Table of Contents
1
UI - 11898512
AU - Korf BR
TI -
Diagnosis and management of neurofibromatosis type 1.
SO - Curr Neurol Neurosci Rep 2001 Mar;1(2):162-7
AD - Partners Center for Human Genetics, Harvard Medical School, 77 Avenue
Louis Pasteur, Suite 642, Boston, MA 02115, USA. bkorf@partners.org
Neurofibromatosis type 1 (NF1) is an autosomal dominant disorder whose
major feature is the occurrence of multiple neurofibromas, which are
benign tumors of the nerve sheath. It affects an estimated one in 3000
to 4000 individuals. In addition to neurofibromas, there are many other
clinical manifestations, including malignant tumors such as gliomas or
malignant peripheral nerve sheath tumors, and nontumor effects such as
skeletal dysplasia and learning disability. Diagnosis is established on
the basis of clinical criteria. Molecular genetic testing is feasible,
but the large size of the gene and wide range of pathogenic mutations
have so far impeded the development of a clinical diagnostic test.
Insights into pathogenesis have followed from identification of the NF1
gene and the development of animal models. The major function of the
gene product appears to be regulation of the ras protein. Tumors are
believed to arise by the loss of function of the NF1 protein, suggesting
that NF1 behaves as a tumor suppressor gene. Heterozygous effects on
some cell types are also likely, however. The role of ras in the
pathogenesis of tumors in NF1 has suggested an approach to treatment
using ras inhibitors, some of which are likely to begin in clinical
trials in NF1 patients in the near future.
2
UI - 11929829
AU - Gutmann DH; Hedrick NM; Li J; Nagarajan R; Perry A; Watson MA
TI -
Comparative gene expression profile analysis of neurofibromatosis
1-associated and sporadic pilocytic astrocytomas.
SO - Cancer Res 2002 Apr 1;62(7):2085-91
AD - Department of Neurology, Washington University School of Medicine, St.
Louis, Missouri 63110, USA. gutmannd@neuro.wustl.edu
Pilocytic astrocytomas (PAs) are WHO grade I brain tumors that do not
typically progress to more malignant grades of astrocytoma. Whereas
there have been significant advances in the molecular genetics of
high-grade astrocytomas, relatively little is known about the genetic
changes associated with PA formation. In an effort to better
characterize these low-grade neoplasms, we compared the gene expression
profiles of six sporadic and two neurofibromatosis 1-associated PAs with
other tissues and cell lines of both astrocytic and oligodendroglial
origin. Hierarchical cluster analysis of gene expression data clearly
delineated PAs from low-grade oligodendrogliomas and normal white
matter. The two NF1-associated tumors and one of the sporadic PAs
displayed expression profiles that were more closely related to those of
cultured normal human fetal astrocytes. However, PAs also expressed
individual genes typically associated with oligodendroglial lineage
(e.g., proteolipid protein and PMP-22). The expression patterns of
specific genes (e.g., ApoD) were unique to PA tumors, whereas genetic
changes characteristic of high-grade astrocytomas were not encountered.
Differential expression of two transcripts, neural cellular adhesion
molecule and connexin-43, was confirmed at the protein level, suggesting
that these cell adhesion molecules might be particularly important in
the molecular pathogenesis of these tumors. We conclude that PAs are
genetically unique gliomas with gene expression profiles that resemble
those of fetal astrocytes and, to a lesser extent, oligodendroglial
precursors.
3
UI - 11952554
AU - Alpsoy E; Ciftcioglu MA; Keser I; De Villiers EM; Zouboulis CC
TI -
Epidermodysplasia verruciformis associated with neurofibromatosis type
1: coincidental association or model for understanding the underlying
mechanism of the disease?
SO - Br J Dermatol 2002 Mar;146(3):503-7
AD - Department of Dermatology, Akdeniz University School of Medicine, 07070
Antalya, Turkey. alpsoy@med.akdeniz.edu.tr
We describe a 25-year-old man with epidermodysplasia verruciformis (EV)
associated with neurofibromatosis type 1 (NF1). The lesions, persisting
for more than 15 years, consisted of widespread planar warts on the
backs of the hands and wrists, and reddish-brown macules on the trunk,
neck and face. During the last 5 years, our patient developed several
epithelial tumours, namely solar keratoses, plaques of Bowen's disease
and squamous cell carcinomas (SCCs). He also presented with NF1 lesions
with neurofibromas, cafe-au-lait macules, axillary freckling and Lisch
nodules. He had left tibial bowing. Polymerase chain reaction analysis
of the skin lesions demonstrated the presence of human papillomavirus
(HPV) 15 in a flat wart, HPV 20 in a plaque of Bowen's disease, and HPV
15 and HPV 20 in an SCC lesion. Both EV and NF1 show an inherited
predisposition to malignancy but the molecular mechanism underlying
tumour development is not fully understood. The appearance of both
diseases in our patient may be a coincidental association but may also
contribute to the identification of loci for susceptibility to NF1 and
EV on chromosome 17.
4
UI - 11760389
AU - Ueki K; Sasaki T; Ishida T; Kirino T
TI -
Spinal tanycytic ependymoma associated with neurofibromatosis type
2--case report.
SO - Neurol Med Chir (Tokyo) 2001 Oct;41(10):513-6
AD - Department of Neurosurgery, University of Tokyo Hospital, Tokyo.
An 18-year-old girl with a 5-year history of neurofibromatosis type 2,
consisting of bilateral acoustic tumors and a meningioma at the planum
sphenoidale, presented with an intramedullary mass at the T-1 level, and
underwent total removal of the tumor. Histological examination showed
that the tumor consisted of markedly elongated spindle-shaped cells,
which were immunopositive for S-100 protein and glial fibrillary acidic
protein. Ultrastructural examination showed microvilli-lined lumina and
prominent intercellular junctions, which were characteristic ependymal
features. These findings were compatible with the diagnosis of tanycytic
ependymoma. This rare subtype of ependymoma appears to arise through
inactivation of NF2, in addition to some typical ependymomas.
5
UI - 11891502
AU - Neumann HP; Hoegerle S; Manz T; Brenner K; Iliopoulos O
TI -
How many pathways to pheochromocytoma?
SO - Semin Nephrol 2002 Mar;22(2):89-99
AD - Nephrology Section, Department of Medicine, Albert-Ludwigs University,
Freiburg, Germany. neumann@mm41.ukl.uni-freiburg.de
Pheochromocytomas, like several other tumors, may be either sporadic or
the manifestation of a familial cancer syndrome. Recently, major
advances have occurred in both the understanding of diverse molecular
mechanisms leading to pheochromocytoma and the diagnostic modalities
available for detection of the disease. Familial pheochromocytoma may be
a manifestation of multiple endocrine neoplasia type 2 (MEN-2), von
Hippel-Lindau (VHL), or neurofibromatosis-1 (NF 1) disease.
Tumor-suppressor genes responsible for the familial occurrence of
extra-adrenal pheochromocytoma, called paraganglioma, have been
identified. This wealth of genetic information, coupled with the
availability of sensitive and specific biochemical tests as well as
imaging studies, allows for genetic screening and early diagnosis of
pheochromocytoma. In addition, genetic screening of relatives at risk is
now feasible. In this article, we review recent clinical and molecular
advances in our understanding of pheochromocytoma. Copyright 2002,
Elsevier Science (USA). All rights reserved.
6
UI - 11827459
AU - Chang LS; Akhmametyeva EM; Wu Y; Zhu L; Welling DB
TI -
Multiple transcription initiation sites, alternative splicing, and
differential polyadenylation contribute to the complexity of human
neurofibromatosis 2 transcripts.
SO - Genomics 2002 Jan;79(1):63-76
AD - Children's Research Institute, Children's Hospital, The Ohio State
University College of Medicine and Public Health, Columbus, OH 43205,
USA. lchang@chi.osu.edu
Northern blot analysis has shown that the human neurofibromatosis type 2
(NF2) cDNA hybridizes to multiple RNA species. To examine whether these
hybridizing RNA species represent NF2 transcripts, we cloned the
complete NF2 cDNA by a combination of techniques: 5' and 3' rapid
amplification of cDNA ends, RT-PCR, and searching and sequencing the
NF2-related cDNA clones from the IMAGE consortium. We showed that human
NF2 transcripts initiate at multiple positions. Analogous to those
reported previously, NF2 transcripts undergo alternative splicing in the
coding exons. We isolated eight alternatively spliced NF2 cDNA isoforms,
including one that contains a new exon termed exon 2', which potentially
could encode proteins of different sizes. We assembled the overlapping
cDNA fragments, and the longest NF2 cDNA, containing all 17 exons,
consists of 6067 nucleotides, which is consistent with the size of the
major RNA species hybridized to the NF2 probe. The cDNA has a
425-nucleotide 5' untranslated region upstream from the ATG start codon,
and a long 3' untranslated region of 3869 nucleotides. We also isolated
two shorter NF2 cDNAs that were terminated by different polyadenylation
signal sequences, which indicates that differential usage of multiple
polyadenylation sites also contributes to the complexity of human NF2
transcripts. By reference to the transcription initiation site mapped,
we analyzed the 5' flanking sequence of the human NF2 gene. Transient
transfection analysis in human 293 kidney, SK-N-AS neuroblastoma, and
NT2/D1 teratocarcinoma cells with NF2 promoter-luciferase chimeric
constructs revealed a core promoter region extending 400 base pairs from
the major transcription initiation site. Although multiple regions are
required for full promoter activity, a site-directed mutagenesis
experiment identified a GC-rich sequence (position -58 to -46), which
could be bound by transcription factor Sp1, as a positive cis-acting
regulatory element. Cotransfection studies in Drosophila melanogaster
SL2 cells showed that Sp1 could activate the NF2 promoter through the
GC-rich sequence.
7
UI - 11979381
AU - Lomas J; Bello MJ; Alonso ME; Gonzalez-Gomez P; Arjona D; Kusak ME; de
TI -
Campos JM; Sarasa JL; Rey JA
Loss of chromosome 22 and absence of NF2 gene mutation in a case of
multiple meningiomas.
SO - Hum Pathol 2002 Mar;33(3):375-8
AD - Department C. Experimental (Laboratorio de Oncogenetica Molecular),
Hospital Universitario La Paz, Madrid, Spain.
Multiple meningiomas are rare, and only 13 cases have been subjected to
molecular genetic analysis to detect mutations of the tumor-suppressor
gene neurofibromatosis type 2 (NF2) located on chromosome 22. Most of
these cases display NF2 gene mutations parallel to loss of the
chromosome 22 homolog, indicating that inactivation of this gene may
represent an early event in the development of multiple meningiomas. We
report a case of a 61-year-old woman who developed multiple (dorsal and
intracranial) meningiomas. Cytogenetic and molecular genetic studies
demonstrated the loss of a copy of chromosome 22 in the 5 meningiomas
studied and the absence of NF2 gene mutations in 4 of those available
for this molecular analysis. These findings, together with similar data
from 2 previously reported cases, suggest the participation of a
tumor-suppressor gene other than NF2 on chromosome 22 in the
pathogenesis of a subgroup of multiple meningiomas. Copyright 2002,
Elsevier Science (USA). All rights reserved.
8
UI - 12011146
AU - Mohyuddin A; Neary WJ; Wallace A; Wu CL; Purcell S; Reid H; Ramsden RT;
TI -
Read A; Black G; Evans DG
Molecular genetic analysis of the NF2 gene in young patients with
unilateral vestibular schwannomas.
SO - J Med Genet 2002 May;39(5):315-22
AD - University Department of Medical Genetics and Regional Genetic Services,
St Mary's Hospital, Hathersage Road, Manchester M13 OJH, UK.
atai_1999@yahoo.com
Neurofibromatosis type 2 (NF2) must be suspected in patients presenting
with a unilateral vestibular schwannoma at a young age who are therefore
at theoretical risk of developing bilateral disease. We identified 45
patients aged 30 years or less at the onset of symptoms of a unilateral
vestibular schwannoma. Molecular genetic analysis of the NF2 gene was
completed on peripheral blood samples in all 45 and on 28 tumour
samples. No pathogenic NF2 mutations were identified in any of the blood
samples. NF2 point mutations were identified in 21/28 (75%) tumour
samples and loss of heterozygosity (LOH) in 21/28 (75%) tumour samples.
Both mutational hits were identified in 18/28 (65%) tumour samples. In
one multilobular tumour, one (presumably first hit) mutation was
confirmed which was common to different foci of the tumour, while the
second mutational event differed between foci. The molecular findings in
this patient were consistent with somatic mosaicism for NF2 and the
clinical diagnosis was confirmed with the presence of two meningiomas on
a follow up MRI scan. A further patient developed a contralateral
vestibular schwannoma on a follow up MRI scan in whom neither of the
truncating mutations in the vestibular schwannoma were present in blood.
It is important when counselling patients with unilateral vestibular
schwannomas to identify (1) those at risk of bilateral disease, (2)
those at risk of developing other tumours, and (3) other family members
at risk of developing NF2. Comparing tumour and blood DNA cannot exclude
mosaicism in the index case and cannot, therefore, be used to predict
those at risk of developing further tumours. However, identification of
both mutations or one mutation plus LOH in the tumour and exclusion of
those mutations in the blood samples of the sibs or offspring of the
affected case may be sufficient to render further screening unnecessary
in these relatives.
9
UI - 11988578
AU - Zhu Y; Ghosh P; Charnay P; Burns DK; Parada LF
TI -
Neurofibromas in NF1: Schwann cell origin and role of tumor environment.
SO - Science 2002 May 3;296(5569):920-2
AD - Center for Developmental Biology, Department of Pathology, University of
Texas Southwestern Medical Center, 6000 Harry Hines Boulevard, Dallas,
TX 75390-9133, USA.
Neurofibromatosis type 1 (NF1) is one of the most prevalent dominantly
inherited genetic diseases of the nervous system. NF1 encodes a tumor
suppressor whose functional loss results in the development of benign
neurofibromas that can progress to malignancy. Neurofibromas are complex
tumors composed of axonal processes, Schwann cells, fibroblasts,
perineurial cells, and mast cells. Through use of a conditional
(cre/lox) allele, we show that loss of NF1 in the Schwann cell lineage
is sufficient to generate tumors. In addition, complete NF1-mediated
tumorigenicity requires both a loss of NF1 in cells destined to become
neoplastic as well as heterozygosity in non-neoplastic cells. The
requirement for a permissive haploinsufficient environment to allow
tumorigenesis may have therapeutic implications for NF1 and other
familial cancers.
10
UI - 11836557
AU - Hung G; Li X; Faudoa R; Xeu Z; Kluwe L; Rhim JS; Slattery W; Lim D
TI -
Establishment and characterization of a schwannoma cell line from a
patient with neurofibromatosis 2.
SO - Int J Oncol 2002 Mar;20(3):475-82
AD - Department of Cell and Molecular Biology, House Ear Institute, Los
Angeles, CA 90057, USA. ghung@hei.org
By using retroviral mediated gene transfer technique, a primary
schwannoma culture from a 56-year-old Neurofibromatosis type 2 (NF2)
patient was immortalized with HPV E6-E7 genes. This cell line, HEI193,
has a unique splice site mutation of the NF2 gene. Both
immunocytochemistry and molecular biology techniques were used to
demonstrate that this cell line is of Schwann cell origin. Comparison of
the primary tumor with HEI193 revealed the same NF2 mutation and an
identical pattern of allele loss at multiple loci, indicating that the
established cell line had maintained many of the properties of the
original tumor. The immortalized cell line was non-tumorigenic in both
severe combined immunodeficient (SCID) mice and nude mice, but has
altered growth properties such as higher proliferation rate and
independence of Schwann cell growth factors. To our knowledge, this is
the first attempt to establish permanent cell lines from human NF2
patients. This Schwann tumor-derived cell line may provide a useful
model system for the study of familial NF2 tumor pathogenesis, for
elucidating NF2 functions and for testing new gene-based therapeutic
approaches.
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