG7, SOX11) and 2 underexpressed (TIMP3, KCNMA1) genes in grade III versus grade I meningiomas. As a further validationstep, we analyzed these genes in a fourth cohort and found that patients with grade II meningiomas with high topoisomerase 2-&agr; protein expressions (>5% labeling index) had shorter times to death than patients with low expressions. We believe that this multistep multicohort approach provides a robust method for reducing false-positives while generating a list of reproducible candidate genes that are associated with clinically aggressive meningiomas and are suitable for analysis for their potential prognostic value.

Meningothelial hyperplasia: a detailed clinicopathologic, immunohistochemical and genetic study of 11 cases.

Meningothelial hyperplasia is a poorly characterized entity, often associated with advanced age, chronic renal failure, trauma, hemorrhage, and neoplasia. In order to elucidate the nature of this lesion, 11 cases defined by the presence of nests of 10 or more cell layers thick, were compared with normal arachnoidal cap cells and meningiomas. Immunohistochemistry and FISH were performed to determine NF2 (merlin), protein 4.1 B, EMA, progesterone receptor (PR), EGFR, survivin, VEGF, PDGF‐BB, PDGFRβ, E‐cadherin, and cathepsin D status. All cases had at least one putative predisposing factor, including hemorrhage (7), chronic renal disease (5), old age (5), trauma (1), and an adjacent optic nerve pilocytic astrocytoma (1). There was typically a discontinuous growth pattern, with no invasion of surrounding normal tissue. No gene deletions were found, though scattered polyploid cells were seen in 2 cases. The immunoprofile was similar to normal cap cells with one exception; whereas normal cells were uniformly negative for PR, nuclear positivity was seen in 64% of hyperplasias, a frequency similar to that of benign meningiomas. Our data suggest that meningothelial hyperplasia is a reactive process that is usually distinguishable from meningioma based on clinicopathologic and genetic features. It may be preneoplastic in some, though further studies are needed to test this hypothesis.

Functional significance of S6K overexpression in meningioma progression

One common genetic change in anaplastic meningiomas is amplification of chromosome 17q23 containing the S6 kinase (S6K) gene. We show, for the first time to our knowledge, increased S6K mRNA expression in anaplastic meningiomas compared with benign tumors. To evaluate S6K as a candidate meningioma progression gene, we generated IOMM‐Lee human meningioma cell lines overexpressing S6K. Whereas no effect of S6K overexpression on meningioma cell growth, motility, or adhesion was observed in vitro, S6K overexpression resulted in increased tumor size in vivo. Collectively, these results suggest that S6K is functionally important for meningioma progression and may represent a target for future meningioma therapy. Ann Neurol 2004

Intramedullary capillary hemangioma of the thoracic spine: case report and review of the literature

Capillary hemangiomas are benign vascular neoplasms. When associated with the spine, these growths frequently involve the vertebral body, but rarely have they been reported to occur as intradural lesions, while even more rarely occurring in a true intramedullary location. We report a rare case of an intramedullary capillary hemangioma of the thoracic spinal cord and a review of the literature.

Glioblastomas with giant cell and sarcomatous features in patients with Turcot syndrome type 1: a clinicopathological study of 3 cases.

BACKGROUNDTurcot syndrome (TS) is a rare genetic disorder of DNA mismatch repair predisposing to glioblastoma (GBM) in the type 1 variant. OBJECTIVEWe report the clinicopathological and genetic features of 3 gliomas in TS type 1 patients. METHODSThree cases were reviewed from our clinical and pathology files at Washington University with the diagnosis of TS 1 and GBM over the past 14 years. All 3 had classic features of GBM, but also demonstrated bizarre multinucleated giant cells and remarkably high mitotic indices. Sarcomatous regions were found in 2. Despite these features, the patients had prolonged survival times of 44, 55, and >29 months (ie, currently alive). Demographic and clinical courses were abstracted from retrospective chart review. Histopathology was reviewed from all cases and reticulin histochemistry was added to identify possible foci of sarcomatous differentiation. RESULTSAll 3 had classic features of GBM, and Ki-67 labeling indices ranged from 18 to 45%. All 3 also showed strong nuclear p53 positivity. Two cases were negative for the isocitrate dehydrogenase 1 (IDH1) mutation, and O6-Methylguanine methyltransferase promoter methylation was seen in one. Fluorescence in situ hybridization was done using 1p/1q, 19p/19q, centromere 7/epithelial growth factor receptor (EGFR), and PTEN/DMBT1 probes. Focal EGFR amplification was seen in one case, although other common alterations of either primary GBMs or gliomas with prolonged survival (1p/19q codeletion) were lacking. CONCLUSIONWe conclude that 1) the giant cell variant of GBM is overrepresented in TS; 2) gliosarcomas may also be encountered; and 3) survival is often favorable, despite histological anaplasia and exuberant proliferation.