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DNA-microarray analysis of brain cancer: molecular classification for therapy

Nature Reviews Neuroscience volume 5, pages 782–792 (2004)Cite this article

Key Points

  • The genomic revolution is transforming clinical medicine — instead of the present model of population risk assessment and empirical treatment, we will move to one of predictive individualized care based on molecular classification and targeted therapy. This review highlights the role of DNA microarrays in developing predictive molecular diagnostics for patients with brain tumours.

  • The molecular events that are crucial for normal development and function are similar between individuals. However, in cancer, genetic and epigenetic alterations result in cascades of deregulated molecular events, which lead to genetically complex, highly individual tumours. Finding consistencies that can be therapeutically exploited is vital for the development of new treatments.

  • Brain cancer is now the leading cause of death from cancer in children under the age of 15 and the second leading cause of death from cancer from age 15 to 34. In adults, brain cancer is proportionately less common than other cancers, yet it accounts for a disproportionate percentage of deaths from cancer.

  • Primary brain tumours arise from the constituent cells of the CNS or their meningeal covering, whereas secondary brain tumours metastasize from a distant site. In 1928, Bailey and Cushing suggested that brain tumours could be classified by their microscopic resemblance to a presumed CNS cell of origin or its developmental precursor. Although recent work shows a more complex pattern, this model has remained a guiding principle for brain tumour classification.

  • New approaches are being developed to specifically target proteins or pathways that are altered in cancer cells. Morphologically identical tumours can be distinct in their mutational patterns, signalling-pathway alterations and gene-expression profiles, and, most importantly, in their response to a range of therapies.

  • Medulloblastomas have distinctive global gene-expression profiles that readily distinguish them from morphological mimics, and DNA microarrays can detect molecular subsets of medulloblastoma cases that differ in survival. Low-grade astrocytomas, oligodendrogliomas and glioblastomas also have distinctive global gene-expression profiles.

  • The fact that DNA microarrays can be used to detect molecular subsets that differ in survival indicates that it will soon be possible to develop gene-based predictors of therapeutic response. DNA microarrays might also facilitate the functional analysis of new anti-cancer compounds and the identification of novel biomarkers and molecular-imaging probes.

  • Cancer cells do not 'invent' new pathways; they use pre-existing pathways in different ways or they combine components of these pathways in a new fashion. By mapping, expanding and refining pathway maps in brain cancer, DNA-microarray studies might provide insight into the connectivity of these pathways in the developing and normally functioning brain.

  • It is possible to imagine a day in the not-too-distant future when serum biomarkers and molecular-imaging probes that are identified by DNA microarrays will be used for screening or early detection. Tumours will undergo microarray analysis to identify pathway alterations that point to the most beneficial therapy, and response to therapy will be monitored using molecular imaging probes and/or serum biomarkers.

Abstract

Primary brain tumours are among the most lethal of all cancers, largely as a result of their lack of responsiveness to current therapy. Numerous new therapies hold great promise for the treatment of patients with brain cancer, but the main challenge is to determine which treatment is most likely to benefit an individual patient. DNA-microarray-based technologies, which allow simultaneous analysis of expression of thousands of genes, have already begun to uncover previously unrecognized patient subsets that differ in their survival. Here, we review the progress made so far in using DNA microarrays to optimize brain cancer therapy.

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Figure 1: Classification scheme for brain tumours.
Figure 2: DNA-microarray analyses can identify relevant clinical subsets of gliomas.
Figure 3: Prospects for integrating genomic analysis of brain tumours with clinical-trial development.

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Acknowledgements

We wish to thank S. Horvath, M. Carlson, W. Freije and Z. Fang for their contribution to this work, and we thank D. Geschwind and H. Kornblum for helpful discussions about this review. The authors are supported by the NINDS and NCI and by Accelerate Brain Cancer Cure, the Packard Foundation, the Harry Allgauer Foundation through The Doris R. Ullmann Fund for Brain Tumor Research Technologies, the Henry E. Singleton Brain Tumor Endowment, Art of the Brain and the Ziering Family Foundation in memory of Sigi Ziering.

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Authors and Affiliations

  1. Departments of Pathology and Laboratory Medicine, the Henry E. Singleton Brain Cancer Research Program at the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, California, USA

    Paul S. Mischel

  2. Department of Neurology, the Henry E. Singleton Brain Cancer Research Program at the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, California, USA

    Timothy F. Cloughesy

  3. Department of Human Genetics, the Henry E. Singleton Brain Cancer Research Program at the David Geffen School of Medicine, University of California Los Angeles, Los Angeles, 90095, California, USA

    Stanley F. Nelson

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  1. Paul S. Mischel
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Correspondence to Paul S. Mischel.

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DATABASES

Entrez Gene

EGFR

ErbB2

FKBP12

p53

SHH

TRKC

YKL40

FURTHER INFORMATION

Encyclopedia of Life Sciences

Brain Cancers

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National Cancer Institute

Glossary

GLIOMA

Any brain tumour that originates from the glial cell lineage.

METASTASIS

The spread of cancer cells from one organ or tissue to another, usually though the blood stream or the lymphatic system.

SINGLE NUCLEOTIDE POLYMORPHISMS

Bi-allelic (typically) base pair substitutions, which are the most common forms of genetic polymorphism.

ALTERNATIVE SPLICING

During splicing, introns are excised from RNA after transcription and the cut ends are rejoined to form a continuous message. Alternative splicing allows the production of different messages from the same DNA molecule.

DESMOPLASTIC

A term that refers to the growth of dense fibrous tissue around a tumour.

cDNA

Complementary DNA that is produced from an RNA template by an RNA-dependent DNA polymerase.

CHEMOTAXIS

The movement of cells in response to a chemical gradient that is provided by chemotactic agents.

RT-PCR

Reverse transcriptase–polymerase chain reaction (PCR) — a reaction in which messenger RNA is converted into DNA (reverse transcription), which is then amplified by PCR.

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Mischel, P., Cloughesy, T. & Nelson, S. DNA-microarray analysis of brain cancer: molecular classification for therapy. Nat Rev Neurosci 5, 782–792 (2004). https://doi.org/10.1038/nrn1518

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