From Cushing to Chromosomes: 100 Years of Glioma Diagnosis and Research
Moderators: Dr. Gregory N. Fuller and Dr. Pieter Wesseling
Section 4 -
Into the 21ST Century: Genomics and the New Mouse Models Synergistically Advancing Glioma Research
Gregory N. Fuller
Department of Pathology
The University of Texas M. D. Anderson Cancer Center
Houston , Texas
Brain tumor pathology is a rapidly evolving field, with new clinicopathologic entities (Table 1), new
diagnostic antibodies (Table 2), and new molecular diagnostic tests (Table 3) continually emerging;
frequent continuing medical education in this area is essential. Gliomas constitute the most common type
of primary brain tumor. As with other types of brain tumors, our knowledge of the gliomas continues to
expand, including newly characterized subtypes, improvements in glioma grading and attendant patient
stratification for prognostic and treatment purposes, and also in our understanding of basic glioma
Table 1. 10 New Types of Brain Tumor Described Over the Past 25 Years*
|Tumor Type||Year Described|
|Pleomorphic xanthoastrocytoma ||1979|
|Central neurocytoma ||1982|
|Dysembryoplastic neuroepithelial tumor ||1988|
|Chordoid glioma ||1998|
|Papillary glioneuronal tumor ||1998-99|
|Rosetted glioneuronal tumor ||1998-99|
|Pilomyxoid astrocytoma ||1999|
|Rosette-forming glioneuronal tumor of the 4th ventricle ||2002|
|Papillary tumor of the pineal region ||2003|
|Monomorphous angiocentric bipolar glioma ||2005|
Table 2. Recently Introduced Diagnostic Antibodies for Brain Tumors
|Inhibin alpha ||Hemangioblastoma|
|INI1/SMARC5/BAF47 ||Rhabdoid and Atypical Teratoid/Rhabdoid Tumor|
|OCT4 ||Germinoma and Embryonal Carcinoma|
|Phospho-histone H3 ||Proliferation Marker; Diffuse Gliomas, Meningiomas|
Table 3. Potentially Useful Glioma Molecular Markers Currently Under
*Fuller GN, Aldape KD, Molecular genetics and neuropathology of intracranial tumors, In: M D Anderson
Cancer Care Series: Tumors of the Brain and Spinal Cord. New York : Springer-Verlag, 2006.
Chromosome 1p and 19q deletion status|
O-6-methylguanine-DNA methyltransferase (MGMT) promoter methylation status
EGFR gene amplification/overexpression
Molecular Classification of the Diffuse Gliomas
The field of glioma classification is currently entering a new era with the introduction of new
paradigms based on molecular information. Rather than supplanting traditional morphology-based
classification schemes, it is anticipated that emerging molecular biologic, genomic, transcriptomic and
proteomic data will complement and augment existing morphologic and immunophenotypic data, providing for
a more accurate and refined stratification of glioma patients for directed therapies and for the
resolution of several problematic issues inherent in histological classifications. Two different
approaches are contributing to the improvement of glioma stratification. The first is the analysis of
alterations of a small number of genes or gene products of recently demonstrated impact on patient
survival and response to therapy, such as the deletion status of chromosomes 1p and 19q in
oligodendroglial tumors, and O(6)-methylguanine-DNA methyltransferase (MGMT)
promoter methylation status in glioblastoma. The second paradigm is a more comprehensive analysis of the
tumor genome, transcriptome or proteome, which may itself provide refined subclassification, or may
identify specific relevant biomolecules for use in the single gene substratification approach. Both
paradigms have already exerted a tangible and growing impact on glioma classification, and it is likely
that we have only just begun to exploit their potential contributions.
New Mouse Models of Diffuse Gliomas
Historically, the most extensively studied glioma animal model has been the xenograft, in which human
glioma tumor cells are injected into immunocompromised mice. The resultant tumors constitute good
genotypic models because the tumor cells are human in origin. However, many human glioma cell lines in
xenograft form exhibit only limited infiltration of the surrounding animal host brain parenchyma.
Diffuse infiltration of brain tissue, which is a critical phenotypic feature of the diffuse gliomas that
severely limits the effectiveness of many treatment modalities, can now be studied in new
transgenic/somatic gene transfer mouse models in which different subtypes of diffuse glioma can be
generated through the introduction of specific combinations of oncogenes. Using the RCAS/tva model,
investigators have generated glioblastomas, low-grade astrocytomas, oligodendrogliomas, anaplastic
oligodendrogliomas, and mixed gliomas. All of these gliomas are virtually identical to their human
counterparts in terms of morphologic features, differentiation marker immunophenotype, and biologic
behavior (see References for additional information about the RCAS/tva model).
Synergy Between Genomics and Mouse Modeling in Advancing Glioma Research: The IGFBP2 Story
Increasingly, investigators are combining the power of genomics technology with the new mouse models.
One illustration of this approach is provided by the discovery and elucidation of the role of
insulin-like growth factor binding protein 2 (IGFBP2) in glioma biology. IGFBP2 was initially shown to
be overexpressed in 80% of glioblastomas by cDNA microarray expression profiling followed by tissue
microarray confirmation. IGFBP2 overexpression was subsequently found to correlate with poor survival in
diffuse gliomas. In vitro functional studies combined with transcriptome
profiling provided evidence that IGFBP2 increases glioma cell migration and invasion by up-regulating the
pathways responsible for those pathways. Finally, using the RCAS-tva mouse model system, IGFBP2 and several known oncogenes, including platelet-derived growth factor
(PDGF), K-Ras, and Akt, were delivered separately and in combination into the developing mouse brain.
The experimental results showed that chronic PDGF signaling leads exclusively to the formation of
low-grade oligodendrogliomas; in contrast, PDGF delivered in combination with IGFBP2 results in
anaplastic oligodendrogliomas formation, and combined activated K-Ras and Akt lead to the formation of
astrocytomas. A similar paradigm is being exploited by investigators world-wide to advance our knowledge
and ability to treat many different forms of cancer.
General Resources for Neuropathology and Genomics of Brain Tumors
Burger PC and Scheithauer BW. Tumors of the Central Nervous System.
AFIP Atlas of Tumor Pathology, 4th Series. Washington, DC: American Registry of Pathology,
Fuller GN, Aldape KD, Molecular genetics and neuropathology of intracranial tumors, In: M D Anderson
Cancer Care Series: Tumors of the Brain and Spinal Cord. New York : Springer-Verlag, 2006.
Fuller GN, Burger PC: Central nervous system. In: Mills SE, ed. Histology
for Pathologists. 3rd ed. New York : Raven Press; 2006.
Kleihues P, Cavenee WK, eds. Pathology and Genetics of Tumours of the Nervous
System. New York : Oxford University Press, 2000.
(Revised WHO Classification scheduled for 2007)
McLendon R, Rosenblum M, Bigner DD, eds. Russell & Rubinstein's Pathology
of Tumors of the Nervous System, 7th ed. London: Arnold, 2006.
Prayson RA. Neuropathology. Philadelphia : Elsevier, 2005.
Zhang W and Fuller GN. Genomic and Molecular Neuro-Oncology. Boston : Jones and Bartlett
Molecular Classification of Brain Tumors
Freije WA, Castro-Vargas FE, Fang Z, Horvath S, Cloughesy T, Liau LM, Mischel PS, Nelson SF. Gene
expression profiling of gliomas strongly predicts survival. Cancer Res. 2004;64:6503-6510. Cancer Res
Fuller GN: Molecular classifications. In: Barnett GH, ed. Current Clinical
Oncology: High-Grade Gliomas: Diagnosis and Treatment. Totawa: Humana Press; 2006.
Fuller GN, Hess, KR, Rhee, CH, Yung WKA, Sawaya RA, Bruner JM, Zhang W. Molecular classification of
human diffuse gliomas by multidimensional scaling analysis of gene expression profiles parallels
mophology-based classification, correlates with survival, and reveals clinically-relevant novel glioma
subsets. Brain Pathology 2002;12:108-116.
Hegi ME, Diserens AC, Gorlia T, Hamou MF, de Tribolet N, Weller M, Kros JM, Hainfellner JA, Mason W,
Mariani L, Bromberg JE, Hau P, Mirimanoff RO,Cairncross JG, Janzer RC, Stupp R. MGMT gene silencing and
benefit from temozolomide in glioblastoma. N Engl J Med 2005;352:997-1003.
Iwadate Y, et al. Molecular classification and survival prediction in human gliomas based on proteome
analysis. Cancer Res 2004;64:2496-2501.
Jeuken JW, von Deimling A, Wesseling P. Molecular pathogenesis of oligodendroglial tumors. J
Jeuken JW, Sprenger SH, Boerman RH, von Deimling A, Teepen HL, van Overbeeke JJ,Wesseling P. Subtyping
of oligo-astrocytic tumours by comparative genomic hybridization. J Pathol 2001;194:81-87.
McDonald JM, Colmam H, Perry A, Aldape K. Molecular and clinical aspects of 1p/19q loss in
oligodendroglioma. In: Zhang W, Fuller GN, eds. Genomic and Molecular
Neuro-Oncology. Boston:Jones and Bartlett, 2004:17-30.
Mischel PS, Cloughesy TF, Nelson SF. DNA-microarray analysis of brain cancer: molecular
classification for therapy. Nat Rev Neurosci. 2004;5:782-792.
Nigro JM, Misra A, Zhang L, Smirnov I, Colman H, Griffin C, Ozburn N, Chen M,Pan E, Koul D, Yung WK,
Feuerstein BG, Aldape KD. Integrated array-comparative genomic hybridization and expression array
profiles identify clinically relevant molecular subtypes of glioblastoma. Cancer Res 2005;65:1678-1686.
Nutt CL, et al. Gene expression-based classification of malignant gliomas correlates better with
survival than histological classification. Cancer Res 2003;63:1602-1607.
Reifenberger G, Louis DN. Oligodendroglioma: toward molecular definitions in neuro-oncology. J
Neuropathol Exp Neurol 2003;62:111-126.
Roerig P, Nessling M, Radlwimmer B, Joos S, Wrobel G, Schwaenen C, Reifenberger G, Lichter P.
Molecular classification of human gliomas using matrix-based comparative genomic hybridization. Int J
Recently Introduced Diagnostic Antibodies
Colman H, Giannini C, Huang L, Gonzalez J, Hess K, Bruner J, Fuller G, Langford L, Pelloski C, Aaron
J, Burger P, Aldape K. Assessment and prognostic significance of mitotic index using the mitosis marker
phospho-histone H3 in low-intermediate grade infiltrating astrocytomas. Amer J
Surg Pathol 2006 30:657-64
Ribalta T, McCutcheon IE, Aldape KD, Bruner JM, Fuller GN. The mitosis-specific antibody
anti-phosphohistone-H3 (PHH3) facilitates rapid reliable grading of meningiomas according to WHO 2000
criteria. Am J Surg Pathol. 2004;28:1532-1536.
Sung M-T, et al. OCT4 is superior to CD30 in the diagnosis of metastatic embryonal carcinomas after
chemotherapy. Human Pathology 2006;37:662-667.
Hattab EM, Tu PH, Wilson JD, Cheng L. OCT4 immunohistochemistry is superior to placental alkaline
phosphatase (PLAP) in the diagnosis of central nervous system germinoma. Am J Surg Pathol.
Jones TD, Ulbright TM, Eble JN, Cheng L. OCT4: A sensitive and specific biomarker for intratubular
germ cell neoplasia of the testis. Clin Cancer Res. 2004; 10:8544-7.
SM, Kuo TT. Immunoreactivity of CD10 and inhibin alpha in differentiating hemangioblastoma of central
nervous system from metastatic clear cell renal cell carcinoma. Mod Pathol. 2005;18:788-94.
Hoang MP, Amirkhan RH. Inhibin alpha distinguishes hemangioblastoma from clear cell
renal cell carcinoma. Am J Surg Pathol. 2003;27:1152-6.
Perry A, Fuller CE,
Judkins AR, Dehner LP, Biegel JA. INI1 expression is retained in composite rhabdoid tumors, including
rhabdoid meningiomas. Mod Pathol. 2005;18:951-8.
Sigauke E, Rakheja D,
Maddox DL, Hladik CL, White CL, Timmons CF, Raisanen J. Absence of expression of SMARCB1/INI1 in
malignant rhabdoid tumors of the central nervous system, kidneys and soft tissue: an immunohistochemical
study with implications for diagnosis. Mod Pathol. 2006;19:717-25.
RCAS/tva Mouse Model for Diffuse Gliomas
Dai C, Lyustikman Y, Shih A, Hu X, Fuller GN, Rosenblum M, Holland EC. The
characteristics of astrocytomas and oligodendrogliomas are caused by two distinct and interchangeable
signaling formats. Neoplasia. 2005;7(4):397-406.
Begemann M, Fuller GN,
Holland EC. Genetic modeling of glioma formation in mice. Brain Pathol. 2002;12:117-32.
Holland EC, Celestino J, Dai C, Schaefer L, Sawaya RA, Fuller GN. Combined activation
of Ras and Akt in neural progenitors induces glioblastoma formation in mice. Nature Genetics 25:55-57,