Genetic analysis of human astrocytic gliomas : xenografts as a research tool
Author: Goike, Helena M.
Date: 1999-12-17
Location: Radiumhemmets föreläsningssal, Karolinska Sjukhuset
Time: 9.30
Department: Institutionen för onkologi-patologi / Department of Oncology-Pathology
Abstract
Cancer is a genetic disorder of somatic cells. An accumulation of genetic
changes is believed to result in neoplastic transformation and malignant
progression. In humans, astrocytic gliomas are the most common primary
tumors of brain tissue. They are malignancy graded according to World
Health Organization criteria. In adults, the tumors include astrocytoma,
(grade II), anaplastic astrocytoma, (grade III) and the most malignant
and common form glioblastoma (grade IV). A significant proportion of
astrocytomas (A) and anaplastic astrocytomas (AA) progress into tumors of
higher malignancy grade. Glioblastomas (GB) arise by progression, but may
also develop de novo. Several genes and chromosomal regions are commonly
found amplified, deleted or mutated in these tumors, suggesting a role
for these abnormalities in the development and progression of astrocytic
gliomas. An accumulation of genetic lesions is seen with increasing
malignancy grade.
The aim of the studies described in this thesis was to document genetic
abnormalities in human astrocytic gliomas and to establish human
astrocytic gliomas as xenografts permitting the development of material
for extensive and detailed studies of genetic abnormalities and their
cell biological consequences. In addition, xenografts provide tumour
tissue with well-documented patterns of genetic abnormalities, in an in
vivo environment, for preliminary testing of novel treatment modalities.
Other aims included the determination of whether the xenografts are
representative of the patient's tumour, and to study whether further
genetic abnormalities arise in xenografts and, if so, to identify these.
A series of 198 astrocytic gliomas was examined for loss of genetic
material on chromosome 10. The microsatellite analysis revealed two
commonly deleted regions on 10p, detected in all malignancy grades.
Deletions on 10q were large and found mainly in the glioblastomas. The
findings suggest that a number of loci on chromosome 10 may harbor tumour
suppressor genes relevant to the development and progression of these
tumors. Loci on 10p may be involved in the development of astrocytomas,
and loci on 10q important in the progression of such astrocytomas to
glioblastoma. The tumor suppressor gene PTEN is located at 10q23, and was
studied in 207 astrocytic gliomas from patients, 23 glioblastoma
xenografts and 13 glioma cell lines. Homozygous deletions were found in
7% of the glioblastomas and 40% of glioblastomas showed mutation of a
single retained allele. The mutations mainly affected structurally
conserved regions. PTEN loss was selected for in the glioblastoma
xenografts. Only a few anaplastic astrocytomas harbored mutations and no
alterations were found in astrocytomas. This suggests that PTEN
abnormalities are associated with astrocytic tumour progression.
A glioblastoma xenograft model was established. Of 47 directly and
subcutaneously transplanted patient tumors, 24 grew on serial passaging.
To preserve the system and to increase accessibility, a cryopreservation
protocol for long term storage of viable tumour tissue from any passage
was developed and demonstrated to work successfully for the majority of
the xenografts. A number of genes previously known to show aberrations in
human glioblastomas were found to become mutated in the xenografts, as
studied by comparing the genetic analysis of patient and xenograft tumour
tissues. Acquisition of additional aberrations during passage as
xenografts was detected. For example, one tumour with an amplified EGFR
gene developed a rearrangement of the gene during xenograft cultivation.
This demonstrates the significance of this aberrant variant reported
earlier in clinical material. Furthermore, selection for tumour cells
harboring genetic abnormalities deregulating the G1/S-phase transition
control and p53 pathways was found in the xenografts. Commonly,
abnormalities affecting both G1/S-phase transition control and p53
pathways developed simultaneously.
In summary, the patient tumors were characterized for genetic
abnormalities. Some of the glioblastomas were successfully cultivated as
xenografts. Cryopreservation was developed, and the xenografts
characterized for the acquisition of and selection for genetic mutations.
The characterized xenografts now offer the possibility of analyzing in
detail the development of genetic changes, their cell biological
consequences and the selection process, as well as offering the
possibility of testing novel treatment modalities.
Issue date: 1999-11-26
Publication year: 1999
ISBN: 91-628-3805-9
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