Molecular Neuro-Oncology Laboratory

David N. Louis, M.D.

Pathology (Neuropathology)
Neurosurgery
Telephone (617) 726-5510
Fax: (617) 726-5079
email louis@helix.mgh.harvard.edu

Louis Group Personnel

David N. Louis, M.D., Principal Investigator
Keisuke Ueki, MD, Post-doctoral fellow
Anat Rachamimov, MD, Post-doctoral fellow
Jon Rosenberg, Medical Student
Michael Platten, Medical Student
David Lisle, Technician
Jen Burwick, Technician

Molecular Neuro-Oncology Laboratory
Neurosurgical Service and Department of Pathology
Neuroscience Center

Research

Astrocytomas are the most common type of primary brain tumor. Their classification, however, remains controversial and effective therapies remain elusive. Elucidating the molecular basis of astrocytoma formation may therefore impact both on diagnostic and therapeutic aspects of clinical neuro-oncology.

The Molecular Neuro-Oncology Laboratory has defined a number of genetic alterations that are distinct for different grades of astrocytoma. The formation of low-grade astrocytoma is associated with inactivation of the p53 tumor suppressor gene, overexpression of platelet-derived growth factor and its receptors, and loss of a tumor suppressor gene on chromosome 22q (not the NF2 gene). The transition to anaplastic astrocytoma involves inactivation of a putative tumor suppressor gene on chromosome 19q. The transition to anaplastic astrocytoma and to glioblastoma multiforme is associated with alterations in the cell-cycle regulatory pathway that includes the retinoblastoma susceptibility gene on chromosome 13q, the CDKN2/p16/MTS1 tumor suppressor gene on chromosomes 9p and the CDK4 oncogene on chromosome 12q. Malignant transformation to glioblastoma multiforme is also associated with loss of chromosome 10 and amplification of the epidermal growth factor receptor gene. Our data further suggest that astrocytomas can be divided into genetic subsets that may reflect different biological forms, one of which is associated with astrocytoma formation in younger adults.

The tumor suppressor gene on chromosome 19q is of particular interest, since this locus is involved in all three types of malignant diffuse gliomas (astrocytomas, oligodendrogliomas and oligoastrocytomas), but not in other types of human cancer. Ongoing efforts to identify this possibly glial-specific tumor suppressor gene on chromosome 19q have led us to an approximately 500 kilobase region. Recent work has focussed on cloning novel genes from this candidate region.

The laboratory is also involved in molecular genetic study of other forms of primary human brain tumors, such as medulloblastomas, meningiomas, schwannomas and hemangiopericytomas.

Selected References:

von Deimling A, von Ammon K, Schoenfeld DA, Wiestler OD, Seizinger BR, Louis DN. Subsets of glioblastoma multiforme defined by molecular genetic analysis. Brain Pathol 3:19-26, 1993.

Rubio M-P, von Deimling A, Yandell DW, Wiestler OD, Gusella JF, Louis DN. Accumulation of wild-type p53 protein in human astrocytomas. Cancer Res 53:3465-3467, 1993.

Rubio M-P, Correa KC, Ramesh V, MacCollin MM, Jacoby LB, von Deimling A, Gusella JF, Louis DN. Analysis of the neurofibromatosis 2 (NF2) gene in human ependymomas and astrocytomas. Cancer Res 54:45-47, 1994. Louis DN. The p53 gene and protein in human brain tumors. J Neuropathol Exp Neurol 53:11-21, 1994.

Henson JW, Schnitker BL, Correa K, von Deimling A, Fassbinder F, Xu H-J, Benedict WF, Yandell DW, Louis DN. The retinoblastoma gene is involved in the malignant progression of astrocytomas. Ann Neurol 36:714-721, 1994.

Rubio M-P, Correa KM, Ueki K, Mohrenweiser HW, Gusella JF, von Deimling A, Louis DN. The putative glioma tumor suppressor gene on chromosome 19q maps between APOC2 and HRC. Cancer Res 54:4760-4763, 1994.

Ueki K, Rubio M-P, Ramesh V, Correa KM, Rutter J, von Deimling A, Buckler AJ, Gusella JF, Louis DN. MTS1 gene mutations are rare in primary human astrocytomas with allelic loss of chromosome 9p. Hum Molec Genet 3:1841-1845, 1994.

Raffel C, Ueki K, Harsh GR, Louis DN. The multiple tumor suppressor 1 / cyclin dependent kinase inhibitor 2 gene (MTS1/CDKN2) in human central nervous system primitive neuroectodermal tumor. Neurosurgery 36:971-974, 1995. Alderson L, Castleberg R, Harsh GR, Louis DN, Henson JW. Human gliomas with wild-type p53 express bcl-2. Cancer Res 55:999-1001, 1995.

Dirven CMF, Tuerlings J, Molenaar WM, Go KG, Louis DN. Glioblastoma multiforme in four siblings: a cytogenetic and molecular genetic study. J Neuro-Oncol 24:251-258, 1995.

Yong WH, Chou D, Ueki K, Harsh GR, von Deimling A, Gusella JF, Mohrenweiser HW, Louis DN. Chromosome 19q deletions in human gliomas overlap telomeric to D19S219 and may target a 425 kb region centromeric to D19S112. J Neuropathol Exp Neurol 54:622-626, 1995.

Joseph JT, Lisle DK, Jacoby LB, Paulus W, Barone R, Cohen M, Roggendorf W, Bruner JM, Gusella JF, Louis DN. NF2 gene analysis distinguishes hemangiopericytoma from meningioma. Am J Pathol (in press).

Ono Y, Ueki K, Joseph JT, Louis DN. Homozygous deletions of the CDKN2/p16 gene in dural hemangiopericytomas. Acta Neuropathol (in press).

Paulus W, Lisle DK, Tonn JC, Roggendorf W, Wolf HK, Reeves SA, Louis DN. Molecular genetic alterations in pleomorphic xanthoastrocytoma. Acta Neuropathol (in press).

Chou D, Miyashita T, Mohrenweiser HW, Ueki K, Kastury K, Druck T, von Deimling A, Huebner K, Reed JC, Louis DN. The BAX gene maps to the glioma candidate region at 19q13.3, but is not altered in human gliomas. Cancer Genet Cytogenet (in press).

Louis DN, Gusella JF. A tiger behind many doors: multiple pathways to malignant glioma. Trends in Genetics 11:412-415, 1995.

Yong WH, Ueki K, Chou D, Reeves SA, von Deimling A, Gusella JF, Mohrenweiser HW, Buckler AJ, Louis DN. Cloning of a highly conserved human protein serine-threonine phosphatase from the glioma candidate region on chromosome 19q13.3. Genomics 29:533-536, 1995.

Ueki K, Ono Y, Henson JW, Efird JT, von Deimling A, Louis DN. CDKN2/p16 or RB alterations occur in the majority of glioblastomas and are inversely correlated. Cancer Res (in press).

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