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Molecular epidemiology integrates molecular technolo-
gies and ideas into epidemiological studies of disease ori-
gins and outcomes. The translational goals of such research
are to understand a disease suf
ficiently to enable the devel
-
opment of strategies to reduce the patient population bur-
den. W
ith respect to glioma origin and survival rates for
adults, approaches based on molecular epidemiology have
been used to classify glial tumors into more homogeneous
categories, to study the roles of common genetic polymor-
phisms, and to identify biomarkers related to developmen
-
tal or environmental risk factors for gliomas. Because there
have been several recent reviews of brain tumor epidemi
-
ology and pathogenesis, we refer interested readers to these
papers for details.
8,14,74,78,115,123,183
The purpose here is to pro
-
vide the context for molecular epidemiology studies of
gliomas, to highlight recent findings, and to suggest prom-
ising paths for future research.
Impact and General Epidemiology of Gliomas
The term “glioma” refers to tumors thought to be of glial
cell origin and includes astrocytic tumors (W
orld Health Or
-
ganization astrocytoma classification of Grades I, II [astro-
cytoma], III [anaplastic astrocytoma], and IV [GBM]), oli
-
godendrogliomas, ependymomas, and mixed gliomas.
28,88,99
Approximately 13,000 deaths and 18,000 new cases of pri-
mary malignant brain and central nervous system tumors
occur annually in the US; approximately 77% of these are
brain gliomas.
28
Primary brain and central nervous system
tumors rank first among cancer types for the average years
of life lost, with an average of 20.1 years (compared, for
example, with 6.1 years for prostate cancer and 1
1.8 years
for lung cancer).
21
Survival from GBM, the most common
form of glioma in adults, is poor; with median survival time
approximately 3.5 months for patients 65 years or older at
diagnosis and only 10 months for those under 65 years,
according to data collected by the Surveillance Epidemiol
-
ogy and End Results Program.
38
Approximately 2% of pa-
tients 65 years of age or older and only 30% of those young-
Neurosurg Focus 19 (5):E5, 2005
The molecular epidemiology of gliomas in adults
MARGARET WRENSCH, PH.D., JAMES L. FISHER, PH.D., JUDITH A. SCHWARTZBAUM, PH.D.,
M
ELISSA BONDY, PH.D., MITCHEL BERGER, M.D., AND KENNETH D. ALDAPE, M.D.
Department of Neurological Surgery, University of California, San Francisco, California; The Arthur
G. James Cancer Hospital and Richard J. Solove Research Institute; The Ohio State University
Comprehensive Cancer Center; Division of Epidemiology and Biometrics, School of Public Health,
The Ohio State University, Columbus, Ohio; Institute of Environmental Medicine, Karolinska
Institute, Stockholm, Sweden; Departments of Epidemiology and Pathology and Brain Tumor Center,
The University of Texas M. D. Anderson Cancer Center, Houston, Texas
In this paper the authors highlight recent findings from molecular epidemiology studies of glioma origin and prog-
nosis and suggest promising paths for future research. The reasons for variation in glioma incidence according to time
period of diagnosis, sex, age, ancestry and ethnicity, and geography are poorly understood, as are factors that affect prog-
nosis. High-dose therapeutic ionizing irradiation and rare mutations in highly penetrant genes associated with certain
rare syndromes—the only two established causes of glioma—can be called upon to explain few cases. Both familial
aggregation of gliomas and the inverse association of allergies and immune-related conditions with gliomas have been
shown consistently, but the explanations for these associations are inadequately developed or unknown. Several bio-
markers do predict prognosis, but only evaluation of loss of 1p and 19q in oligodendroglial tumors are incorporated in
clinical practice. Ongoing research focuses on classifying homogeneous groups of tumors on the basis of molecular
markers and identifying inherited polymorphisms that may influence survival or risk. Because most cases of glioma have
yet to furnish either an environmental or a genetic explanation, the greatest potential for discovery may lie in genomic
studies in conjunction with continued evaluation of environmental and developmental factors. Large sample sizes and
multidisciplinary teams with expertise in neuropathology, genetics, epidemiology, functional genomics, bioinformatics,
biostatistics, immunology, and neurooncology are required for these studies to permit exploration of potentially relevant
pathways and modifying effects of other genes or exposures, and to avoid false-positive findings. Improving survival
rates for patients harboring astrocytic tumors will probably require many randomized clinical trials of novel treatment
strategies.
KEY WORDS • glioma • polymorphism • epidemiology • tumor marker •
survival • prognosis
Neurosurg. Focus / Volume 19 / November, 2005
1
Abbreviations used in this paper: CI = confidence interval;
CYP = cytochrome P-450; EGFR = epidermal growth factor recep-
tor; GBM = glioblastoma multiforme; GST = glutathione
S-trans-
ferase; IL = interleukin; OR = odds ratio.
er than 45 years at GBM diagnosis survive for 2 years.
28
Furthermore, although survival rates for individuals with
GBM have shown no notable improvements in population
statistics for more than 30 years,
38
recent clinical trial data on
the use of combined radiotherapy and temozolomide found
a median survival period of 14.6 months compared with 12
months for patients treated with radiotherapy alone.
154
GENERAL MOLECULAR PATHOLOGICAL
NATURE OF GLIOMAS
Commonly Altered Chromosomal Regions
Classic cytogenetic and array-based comparative genom-
ic hybridization studies of gliomas have identified copy
number changes (deletions, amplifications, and gains) in
several regions; deletions and loss of heterozygosity in
tumors may indicate genes involved in tumor suppression,
whereas amplifications and gains may point to genes in-
volved in tumor initiation or progression (for example, on-
cogenes). The more regularly observed of these changes,
which may vary by histological type, as well as some can-
didate genes in the regions include gains and deletions in 1p
(1p36.31-pter, 1p36.22-p36.31, and p34.2-p36.1), gains in
1q32 (
RIPK5, MDM4, PIK3C2B, and others), deletion of
4q (NEK1 and NIMA), amplifications and gains in chromo-
some 7 (7p11.2-p12, EGFR), deletions in chromosome 9
(9p21-p24, CDKN2), deletions in chromosome 10 (10q23,
PTEN; 10q25-q26, MGMT), deletions in chromosome 11
(11p [between CDKN1C and RRAS2]), amplifications of 12
(12q13.3-q15, MDM2, CDK4, and many others), loss of 13
(13p11-p13 and 13q14-q34, RB1), loss of 19 (19q13,
GLTSCR1, GLTSCR2, LIG1, PSCD2, and numerous oth-
ers), loss of 22 (the 22q11.21-12.2 region has 28 genes
including INI1, known for its involvement in rhabdoid
tumors, and q13.1-13.3). These issues are reviewed by Ichi-
mura, et al.,
74
and many others.
17,45,49,60,69,77,87,118,126,130,131,133,151,
155,156
This brief summary demonstrates that although sever-
al well-known tumor suppressor genes and oncogenes oc-
cur in these regions, many genes in the regions have yet
to be identified for their specific relationship to glioma gen-
esis.
Dysregulated Pathways in Astrocytic Gliomas
Classic molecular and cytogenetic studies of tumors as
well as the newer array-based assays of comparative ge-
nomic hybridization and RNA expression indicate substan
-
tial heterogeneity of genes and gene expression within and
between histological grades of astrocytic tumors and
between dif
ferent histological types of gliomas.
51,74,89,94,113,
114,128
It has become increasingly apparent that such hetero-
geneity at the cellular level reflects the action of different
causal mechanisms in the pathogenesis of the disease. Be
-
cause astrocytic gliomas compose more than 70% of all
adult gliomas, we emphasize pathways known to be impor-
tant for these tumors and do not provide a comprehensive
review here of this rapidly expanding area of research. The
phenotype called GBM arises from dysregulation of sever
-
al different pathways. Dysregulation can occur from a vari
-
ety of genetic and epigenetic mechanisms, including gene
mutation, amplification, deletion, methylation or demethy
-
lation, whole or partial chromosome gains or losses, and
transcriptional interference.
7
4,82,88–90,177
Several interrelated
pathways are well established as being dysregulated in
GBM and other gliomas. Recurring themes are that these
pathways are involved in cell-cycle signaling and control
(proliferation and apoptosis), cytoskeleton regulation, tran-
scription, growth signaling, cell adhesion, migration, and
cytokine response (Table 1).
74
Molecular Pathways to GBM
Progress has been made with respect to elucidating the
genetic pathways that lead to GBMs. It is now believed that
these tumors arise by two pathways that can be defined in
clinical terms: one pathway results from tumor progression
from lower-grade astrocytomas (“secondary” GBM) and a
second pathway has no clinically evident precursor (“pri-
mary” or “de novo” GBM). Interestingly, examination of
two molecular aberrations,
TP53 mutation and EGFR am-
plification, has led to their correlation with the type of GBM
defined on a clinical basis.
94,164
Specifically, tumors with
TP53 mutations are more likely to be secondary GBMs,
arising from lower grade precursors, whereas a de novo
GBM is more likely to harbor
EGFR amplification. Al-
though this distinction is not absolute and has recently been
called into question,
116
it raises the possibility that distinct
subtypes of GBM may be similar histologically yet display
clinical differences, specifically in response to therapeutic
agents. Molecular subtyping is currently not routine but is
likely to be of use in the future as an adjunct to histological
analysis in the classification of these tumors.
Population Studies of Tumor Markers in Astrocytic
Gliomas
To date only two studies have presented data on genetic
and molecular tumor markers for relatively large numbers
of population-based glioma cases.
114,177
Although in each
study five or six tumor markers were assessed, only two
(
EGFR amplification and TP53 mutation) were measured
in both studies. Interestingly, the percentage of GBMs with
EGFR amplification was identical in the two studies (36%
of 371 de novo GBMs from Zurich and 36% of 386 GBMs
from the San Francisco Bay area). The percentage of tu
-
mors with a
TP53 mutation varied from 28% of 386 GBMs
from Zurich to only 15% of 409 GBMs from San Fran-
cisco; percentages in clinical series have ranged from 20 to
30%.
81
Despite some inconsistencies, these findings sup-
port the hypothesis, proposed in smaller clinical series, that
astrocytic tumors may arise through different pathways and
may reflect the action of dif
ferent causal mechanisms. T
o
summarize current findings for astrocytic tumors, TP53 tu
-
mor mutations are associated with a younger age at diag-
nosis and are more common in lower
-grade tumors and in
GBMs arising from them;
82,89,114,127,177
TP53 tumor mutations
are more common in non-Caucasians, whereas tumors
overexpressing
EGFR or containing p16 deletions are more
common in Caucasians;
106,177
MGMT 84Phe carriers are
overrepresented among GBM cases in which tumors do not
overexpress TP53 protein;
177
and the GSTT1 constitutive
deletion is more common among GBM cases in which the
tumor displays the
TP53 mutation.
181
M. Wrensch, et al.
2
Neurosurg. Focus / Volume 19 / November, 2005
SURVIVAL RATES AND PROGNOSIS FOR
PATIENTS WITH GLIOMAS
Information on survival rates and prognosis for patients
with gliomas comes from clinical trials and population reg-
istry data. Studies from the Radiation Therapy Oncology
Group and other clinical trial groups provide useful infor-
mation on prognostic factors from cases whose pathologi-
cal features have been centrally reviewed and for patients
who qualify for and are treated in clinical trials. Because the
majority of patients do not enter clinical trials, however, the
results might not be applicable to or representative of the
general population of patients with gliomas. Survival rate
estimates based on population registry data can represent
the full spectrum of patients in whom gliomas are diag-
nosed, yet pathological diagnoses are subject to consider-
able variability depending on numerous factors, including
the pathologist’s neuropathological training
1
and the time
and place the diagnosis was made.
35,83
Also, population reg-
istries do not generally have treatment data as extensive as
that available from clinical trials.
Histological type and grade of tumor
, patient age, extent
of lesion resection, tumor location, whether the patient un-
dergoes radiation therapy, and some chemotherapy proto-
cols have been consistently and convincingly linked to sur
-
vival in both population registry and clinical trial data.
29,36,
38,39,66,93,96,141,142
The Karnofsky Performance Scale score at
diagnosis and other measures of mental and physical func-
tionality also predict survival for patients with GBMs and
anaplastic astrocytomas enrolled in the Radiation Therapy
Oncology Group and other multiinstitutional clinical tri-
als.
36,93,141
In addition to these factors, investigators are currently
trying to identify and understand tumor markers or patient
characteristics that might influence survival or response to
treatment;
10,25,51,53,92,97,113,117,125,137,144,146,158,170,189
specific exam-
ples are presented later in this paper. A key unsolved prob-
lem in neurooncology is the strong and consistent inverse
relationship of age to survival. The reasons, whether they
pertain to properties related to the tumor or the host, are not
well understood. The response of tumors to radiation has
been reported to be poorer in older patients.
5
In this regard,
one contributing factor may be related to different frequen-
cies of molecular or chromosomal aberrations among tu
-
mors in older patients compared with those in younger pa
-
tients (a topic that will be discussed subsequently). One
difficulty in identifying prognostic factors in rapidly fatal
gliomas such as GBMs may be related to the narrow range
of survival time experienced by the vast majority of pa-
tients. One method to address this limitation is to compare
tumors from rare long-term survivors with those from typi-
cal GBM survivors. Studies performed at the University of
Texas M. D. Anderson Cancer Center, using both a candi-
date gene approach
23
and a genome-wide screen,
22
have in-
dicated that differences exist between tumors obtained in
long-term survivors and those obtained from typical GBM
survivors.
22
Although such studies may not be as easily ex-
tended to clinical use as prognostic markers, they point to
aberrations that may be responsible for the nearly uniform-
ly poor prognosis for patients with GBM.
Studies of Tumor Markers in Relation to Survival
Combined losses of 1p and 19q in oligodendroglial tu-
mors are well-established favorable prognostic indica-
tors.
25,49,50,61,70,76,87,148,149,161
In astrocytic tumors, amplification/
overexpression of EGFR is more common in older patients,
especially those with anaplastic astrocytoma;
177
this ampli
-
fication/overexpression may also contribute to resistance to
therapeutic modalities.
6,191
Although EGFR amplification is
more common in tumors from older individuals, it is not
exclusive to that age group and may be associated with poor
survival rates in younger (, 55–60 years of age) adults with
GBM.
146,150
A subset of tumors with EGFR amplification
demonstrates an additional change in the EGFR gene result-
ing from an internal rearrangement called EGFRvIII. Al-
though the results of lar
ge studies have yet to be reported,
the presence of the
EGFRvIII allele may also be a negative
prognostic factor.
48,64
Data from a recent large prospective
trial of patients with newly diagnosed GBMs have indicat
-
ed that methylation of the MGMT promoter in GBM tumor
samples was a marker of improved outcome, as measured
by the 2-year survival rate.
154
Interestingly
,
MGMT methy
-
lation appeared to be much more strongly associated with
survival among patients who received frontline temozolo
-
mide than among those who did not,
63
raising the possibili
-
ty that MGMT methylation may be a predictive marker of
response to this alkylating agent.
Neurosurg. Focus / Volume 19 / November, 2005
Molecular epidemiology of gliomas in adults
3
TABLE 1
Pathways dysregulated in GBM and other gliomas*
Important Pathways Pathway Functions and Effects
Rb/p16/p15/CDK4/ cell cycle checkpoint pathway controlling
CyclinD DNA-dependent transcription; under
the influence of receptor-dependent
growth factors signals cell proliferation
through influence on S-phase genes &
TP53 pathways by stimulating p14ARF
TP53/MDM2/p14ARF cell cycle arrest; apoptosis; dysregulation
enhances cell proliferation, which
combined w/ apoptotic failure leads to
genomic instability
EGF/EGFRPDGFalphaR growth signaling stimulates cell proliferation,
focal adhesion, MAPK (mitogen
activated protein kinase) signaling,
calcium signaling, actin cytoskeleton
r
egulation, & cytokine–cytokine
r
eceptor interactions
Ras/Raf/MAPK pleiotropic effectors of cell physiology
involved in gene expression, cell
cycle, apoptosis, cell differentiation,
& cell migration
PI3-kinase/AKT pleiotropic effectors preventing apoptosis
& influencing focal adhesion, MAPK
signaling, tight junction, and Toll-like
receptor signaling
WNT signaling cell cycle control, TGF-b; other
components of WNT signaling affect
focal adhesion, cytoskeletal change,
& gene transcription
HIF1-
a
/VEGF response to hypoxia/angiogenesis
PTEN pleiotropic effector involved in focal
adhesion, phosphatidylinositol signaling
system (suppresses PI3-kinase/AKT activa-
tion), tight junction
* Summarized from Ichimura, et al., with additional information from http:
//www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search&DB=gene.
Insights From Expression Array Studies of Gliomas
In two recent studies the investigators assessed the prog-
nosis for patients with gliomas from expression profiles
alone
51
or in conjunction with comparative genomic hybrid-
ization.
113
Although some a priori candidate genes were val-
idated, it was important that many new genes whose expres-
sion had not been previously linked to patients surviving
gliomas were also identified, and abnormal expression in
certain classes of genes predicted survival. For example,
best, intermediate, and worst survival times were associated
with the abnormal expression of neurogenesis genes, cell
proliferation and mitosis genes, and extracellular and extra-
cellular matrix genes, respectively.
51
Other important find-
ings include the following: 1) loss of chromosome 10 was
accompanied by gene expression changes across the
genome; and 2) the copy number loss of chromosome 10
and gains of chromosomes 7, 19, and 20 were highly corre-
lated with one another.
113
These findings, although compel-
ling, are nevertheless preliminary because of the relatively
small sample sizes typical of expression array studies. Can-
didate markers identified in such genome-wide screens,
however, represent promising leads for possible validation
in larger studies. A recent array study of oligodendroglioma
and oligoastrocytoma found that a tumor gain of 8q may be
a negative prognostic factor.
87
Constitutive Genetic Influences on Prognosis and Survival
for Patients With Gliomas
It is being increasingly demonstrated that common gene
polymorphisms influence response to cancer therapies or
otherwise influence prognosis and survival (recent reviews
on this topic include papers by Loktionov
98
and Nagasubra-
manian, et al.
109
). Survival after a diagnosis of glioma has
been associated with polymorphisms in EGF, GSTP1, and
GSTM1; HLA A*32 and B*55; and GLTSCR1 S397S and
ERCC2 D711D.
10,117,158,187
Because none of these findings
has yet been replicated, cautious interpretation is advised.
Potentially relevant associations between polymorphisms in
genes and treatment response or survival for other cancer
sites include the following: IL6 and aggressive breast can
-
cer and ovarian cancer, ATM and radiosensitivity of breast
cancer patients, TGFB1 and breast cancer survival, TNF and
myeloma relapse, GSTP1 and myeloma outcomes, MDR1
and acute leukemia survival, FGFR4 and soft-tissue sarco-
ma survival, TYMS and colorectal cancer survival,
CDKN2A and bladder cancer survival, and TP53 and lung
cancer prognosis.
4,31,37,42,62,67,73,75,108,1
12,135,143,167,168
One proposed
mechanism is that TP53 variants alter function and the re-
sponse of tumor cells to chemotherapeutic agents.
157
The
limited studies that have been performed to date have pro-
vided several potentially fruitful areas of discovery regard-
ing genetic variation in relation to survival rates for patients
with gliomas (for example, signaling pathways for growth
factors, cell cycle regulators, modifiers of drug metabolism,
and radiotherapy and the immune response).
ENVIRONMENTAL, DEVELOPMENTAL, AND
GENETIC RISK FACTORS FOR GLIOMAS
The only exogenous environmental cause of gliomas that
has been unequivocally established is high-dose therapeu
-
tic radiation; high-dose chemotherapy for other cancers is a
strong possibility as well.
4
3,115,183
Genetic factors influence
risk from these exposures; Relling, et al.,
132
showed that
among children treated with cranial radiotherapy and inten-
sive antimetabolite therapy for acute lymphocytic leuke-
mia, those with germline polymorphisms leading to low or
absent thiopurine methyltransferase activity were signifi-
cantly more likely than those without such polymorphisms
to develop brain cancer.
Although abundant data obtained in animal and other
studies support the biological plausibility of neurocarcino-
genecity of endogenous and exogenous chemicals (for ex-
ample,
N-nitroso compounds, reactive oxygen and nitrogen
species, several industrially used chemicals, and polycyclic
aromatic hydrocarbons) to which people are exposed
through their essential cellular metabolism, diet, occupation,
and personal habits, inconsistent or often null findings from
human studies result from a variety of issues.
3,11,12,20,27,30,32–34,58,
5
9,68,71,80,91,95,100,105,1
11,115,120,124,159,171,183,190
These include small study
sample sizes, chance reporting of false-positive results, im-
precise exposure measures (from proxy reporting and expo-
sure history recall issues), inherited or developmental varia-
tion in metabolic and repair pathways, unaccounted for
protective exposures, differential diffusion of chemicals ac-
ross the blood–brain barrier, differentially expressed meta-
bolic and repair pathways in the brain, and disease hetero-
geneity.
55,78,115,145,169
Progress has been made in understanding
environmental contributors to other cancers by joint consid-
eration of inherited variation in detoxification, metabolism,
or repair and histological or molecular tumor subtypes, such
as TP53 mutations. Two classic examples include the dem-
onstration that specific TP53 mutations in hepatocellular
carcinoma occurred exclusively in carriers of variants in
epoxide hydrolase and glutathione transferase mu
103
and the
finding that TP53 mutations in patients with lung cancer
were more common in heavy smokers compared with non-
smokers and that homozygous carriers of the glutathione
transferase mu deletion were more likely to have transver-
sion mutations in TP53.
134
More recent examples have
shown interactions between a vitamin D receptor polymor-
phism and dietary calcium and vitamin D intake in evaluat-
ing the risk of colorectal adenoma,
18,86
interactions of a de
-
toxification gene variation with different environmental
exposures in gauging lung cancer risk,
72,104,147
and different
polymorphisms and parental characteristics associated with
varying risks of molecularly defined subgroups of childhood
leukemia.
173,176
Because only a small proportion of gliomas are likely to
be caused by the effects of inherited rare mutations or high-
dose radiation, researchers have focused on polymorphisms
in genes that might influence susceptibility to brain tumors
in concert with environmental exposures.
Polymorphisms in Carcinogen Metabolism and Gliomas
Glutathione S-transferases and CYPs, as part of the
Phase 1 and 2 detoxification process, are involved in the
metabolism of many electrophilic compounds, including
carcinogens, mutagens, cytotoxic drugs, and metabolites,
as well as in the detoxification of products of reactive oxi
-
dation.
26,47,52,54,122,136,152,153,160,163,188
Several case–control stud
-
ies of the statuses of GSTs and CYPs 1A1, 2D6, and 1E1
have yielded few positive and replicable associations,
41,
M. Wrensch, et al.
4
Neurosurg. Focus / Volume 19 / November, 2005
44,84,121,162,178,181
although the results of some studies indicated
specific findings for tumor subtypes (for example, the
GSTM1 deletion was more common in GBM cases with
the TP53 mutation than in those without (OR 2.8, 95% CI
0.93–8.4);
181
the GSTM1 deletion was less common (p =
0.03) and GSTP1 A114V V-carriers were more common
than expected (p = 0.06) among oligodendroglioma cas-
es.
41
The significant multiplicative effects of GSTP1 I105V
and CYP2E1 RsaI variants
4
1
suggest that gene interactions
may be important.
Gliomas and DNA Repair Gene Polymorphisms
The study of the inherited variation in DNA repair in-
volves another category of genes that have been extensively
investigated with respect to cancer because of the impor-
tance of DNA repair in maintaining genomic integrity.
9,107,179
In 2002, Goode and colleagues
56
reviewed 30 studies report-
ing on DNA repair polymorphisms in adult gliomas and
cancer of the bladder, breast, lung, skin, prostate, head and
neck, stomach, and esophagus; the number of studies pub
-
lished has more than quadrupled in the past 3 years. Gliomas
and glioma subtypes have been significantly associated with
variants in
ERCC1, ERCC2, the nearby gene GL
TSCR1
(glioma tumor suppressor candidate of unknown function),
PRKDC (also known as XRCC7), and MGMT,
166,177,180,187
but
too few studies have been performed to assess consistency.
The complexity of the DNA repair pathway is increasingly
being revealed, with 130 known genes involved in base ex-
cision repair, direct reversal of damage, mismatch repair, nu-
cleotide excision repair, homologous recombination, non-
homologous end joining, sanitization of nucleotide pools,
activity of DNA polymerases, editing and processing of nu-
cleases, and postreplicative repair; genes associated with
sensitivity to DNA damaging agents; and others suspected
of influencing DNA repair functioning are also involved.
179
Studies focusing on constellations of DNA repair variants
involved in these pathways might help elucidate their roles
in gliomagenesis and progression.
Gliomas and Polymorphisms in Cell Cycle Regulation
Dysregulation of the cell cycle (control of proliferation
and apoptosis) is a hallmark of most gliomas reviewed by
Ichimura, et al.,
74
and MDM2 is a key molecule in main-
taining the fidelity of this process. In one study
,
13
the G var
-
iant of SNP309 in the MDM2 promoter led to higher ex-
pression of MDM2, with concomitant reduced expression
of TP53, and was found to be significantly associated with
an earlier patient age at tumor development and multiple
tumor sites in patients with Li–Fraumeni syndrome, in
whom brain tumors are one component.
Infections and Immunological Risk Factors for Gliomas
Among the most intriguing and consistent findings of the
past decade are statistically significant inverse associations
between gliomas that develop during adulthood and histo-
ries of allergies, chicken pox, and anti–varicella-zostervirus
immunoglobulins G and E.
19,138,140,174,175,182,184–186
To address
lingering doubts that the negative association of gliomas
with an allergy history might result from recall issues,
Schwartzbaum and colleagues
139
recently demonstrated that
single nucleotide polymorphisms in genes related to asthma
are also related to GBM, but in the opposite direction to
their association with asthma. To clarify the observed in-
verse associations of gliomas with asthma, Schwartzbaum,
et al.,
139
studied the associations of GBMs with polymor-
phisms known to be strongly associated with asthma. They
examined five single nucleotide polymorphisms in three
genes, IL4RA, IL13, and ADAM33; IL4RA T478C TC, CC
and A551G AG, AA were significantly positively associated
with GBMs (OR 1.64, 95% CI 1.05–2.55 and OR 1.61,
95% CI 1.05–2.47, respectively, whereas IL13 C1112T CT,
TT was inversely associated with GBMs (OR 0.56, 95% CI
0.33–0.96). The polymorphism–GBM associations are in
the opposite direction of the polymorphism–asthma associ-
ations and because the investigators used germline poly-
morphisms as biomarkers of the susceptibility to asthma
and allergies, the results cannot be attributed to either a
recall bias or to the effects of GBMs on the immune system.
These findings may validate the association between self-
reported allergic conditions and GBMs; however, IL-13 or
its shared receptor with IL-4, IL-4RA, may play indepen-
dent roles in allergic conditions and GBMs. Alternatively,
some aspect of allergic conditions themselves may reduce
the risk of the development of a GBM or glioma. In either
case, these results for allergic conditions and viral infections
are consistent with our hypothesis that it is the specific na-
ture of the immune system’s response to antigens and not
exposure to the antigen per se that is responsible for the in-
verse associations with gliomas, because there is nearly uni-
versal exposure to antigens for both varicella-zostervirus
and allergies to pollen, food, and so forth.
Tang and colleagues
158
demonstrated that GBM is posi-
tively associated with human leukocyte antigen genotypes/
haplotypes
B*13 and B*07-Cw*07 (p = 0.01 and p ,
0.001, respectively) and is inversely associated with Cw*01
(p = 0.05). Interestingly, if confirmed, these results may par-
tially explain the higher incidence of GBM in Caucasians
because
B*07 and B*07-Cw*07 are much more common in
Caucasians.
A variety of other viral infections (simian virus 40, JC,
BK, other papovaviruses, adenoviruses, retroviruses, the
herpesviruses cytomegalovirus and HHV-6, and influenza)
and parasitic infections
(Toxoplasma gondii) have been in-
vestigated in relation to gliomagenesis in experimental stud-
ies on animals and in limited epidemiological studies, but
conclusions regarding the role (if any) of these infectious
agents in human gliomas have remained elusive.
2,78,183
Genetic Syndromes, Familial Aggregation, Linkage, and
Mutagen Sensitivity
In addition to results from genetic polymorphism stud-
ies, evidence suggesting genetic susceptibility to brain can-
cer comes from studies of genetic syndromes, familial ag
-
gregation, linkage, and mutagen sensitivity. Although the
handful of genetic syndromes (caused by inherited rare mu-
tations) associated with increased risk of brain tumors (for
a review see other studies
14,46,74
) account for a small pro-
portion of cases, they provide an important starting point
for identifying candidate genes and pathways that could be
involved in gliomagenesis.
14,46,74
Syndromes that include gliomas or medulloblastomas
(with gene names and chromosome location) are neurofi-
bromatosis T
ypes 1 and 2 (
NF1, 17q1
1;
NF2, 22q12), tuber
-
Neurosurg. Focus / Volume 19 / November, 2005
Molecular epidemiology of gliomas in adults
5
ous sclerosis (TSC1, 9q34; TSC2, 16p13), retinoblastoma
(RB1, 13q14), Li–Fraumeni syndrome (TP53, 17p13), and
Turcot syndrome and multiple hamartoma (APC, 5q21;
hMLH1, 3p21.3; hMSH2, 2p22-21; PMS2, 7p22; and PTEN,
10q23.3). The roles of more common variants in many of
these genes (and related pathways) in sporadic gliomas are
unknown.
74
Demonstration of familial aggregation does not prove a
genetic origin, but it is often among the first indicators that
genetic susceptibility may play a part in the pathogenesis of
a complex disease. Relative risks of brain tumors among
family members of patients who harbor them have ranged
from 1 to 10; in large, well-conducted studies, familial glio-
ma risks are approximately twofold, similar in magnitude to
the familial association involved in breast cancer and other
cancers for which susceptibility genes have been identified
(for a review see Bondy, et al.,
14
and other studies
65,101,182
).
The pattern of brain tumor occurrence in families has been
attributed to environmental causes in one study
57
and to mul-
tifactorial causes, polygenic causes, and autosomal re-
cessive inheritance in others.
14,40,102
Paunu, et al.,
119
recently
published evidence of a statistically significant linkage to
15q23-q26.3 in 15 Finnish families with multiple cases of
glioma (after stringent control for multiple testing, p = 0.03).
Gamma radiation–induced mutagen sensitivity is more
commonly found in peripheral lymphocytes in glioma cases
than in control cases,
15,16
and it has been suggested that such
a mutagen sensitivity is at least partly attributable to inher-
ited variation in capacity to repair radiation damage.
FUTURE STUDIES IN THE MOLECULAR
EPIDEMIOLOGY OF GLIOMAS
Suspected and novel inherited variations in glioma sus-
ceptibility and prognosis are likely to be confirmed and
identified through multidisciplinary studies involving path-
ologists, geneticists, epidemiologists, functional genomi-
cists, bioinformaticians, biostatisticians, immunobiologists,
and clinicians. These studies will require integration of the
following: 1) traditional and molecular pathological analy-
sis involving cytogenetic and epigenetic classifications of
tumors to reduce and refine glioma subgroups; 2) new ge-
nomic technologies and bioinformatic/biostatistical tools
with which to interrogate and explore candidate genes, re-
gions, and pathways and to enhance new discoveries; 3)
high-quality population resources for causal studies to aid
in the selection of cases and controls with well-document-
ed familial and demographic data as well as environmental
exposure and personal medical history; and 4) case groups
with clearly defined treatment histories for prognostic stud-
ies. We hypothesize that demographic, environmental, and
immunological factors are likely to influence the suscepti
-
bility of patients and disease prognosis, and that different
constellations of factors may be involved with different his-
tological and molecular subtypes of glioma.
This brief summary of published case–control studies of
polymorphisms involving glioma status and prognosis il
-
lustrates several important and widespread problems in
current research into the association between genes and dis
-
eases, including the paucity of studies assessing consisten
-
cy for many reported associations, the reporting of false-
positive results, and the lack of consideration of functional
significance of the polymorphisms studied.
7,24,129,165,172
Al-
though the most likely explanation of discrepant results
among studies is the chance reporting of positive findings
in small studies, it is also possible that discrepancies derive
from different effects in different populations arising from
different exposure and developmental experiences and/or
disease heterogeneity. Lack of information on the function-
al relevance of polymorphisms can also limit reasonable in-
ferences. Future studies will need to include replication or
use other means to reduce reporting of false positives.
Different study designs are encouraged because no ideal
design is available for the discovery of genetic and environ-
mental associations regarding heterogeneous and relatively
rare diseases such as gliomas. Both familial linkage studies
and case–control studies may prove helpful in discovering
genes associated with glioma susceptibility. For adequate
sample sizes and expertise, consortia will be essential for
familial linkage studies, studies of gene–environment inter
-
actions with even a relatively common glioma subtype such
as GBM, and basic epidemiological studies of less common
subtypes such as oligodendroglial tumors and other low-
grade glial tumors. The Brain Tumor Epidemiology Con-
sortium (an international group of brain tumor researchers)
already has several initiatives in process in these and other
areas of brain tumor research.
7
9
SUMMARY
The reasons for variations in glioma incidence according
to time of diagnosis, sex, age, ancestry/ethnicity, and geog
-
raphy are poorly understood, as are factors affecting prog
-
nosis. There are few established risk factors for gliomas;
ionizing radiation and rare mutations in highly penetrant
genes associated with certain diseases and syndromes can
only be cited to explain relatively few cases. Both familial
aggregation of gliomas and the inverse association of aller-
gies and immune-related conditions with gliomas have been
shown consistently, but the explanations for these associa-
tions are inadequately developed or unknown. Ongoing re-
search on gliomas focuses on classifying homogeneous
groups of tumors on the basis of molecular markers and
identifying genetic polymorphisms that, in conjunction with
developmental experiences and environmental exposures,
may increase brain tumor risk. Rather than examine indi-
vidual genetic polymorphisms in isolation, new research
focuses on genetic polymorphisms in pathways involved in
carcinogenesis. Related pathways are also studied simulta-
neously so that confounding by genes with similar functions
can be avoided. Large sample sizes are required for such
studies, and these large studies will avoid false-positive
findings and permit examination of the modifying effects of
polymorphisms on environmental exposures, as well as of
the potential for interaction between germline mutations
and sporadic tumor mutations. Khoury and colleagues
85
re-
cently ar
gued for the importance of genomic studies of dis
-
eases with known strong environmental contributors by
stating,
because almost all human diseases result from interactions
between genetic variants and the environment, suggesting that
genomic research will not contribute to preventing conditions
with known environmental risk factors could perpetuate the
false competition between nature and nurture.
For diseases such as gliomas, for which most cases have
M. Wrensch, et al.
6
Neurosurg. Focus / Volume 19 / November, 2005
yet to be linked to either an environmental or a genetic
cause, the greatest potential for discovery may lie in geno-
mic studies in conjunction with continued evaluation of en-
vironmental and developmental factors.
Some limited success has been achieved in advancing the
treatment of gliomas (as in the case of oligodendrogliomas),
but improving the survival rates for patients harboring
astrocytic tumors will probably require many randomized
clinical trials of novel treatment strategies. In conclusion,
most gliomas have extremely poor prognoses and we have
limited knowledge of their causes, how to treat them, and
other factors that determine prognoses. Thus, there is a
great need for large, well-designed epidemiological studies
of potential genetic and environmental risk factors and for
randomized controlled trials of prognostic factors and treat-
ment strategies for gliomas.
References
1. Aldape K, Simmons ML, Davis RL, et al: Discrepancies in di-
agnoses of neuroepithelial neoplasms: the San Francisco Bay
Area Adult Glioma Study.
Cancer 88:2342–2349, 2000
2.
Aldape KD, Okcu MF, Bondy ML, et al: Molecular epidemiol-
ogy of glioblastoma.
Cancer J 9:99–106, 2003
3. Ames BN, Shigenaga MK, Hagen TM: Oxidants, antioxidants,
and the degenerative diseases of aging.
Proc Natl Acad Sci U
S A 90:
7915–7922, 1993
4. Angele S, Romestaing P, Moullan N, et al: ATM haplotypes and
cellular response to DNA damage: association with breast cancer
risk and clinical radiosensitivity.
Cancer Res 63:8717–8725,
2003
5. Barker FG II, Chang SM, Larson DA, et al: Age and radiation
response in glioblastoma multiforme.
Neurosurgery 49:
1288–1298, 2001
6. Barker FG II, Simmons ML, Chang SM, et al: EGFR overex-
pression and radiation response in glioblastoma multiforme.
Int
J Radiat Oncol Biol Phys 51:
410–418, 2001
7. Begg CB: Reflections on publication criteria for genetic as-
sociation studies.
Cancer Epidemiol Biomarkers Prev 14:
1364–1365, 2005
8. Berleur MP, Cordier S: The role of chemical, physical, or viral
exposures and health factors in neurocarcinogenesis: implica-
tions for epidemiologic studies of brain tumors.
Cancer Causes
Control 6:
240–256, 1995
9. Berwick M, Vineis P: Markers of DNA repair and susceptibili-
ty to cancer in humans: an epidemiologic review.
J Natl Can-
cer Inst 92:
874–897, 2000
10. Bhowmick DA, Zhuang Z, Wait SD, et al: A functional poly-
morphism in the EGF gene is found with increased frequency
in glioblastoma multiforme patients and is associated with more
aggressive disease.
Cancer Res 64:1220–1223, 2004
11. Block G, Patterson B, Subar A: Fruit, vegetables, and cancer
prevention: a review of the epidemiological evidence.
Nutr
Cancer 18:
1–29, 1992
12. Boeing H, Schlehofer B, Blettner M, et al: Dietary carcinogens
and the risk for glioma and meningioma in Germany.
Int J
Cancer 53:
561–565, 1993
13. Bond GL, Hu W, Bond EE, et al: A single nucleotide polymor-
phism in the
MDM2 promoter attenuates the p53 tumor sup-
pressor pathway and accelerates tumor formation in humans.
Cell 119:591–602, 2004
14. Bondy M, Wiencke J, Wrensch M, et al: Genetics of primary
brain tumors: a review.
J Neurooncol 18:69–81, 1994
15. Bondy ML, Kyritsis AP, Gu J, et al: Mutagen sensitivity and risk
of gliomas: a case-control analysis.
Cancer Res 56:1484–1486,
1996
16. Bondy ML, Wang LE, El-Zein R, et al: Gamma-radiation sen-
sitivity and risk of glioma.
J Natl Cancer Inst 93:1553–1557,
2001
17. Boon K, Edwards JB, Siu IM, et al: Comparison of medullo-
b
lastoma and normal neural transcriptomes identifies a re-
stricted set of activated genes.
Oncogene 22:7687–7694, 2003
18. Boyapati SM, Bostick RM, McGlynn KA, et al: Calcium, vita-
m
in D, and risk for colorectal adenoma: dependency on vitamin
D receptor BsmI polymorphism and nonsteroidal anti-inflam-
m
atory drug use?
C
ancer Epidemiol Biomarkers Prev 12:
631–637, 2003
19. Brenner AV, Linet MS, Fine HA, et al: History of allergies and
a
utoimmune diseases and risk of brain tumors in adults.
I
nt J
Cancer 99:
252–259, 2002
20. Burch JD, Craib KJ, Choi BC, et al: An exploratory case-control
study of brain tumors in adults.
J Natl Cancer Inst 78:601–609,
1987
21. Burnet NG, Jefferies SJ, Benson RJ, et al: Years of life lost
(YLL) from cancer is an important measure of population bur-
den—and should be considered when allocating research funds.
Br J Cancer 92:241–245, 2005
22. Burton EC, Lamborn KR, Feuerstein BG, et al: Genetic aberra-
tions defined by comparative genomic hybridization distinguish
long-term from typical survivors of glioblastoma.
Cancer Res
62:
6205–6210, 2002
23. Burton EC, Lamborn KR, Forsyth P, et al: Aberrant p53, mdm2,
and proliferation differ in glioblastomas from long-term com-
pared with typical survivors.
Clin Cancer Res 8:180–187, 2002
24. Byrnes G, Gurrin L, Dowty J, et al: Publication policy or publica-
tion bias?
Cancer Epidemiol Biomarkers Prev 14:1363, 2005
25. Cairncross JG, Ueki K, Zlatescu MC, et al: Specific genetic pre-
dictors of chemotherapeutic response and survival in patients
with anaplastic oligodendrogliomas.
J Natl Cancer Inst 90:
1473–1479, 1998
26. Caporaso N, Landi MT, Vineis P: Relevance of metabolic poly-
morphisms to human carcinogenesis: evaluation of epidemio-
logic evidence. Pharmacogenetics 1:4–19, 1991
27. Carozza SE, Wrensch M, Miike R, et al: Occupation and adult
gliomas.
Am J Epidemiol 152:838–846, 2000
28. CBTRUS:
Statistical Report: Primary Brain Tumors in the
United States, 1995–1999.
(http://www.cbtrus.org/reports//
2002/2002report.pdf) [Accessed 19 October 2005]
29. CBTRUS:
Statistical Report: Primary Brain Tumors in the
United States, 1997–2001.
(http://www.cbtrus.org/reports//
2004–2005/2005report.pdf) [Accessed 19 October 2005]
30. Chen H, Ward MH, Tucker KL, et al: Diet and risk of adult glio-
ma in eastern Nebraska, United States.
Cancer Causes Con-
trol 13:
647–655, 2002
31. Chen J, Hunter DJ, Stampfer MJ, et al: Polymorphism in the
thymidylate synthase promoter enhancer region modifies the
risk and survival of colorectal cancer.
Cancer Epidemiol Bio-
markers Prev 12:
958–962, 2003
32. Cobbs CS, Whisenhunt TR, Wesemann DR, et al: Inactivation of
wild-type p53 protein function by reactive oxygen and nitrogen
species in malignant glioma cells.
Cancer Res 63:8670–8673,
2003
33. Cocco P, Dosemeci M, Heineman EF: Brain cancer and occu-
pational exposure to lead. J Occup Environ Med 40:937–942,
1998
34. Cocco P, Heineman EF, Dosemeci M: Occupational risk factors
for cancer of the central nervous system (CNS) among US wo-
men.
Am J Ind Med 36:70–74, 1999
35. Coons SW, Johnson PC, Scheithauer BW, et al: Improving diag-
nostic accuracy and interobserver concordance in the classifica-
tion and grading of primary gliomas.
Cancer 79:1381–1393,
1997
36. Curran WJ Jr, Scott CB, Horton J, et al: Recursive partitioning
analysis of prognostic factors in three Radiation Therapy On
-
cology Group malignant glioma trials.
J Natl Cancer Inst 85:
704–710, 1993
Neurosurg. Focus / Volume 19 / November, 2005
Molecular epidemiology of gliomas in adults
7
37. Dasgupta RK, Adamson PJ, Davies FE, et al: Polymorphic vari-
ation in GSTP1 modulates outcome following therapy for mul-
tiple myeloma.
Blood 102:2345–2350, 2003
38. Davis FG, Freels S, Grutsch J, et al: Survival rates in patients
with primary malignant brain tumors stratified by patient age
and tumor histological type: an analysis based on Surveillance,
Epidemiology, and End Results (SEER) data, 1973–1991.
J
N
eurosurg 88:
1
–10, 1998
39. Davis FG, McCarthy B, Jukich P: The descriptive epidemiology
of brain tumors.
Neuroimaging Clin N Am 9:581–594, 1999
4
0. de Andrade M, Barnholtz JS, Amos CI, et al: Segregation analy-
sis of cancer in families of glioma patients.
Genet Epidemiol
20:
258–270, 2001
41. De Roos AJ, Rothman N, Inskip PD, et al: Genetic polymorphisms
in GSTM1, -P1, -T1, and CYP2E1 and the risk of adult brain
tumors.
Cancer Epidemiol Biomarkers Prev 12:14–22, 2003
42. DeMichele A, Martin AM, Mick R, et al: Interleukin-6
2174G→C polymorphism is associated with improved outcome
in high-risk breast cancer.
Cancer Res 63:8051–8056, 2003
43. Edick MJ, Cheng C, Yang W, et al: Lymphoid gene expression
as a predictor of risk of secondary brain tumors.
Genes Chro-
mosomes Cancer 42:
107–116, 2005
44. Elexpuru-Camiruaga J, Buxton N, Kandula V, et al: Susceptibil-
ity to astrocytoma and meningioma: influence of allelism at glu-
tathione S-transferase (GSTT1 and GSTM1) and cytochrome P-
450 (CYP2D6) loci.
Cancer Res 55:4237–4239, 1995
45. Eley GD, Reiter JL, Pandita A, et al: A chromosomal region
7p11.2 transcript map: its development and application to the
study of EGFR amplicons in glioblastoma.
Neuro-oncol 4:
86–94, 2002
46. El-Zein R, Minn AY, Wrensch M, et al: Epidemiology of brain
tumors, in Levin VA (ed):
Cancer in the Nervous System, ed
2.
New York: Oxford University Press, 2002, pp 252–266
47. Evans WE, Relling MV: Pharmacogenomics: translating func-
tional genomics into rational therapeutics.
Science 286:487–491,
1999
48. Feldkamp MM, Lala P, Lau N, et al: Expression of activated ep-
idermal growth factor receptors, Ras-guanosine triphosphate,
and mitogen-activated protein kinase in human glioblastoma
multiforme specimens.
Neurosurgery 45:1442–1453, 1999
49. Felsberg J, Erkwoh A, Sabel MC, et al: Oligodendroglial tu-
mors: refinement of candidate regions on chromosome arm 1p
and correlation of 1p/19q status with survival.
Brain Pathol
14:
121–130, 2004
50. Fortin D, Cairncross GJ, Hammond RR: Oligodendroglioma:
an appraisal of recent data pertaining to diagnosis and treat
-
ment.
Neurosurgery 45:1279–1291, 1999
51. Freije WA, Castro-Vargas FE, Fang Z, et al: Gene expression
profiling of gliomas strongly predicts survival.
Cancer Res 64:
6503–6510, 2004
52. Friedberg T: Cytochrome P450 polymorphisms as risk factors
for steroid hormone-related cancers.
Am J Pharmacogeno-
mics 1:
83–91, 2001
53.
Fukuda ME, Iwadate Y, Machida T, et al: Cathepsin D is a
potential serum marker for poor prognosis in glioma patients.
Cancer Res 65:5190–5194, 2005
54. Garte S, Gaspari L, Alexandrie AK, et al: Metabolic gene poly-
morphism frequencies in control populations.
Cancer Epide-
miol Biomarkers Prev 10:
1239–1248, 2001
55.
Gobbel GT, Bellinzona M, Vogt AR, et al: Response of postmi-
totic neurons to X-irradiation: implications for the role of DNA
damage in neuronal apoptosis.
J Neurosci 18:147–155, 1998
56. Goode EL, Ulrich CM, Potter JD: Polymorphisms in DNA re-
pair genes and associations with cancer risk.
Cancer Epide
-
miol Biomarkers Prev 11:
1513–1530, 2002
57. Grossman SA, Osman M, Hruban R, et al: Central nervous sys-
tem cancers in first-degree relatives and spouses.
Cancer In-
vest 17:
299–308, 1999
58. Guo WD, Linet MS, Chow WH, et al: Diet and serum markers
in relation to primary brain tumor risk in China.
Nutr Cancer
22:
143–150, 1994
59. Gurney JG, Chen M, Skluzacek MC, et al: Null association
between frequency of cured meat consumption and methylva-
line and ethylvaline hemoglobin adduct levels: the
N-nitroso
brain cancer hypothesis.
Cancer Epidemiol Biomarkers Prev
11:
421–422, 2002
6
0. Hartmann C, Johnk L, Kitange G, et al: Transcript map of the 3.7-
Mb
D19S112-D19S246 candidate tumor suppressor region on the
long arm of chromosome 19.
Cancer Res 62:4100–4108, 2002
6
1. Hashimoto N, Murakami M, Takahashi Y, et al: Correlation be-
tween genetic alteration and long-term clinical outcome of pa-
tients with oligodendroglial tumors, with identification of a
consistent region of deletion on chromosome arm 1p.
Cancer
97:
2254–2261, 2003
62. Hefler LA, Grimm C, Ackermann S, et al: An interleukin-6 gene
promoter polymorphism influences the biological phenotype of
ovarian cancer.
Cancer Res 63:3066–3068, 2003
63. Hegi ME, Diserens AC, Gorlia T, et al:
MGMT gene silencing
and benefit from temozolomide in glioblastoma.
N Engl J Med
352:
997–1003, 2005
64. Heimberger AB, Hlatky R, Suki D, et al: Prognostic effect of epi-
dermal growth factor receptor and EGFRvIII in glioblastoma mul-
tiforme patients.
Clin Cancer Res 11:1462–1466, 2005
65. Hemminki K, Li X, Vaittinen P, et al: Cancers in the first-de-
gree relatives of children with brain tumours.
Br J Cancer
83:
407–411, 2000
66. Horn B, Heideman R, Geyer R, et al: A multi-institutional retro-
spective study of intracranial ependymoma in children: identifica-
tion of risk factors.
J Pediatr Hematol Oncol 21:203–211, 1999
67. Hsia TC, Chiang HC, Chiang D, et al: Prediction of survival in
surgical unresectable lung cancer by artificial neural networks
including genetic polymorphisms and clinical parameters.
J
Clin Lab Anal 17:
229–234, 2003
68. Hu J, La Vecchia C, Negri E, et al: Diet and brain cancer in
adults: a case-control study in northeast China.
Int J Cancer
81:
20–23, 1999
69. Huang B, Starostik P, Kuhl J, et al: Loss of heterozygosity on
chromosome 22 in human ependymomas.
Acta Neuropathol
(Berl) 103:
415–420, 2002
70. Huang H, Okamoto Y, Yokoo H, et al: Gene expression profil-
ing and subgroup identification of oligodendrogliomas.
Onco-
gene 23:
6012–6022, 2004
71. Huncharek M, Kupelnick B, Wheeler L: Dietary cured meat and
the risk of adult glioma: a meta-analysis of nine observational
studies.
J Environ Pathol Toxicol Oncol 22:129–137, 2003
72. Hung RJ, Boffetta P, Brockmoller J, et al: CYP1A1 and GSTM1
genetic polymorphisms and lung cancer risk in Caucasian non-
smokers: a pooled analysis.
Carcinogenesis 24:875–882, 2003
73.
Iacopetta B, Grieu F, Joseph D: The
2174 G/C gene polymor
-
phism in interleukin-6 is associated with an aggressive breast
cancer phenotype.
Br J Cancer 90:419–422, 2004
74. Ichimura K, Ohgaki H, Kleihues P, et al: Molecular pathogene-
sis of astrocytic tumours.
J Neurooncol 70:137–160, 2004
75. Illmer T, Schuler US, Thiede C, et al:
MDR1 gene polymor-
phisms affect therapy outcome in acute myeloid leukemia pa-
tients.
Cancer Res 62:4955–4962, 2002
76. Ino Y, Betensky RA, Zlatescu MC, et al: Molecular subtypes of
anaplastic oligodendroglioma: implications for patient manage-
ment at diagnosis.
Clin Cancer Res 7:839–845, 2001
77. Ino Y, Silver JS, Blazejewski L, et al: Common regions of dele-
tion on chromosome 22q12.3-q13.1 and 22q13.2 in human as-
trocytomas appear related to malignancy grade.
J Neuropathol
Exp Neurol 58:
881–885, 1999
78. Inskip PD, Linet MS, Heineman EF: Etiology of brain tumors
in adults.
Epidemiol Rev 17:382–414, 1995
79. Ioannidis JP, Bernstein J, Boffetta P, et al: A network of inves-
tigator networks in human genome epidemiology.
Am J Epi-
demiol 162:
302–304, 2005
M. Wrensch, et al.
8
Neurosurg. Focus / Volume 19 / November, 2005
80. Ito N, Hirose M: Antioxidants—carcinogenic and chemopre-
ventive properties.
Adv Cancer Res 53:247–302, 1989
81. James CD, Smith JS, Jenkins RB: Genetic and molecular basis
of primary central nervous system tumors, in Levin VA (ed):
Cancer in the Nervous System, ed 2. New York: Oxford Uni-
versity Press, 2002, pp 239–251
82. James D: Genetic Aspects, in Bernstein M, Berger M (eds):
N
euro-Oncology: The Essentials.
N
ew York: Thieme Medi-
cal Publishers, 2000, pp 42–48
83. Karak AK, Singh R, Tandon PN, et al: A comparative survival
e
valuation and assessment of interclassification concordance in
adult supratentorial astrocytic tumors.
Pathol Oncol Res 6:
46–52, 2000
84. Kelsey KT, Wrensch M, Zuo ZF, et al: A population-based case-
control study of the CYP2D6 and GSTT1 polymorphisms and
malignant brain tumors.
Pharmacogenetics 7:463–468, 1997
85. Khoury MJ, Davis R, Gwinn M, et al: Do we need genomic re-
search for the prevention of common diseases with environ-
mental causes?
Am J Epidemiol 161:799–805, 2005
86. Kim HS, Newcomb PA, Ulrich CM, et al: Vitamin D receptor
polymorphism and the risk of colorectal adenomas: evidence of
interaction with dietary vitamin D and calcium.
Cancer Epide-
miol Biomarkers Prev 10:
869–874, 2001
87. Kitange G, Misra A, Law M, et al: Chromosomal imbalances
detected by array comparative genomic hybridization in human
oligodendrogliomas and mixed oligoastrocytomas.
Genes Chro-
mosomes Cancer 42:
68–77, 2005
88. Kleihues P, Cavenee WK:
Tumors of the Central Nervous
System: Pathology and Genetics.
Lyon, France: International
Agency for Research on Cancer, 1997
89. Kleihues P, Ohgaki H: Phenotype vs genotype in the evolution
of astrocytic brain tumors.
Toxicol Pathol 28:164–170, 2000
90. Kleihues P, Schauble B, zur Hausen A, et al: Tumors associat-
ed with p53 germline mutations: a synopsis of 91 families.
Am
J Pathol 150:
1–13, 1997
91. Krishnan G, Felini M, Carozza SE, et al: Occupation and adult
gliomas in the San Francisco Bay Area.
J Occup Environ Med
45:
639–647, 2003
92. Kyritsis AP, Bondy ML, Hess KR, et al: Prognostic significance
of p53 immunoreactivity in patients with glioma.
Clin Cancer
Res 1:
1617–1622, 1995
93. Lamborn KR, Chang SM, Prados MD: Prognostic factors for
survival of patients with glioblastoma: recursive partitioning
analysis.
Neuro-oncol 6:227–235, 2004
94.
Lang FF, Miller DC, Koslow M, et al: Pathways leading to glio-
blastoma multiforme: a molecular analysis of genetic alter
-
ations in 65 astrocytic tumors.
J Neurosurg 81:427–436, 1994
95. Lee M, Wrensch M, Miike R: Dietary and tobacco risk factors
for adult onset glioma in the San Francisco Bay Area
(California, USA).
Cancer Causes Control 8:13–24, 1997
96. Levin V, Liebel S, Gutin P: Neoplasms of the central nervous
system (section 2), in DeVita VTJ, Hellman S, Rosenberg SA
(eds):
Cancer: Principles and Practice of Oncology, ed 6.
Philadelphia: Lippincott Williams & Wilkins, 2001, Vol 2, pp
2100–2160
97. Lin H, Bondy ML, Langford LA, et al: Allelic deletion analyses
of MMAC/PTEN and DMBT1 loci in gliomas: relationship to
prognostic significance.
Clin Cancer Res 4:2447–2454, 1998
98. Loktionov A: Common gene polymorphisms, cancer progres-
sion and prognosis.
Cancer Lett 208:1–33, 2004
99. Louis DN, Stemmer-Rachamimov AO: Pathology and classifi-
cation, in Bernstein M, Berger M (eds):
Neuro-Oncology: The
Essentials.
New York: Thieme Medical Publishers, 2000, pp
18–29
100. Maekawa A, Mitsumori K: Spontaneous occurrence and
chemical induction of neurogenic tumors in rats—influence of
host factors and specificity of chemical structure.
Crit Rev
Toxicol 20:
287–310, 1990
101. Malmer B, Grönberg H, Bergenheim AT, et al: Familial aggre-
gation of astrocytoma in northern Sweden: an epidemiological
cohort study.
Int J Cancer 81:366–370, 1999
102. Malmer B, Iselius L, Holmberg E, et al: Genetic epidemiology
of glioma.
Br J Cancer 84:429–434, 2001
103. McGlynn KA, Rosvold EA, Lustbader ED, et al: Suscep-
t
ibility to hepatocellular carcinoma is associated with genetic
variation in the enzymatic detoxification of aflatoxin B1.
Proc
N
atl Acad Sci U S A 92:
2
384–2387, 1995
1
04. Miller DP, De Vivo I, Neuberg D, et al: Association between
self-reported environmental tobacco smoke exposure and lung
c
ancer: modification by GSTP1 polymorphism.
I
nt J Cancer
104:
758–763, 2003
105. Mills PK, Preston-Martin S, Annegers JF, et al: Risk factors
for tumors of the brain and cranial meninges in Seventh-Day
Adventists.
Neuroepidemiology 8:266–275, 1989
106. Mochizuki S, Iwadate Y, Namba H, et al: Homozygous deletion
of the p16/MTS-1/CDKN2 gene in malignant gliomas is infre-
quent among Japanese patients.
Int J Oncol 15:983–989, 1999
107. Mohrenweiser HW, Wilson DM III, Jones IM: Challenges and
complexities in estimating both the functional impact and the
disease risk associated with the extensive genetic variation in
human DNA repair genes.
Mutat Res 526:93–125, 2003
108. Morimoto Y, Ozaki T, Ouchida M, et al: Single nucleotide
polymorphism in fibroblast growth factor receptor 4 at codon
388 is associated with prognosis in high-grade soft tissue sar-
coma.
Cancer 98:2245–2250, 2003
109. Nagasubramanian R, Innocenti F, Ratain MJ: Pharmacogenetics
in cancer treatment.
Annu Rev Med 54:437–452, 2003
110. National Center for Biotechnology Information:
Entrez Gene.
(http://www.ncbi.nlm.nih.gov/entrez/query.fcgi?CMD=search
&DB=gene) [Accessed 11 November 2005]
111. Navas-Acien A, Pollan M, Gustavsson P, et al: Occupation,
exposure to chemicals and risk of gliomas and meningiomas in
Sweden.
Am J Ind Med 42:214–227, 2002
112. Neben K, Mytilineos J, Moehler TM, et al: Polymorphisms of
the tumor necrosis factor-
a gene promoter predict for outcome
after thalidomide therapy in relapsed and refractory multiple
myeloma.
Blood 100:2263–2265, 2002
113. Nigro JM, Misra A, Zhang L, et al: Integrated array-compara-
tive genomic hybridization and expression array profiles iden-
tify clinically relevant molecular subtypes of glioblastoma.
Cancer Res 65:1678–1686, 2005
114. Ohgaki H, Dessen P, Jourde B, et al: Genetic pathways
to glioblastoma: a population-based study.
Cancer Res 64:
6892–6899, 2004
115.
Ohgaki H, Kleihues P: Epidemiology and etiology of gliomas.
Acta Neuropathol (Berl) 109:93–108, 2005
116. Okada Y, Hurwitz EE, Esposito JM, et al: Selection pressures
of
TP53 mutation and microenvironmental location influence
Epidermal Growth Factor Receptor gene amplification in hu
-
man glioblastomas.
Cancer Res 63:413–416, 2003
117. Okcu MF, Selvan M, Wang LE, et al: Glutathione
S-trans-
ferase polymorphisms and survival in primary malignant glio-
ma.
Clin Cancer Res 10:2618–2625, 2004
118. Oskam NT, Bijleveld EH, Hulsebos TJ: A region of common
deletion in 22q13.3 in human glioma associated with astrocy-
toma progression.
Int J Cancer 85:336–339, 2000
119. Paunu N, Lahermo P, Onkamo P, et al: A novel low-pene-
trance locus for familial glioma at 15q23-q26.3.
Cancer Res
62:
3798–3802, 2002
120. Peterson DL, Sheridan PJ, Brown WE Jr: Animal models for
brain tumors: historical perspectives and future directions.
J
Neurosurg 80:
865–876, 1994
121. Pinarbasi H, Silig Y, Gurelik M: Genetic polymorphisms of
GSTs and their association with primary brain tumor inci-
dence.
Cancer Genet Cytogenet 156:144–149, 2005
122. Poulsen HE, Loft S, Wassermann K: Cancer risk related to ge-
netic polymorphisms in carcinogen metabolism and DNA
repair.
Pharmacol Toxicol 72 (Suppl 1):93–103, 1993
Neurosurg. Focus / Volume 19 / November, 2005
Molecular epidemiology of gliomas in adults
9
123. Preston-Martin S, Mack WJ: Neoplasms of the nervous sys-
tem, in Schottenfeld D, Fraumeni JF Jr (eds):
Cancer Epide-
miology and Prevention, ed 2.
New York: Oxford University
Press, 1996, pp 1231–1281
124. Preston-Martin S, Pogoda JM, Mueller BA, et al: Maternal
consumption of cured meats and vitamins in relation to pedi-
atric brain tumors.
Cancer Epidemiol Biomarkers Prev 5:
599–605, 1996
125. Puduvalli VK, Kyritsis AP, Hess KR, et al: Patterns of expres-
s
ion of Rb and p16 in astrocytic gliomas, and correlation with
survival.
Int J Oncol 17:963–969, 2000
1
26. Rasheed BK, McLendon RE, Friedman HS, et al: Chromo-
some 10 deletion mapping in human gliomas: a common dele-
tion region in 10q25.
Oncogene 10:2243–2246, 1995
127. Rasheed BK, McLendon RE, Herndon JE, et al: Alterations of
the TP53 gene in human gliomas.
Cancer Res 54:1324–1330,
1994
128. Rasheed BK, Wiltshire RN, Bigner SH, et al: Molecular patho-
genesis of malignant gliomas.
Curr Opin Oncol 11:162–167,
1999
129. Rebbeck TR, Martinez ME, Sellers TA, et al: Genetic varia-
tion and cancer: improving the environment for publication of
association studies.
Cancer Epidemiol Biomarkers Prev
13:
1985–1986, 2004
130. Reifenberger G, Ichimura K, Reifenberger J, et al: Refined map-
ping of 12q13-q15 amplicons in human malignant gliomas sug-
gests CDK4/SAS and MDM2 as independent amplification tar-
gets.
Cancer Res 56:5141–5145, 1996
131. Reifenberger G, Reifenberger J, Ichimura K, et al: Amplification
at 12q13–14 in human malignant gliomas is frequently accom-
panied by loss of heterozygosity at loci proximal and distal to
the amplification site.
Cancer Res 55:731–734, 1995
132. Relling MV, Rubnitz JE, Rivera GK, et al: High incidence of
secondary brain tumors after radiotherapy and antimetabolites.
Lancet 354:34–39, 1999
133. Riemenschneider MJ, Knobbe CB, Reifenberger G: Refined
mapping of 1q32 amplicons in malignant gliomas confirms
MDM4 as the main amplification target. Int J Cancer 104:
752–757, 2003
134. Ryberg D, Kure E, Lystad S, et al: p53 mutations in lung tu-
mors: relationship to putative susceptibility markers for can-
cer.
Cancer Res 54:1551–1555, 1994
135. Sakano S, Berggren P, Kumar R, et al: Clinical course of blad-
der neoplasms and single nucleotide polymorphisms in the
CDKN2A gene. Int J Cancer 104:98–103, 2003
136. Salinas AE, Wong MG: Glutathione
S-transferases—a review.
Curr Med Chem 6:279–309, 1999
137. Sano T, Lin H, Chen X, et al: Differential expression of
MMAC/PTEN in glioblastoma multiforme: relationship to
localization and prognosis.
Cancer Res 59:1820–1824, 1999
138. Schlehofer B, Blettner M, Preston-Martin S, et al: Role of med-
ical history in brain tumor development. Results from the inter-
national adult brain tumor study.
Int J Cancer 82:155–160,
1999
139. Schwartzbaum J, Ahlbom A, Malmer B, et al: Polymorphisms
associated with asthma are inversely related to glioblastoma
multiforme.
Cancer Res 65:6459–6465, 2005
140. Schwartzbaum J, Jonsson F, Ahlbom A, et al: Cohort studies
of association between self-reported allergic conditions, im-
mune-related diagnoses and glioma and meningioma risk.
Int
J Cancer 106:
423–428, 2003
141. Scott CB, Scarantino C, Urtasun R, et al: Validation and pre-
dictive power of Radiation Therapy Oncology Group (RTOG)
recursive partitioning analysis classes for malignant glioma
patients: a report using RTOG 90–06.
Int J Radiat Oncol
Biol Phys 40:
51–55, 1998
142. Scott JN, Rewcastle NB, Brasher PM, et al: Long-term
glioblastoma multiforme survivors: a population-based study.
Can J Neurol Sci 25:197–201, 1998
143. Shu XO, Gao YT, Cai Q, et al: Genetic polymorphisms in the
TGF-
b
1 gene and breast cancer survival: a report from the
Shanghai Breast Cancer Study.
Cancer Res 64:836–839, 2004
144. Sigurdson AJ, Bondy ML, Hess KR, et al: Gamma-ray muta-
gen sensitivity and survival in patients with glioma.
Clin
Cancer Res 4:
3031–3035, 1998
145. Silasi G, Diaz-Heijtz R, Besplug J, et al: Selective brain re-
sponses to acute and chronic low-dose X-ray irradiation in
males and females.
Biochem Biophys Res Commun 325:
1223–1235, 2004
146. Simmons ML, Lamborn KR, Takahashi M, et al: Analysis of
complex relationships between age, p53, epidermal growth
factor receptor, and survival in glioblastoma patients.
Cancer
Res 61:
1122–1128, 2001
147. Skuladottir H, Autrup H, Autrup J, et al: Polymorphisms in
genes involved in xenobiotic metabolism and lung cancer risk
under the age of 60 years. A pooled study of lung cancer patients
in Denmark and Norway.
Lung Cancer 48:187–199, 2005
148. Smith JS, Alderete B, Minn Y, et al: Localization of common
deletion regions on 1p and 19q in human gliomas and their asso-
ciation with histological subtype. Oncogene 18:4144–4152,
1999
149. Smith JS, Perry A, Borell TJ, et al: Alterations of chromosome
arms 1p and 19q as predictors of survival in oligodendro-
gliomas, astrocytomas, and mixed oligoastrocytomas.
J Clin
Oncol 18:
636–645, 2000
150. Smith JS, Tachibana I, Passe SM, et al: PTEN mutation,
EGFR amplification, and outcome in patients with anaplastic
astrocytoma and glioblastoma multiforme. J Natl Cancer Inst
93:
1246–1256, 2001
151. Smith JS, Tachibana I, Pohl U, et al: A transcript map of the
chromosome 19q-arm glioma tumor suppressor region.
Genomics 64:44–50, 2000
152. Strange RC, Fryer AA: The glutathione S-transferases: influ-
ence of polymorphism on cancer susceptibility.
IARC Sci
Pub 148:
231–249, 1999
153. Strange RC, Lear JT, Fryer AA: Polymorphism in glutathione
S-transferase loci as a risk factor for common cancers. Arch
Toxicol Suppl 20:
419–428, 1998
154. Stupp R, Mason WP, van den Bent MJ, et al: Radiotherapy
plus concomitant and adjuvant temozolomide for glioblas-
toma.
N Engl J Med 352:987–996, 2005
155. Su WT, Alaminos M, Mora J, et al: Positional gene expression
analysis identifies 12q overexpression and amplification in a sub-
set of neuroblastomas. Cancer Genet Cytogenet 154:131–137,
2004
156.
Suarez-Merino B, Hubank M, Revesz T, et al: Microarray
analysis of pediatric ependymoma identifies a cluster of 112
candidate genes including four transcripts at 22q12.1-q13.3.
Neuro-oncol 7:20–31, 2005
157.
Sullivan A, Syed N, Gasco M, et al: Polymorphism in wild-
type p53 modulates response to chemotherapy
in vitro and in
vivo
. Oncogene 23:3328–3337, 2004
158. Tang J, Shao W, Dorak MT, et al: Positive and negative asso-
ciations of human leukocyte antigen variants with the onset
and prognosis of adult glioblastoma multiforme. Cancer Epi-
demiol Biomarkers Prev 14:
2040–2044, 2005
159. Tedeschi-Blok N, Schwartzbaum J, Lee M, et al: Dietary cal-
cium consumption and astrocytic glioma: the San Francisco
Bay Area Adult Glioma Study, 1991–1995.
Nutr Cancer 39:
196–203, 2001
160. Thier R, Bruning T, Roos PH, et al: Markers of genetic sus-
ceptibility in human environmental hygiene and toxicology:
the role of selected CYP, NAT and GST genes.
Int J Hyg En-
viron Health 206:
149–171, 2003
161. Thiessen B, Maguire JA, McNeil K, et al: Loss of heterozy-
gosity for loci on chromosome arms 1p and 10q in oligoden
-
droglial tumors: relationship to outcome and chemosensitivity.
J Neurooncol 64:271–278, 2003
M. Wrensch, et al.
10
Neurosurg. Focus / Volume 19 / November, 2005
162. Trizna Z, de Andrade M, Kyritsis AP, et al: Genetic polymor-
phisms in glutathione
S-transferase m and u, N-acetyltrans-
ferase, and
CYP1A1 and risk of gliomas. Cancer Epidemiol
Biomarkers Prev 7:
553–555, 1998
163. Tsigelny IF, Kotlovyi V, Wasserman L: SNP analysis com-
b
ined with protein structure prediction defines structure-func-
tional relationships in cancer related cytochrome P450 estro-
gen metabolism.
Curr Med Chem 11:525–538, 2004
164. von Deimling A, Louis DN, Wiestler OD: Molecular pathways
in the formation of gliomas.
Glia 15:328–338, 1995
165. Wacholder S, Chanock S, Garcia-Closas M, et al: Assessing
the probability that a positive report is false: an approach for
molecular epidemiology studies.
J Natl Cancer Inst 96:
4
34–442, 2004
166. Wang LE, Bondy ML, Shen H, et al: Polymorphisms of DNA re-
pair genes and risk of glioma.
Cancer Res 64:5560–5563, 2004
167. Wang YC, Chen CY, Chen SK, et al:
p53 codon 72 polymor-
phism in Taiwanese lung cancer patients: association with
lung cancer susceptibility and prognosis.
Clin Cancer Res 5:
129–134, 1999
168. Wang YC, Lee HS, Chen SK, et al: Prognostic significance of
p53 codon 72 polymorphism in lung carcinomas. Eur J Can-
cer 35:
226–230, 1999
169. Watts LT, Rathinam ML, Schenker S, et al: Astrocytes protect
neurons from ethanol-induced oxidative stress and apoptotic
death.
J Neurosci Res 80:655–666, 2005
170. Wei Q, Bondy ML, Mao L, et al: Reduced expression of mis-
match repair genes measured by multiplex reverse transcrip-
tion-polymerase chain reaction in human gliomas.
Cancer
Res 57:
1673–1677, 1997
171. Wesseling C, Pukkala E, Neuvonen K, et al: Cancer of the
brain and nervous system and occupational exposures in Fin-
nish women.
J Occup Environ Med 44:663–668, 2002
172. Whittemore AS: Genetic association studies: time for a new par-
adigm?
Cancer Epidemiol Biomarkers Prev 14:1359–1360,
2005
173. Wiemels JL, Smith RN, Taylor GM, et al: Methylenetetrahydro-
folate reductase (MTHFR) polymorphisms and risk of molecu-
larly defined subtypes of childhood acute leukemia.
Proc Natl
Acad Sci U S A 98:
4004–4009, 2001
174. Wiemels JL, Wiencke JK, Patoka J, et al: Reduced immuno-
globulin E and allergy among adults with glioma compared
with controls.
Cancer Res 64:8468–8473, 2004
175. Wiemels JL, Wiencke JK, Sison JD, et al: History of allergies
among adults with glioma and controls.
Int J Cancer 98:
609–615, 2002
176. Wiemels JL, Zhang Y, Chang J, et al:
RAS mutation is associat-
ed with hyperdiploidy and parental characteristics in pediatric
acute lymphoblastic leukemia.
Leukemia 19:415–419, 2005
177. Wiencke J, Aldalpe K, McMillan A, et al: Molecular features of
adult glioma associated with patient race/ethnicity, age, and a
polymorphism in
O
6
-methylguanine-DNA-methyltransferase.
Cancer Epidemiol Biomarkers Prev 14:1774–1783, 2005
178. Wiencke JK, Wrensch MR, Miike R, et al: Population-based
study of glutathione S-transferase mu gene deletion in adult
glioma cases and controls.
Carcinogenesis 18:1431–1433, 1997
179. Wood RD, Mitchell M, Sgouros J, et al: Human DNA repair
genes.
Science 291:1284–1289, 2001
180. Wrensch M, Kelsey K, Liu M, et al:
ERCC1 and ERCC2 poly-
morphisms and adult glioma.
Neuro-oncol 7:495–507, 2005
181. Wrensch M, Kelsey KT, Liu M, et al: Glutathione-
S-trans-
ferase variants and adult glioma.
Cancer Epidemiol Biomar-
kers Prev 13:
461–467, 2004
182. Wrensch M, Lee M, Miike R, et al: Familial and personal med-
ical history of cancer and nervous system conditions among
adults with glioma and controls.
Am J Epidemiol 145:581–593,
1997
183. Wrensch M, Minn Y, Chew T, et al: Epidemiology of primary
brain tumors: current concepts and review of the literature.
Neuro-oncol 4:278–299, 2002
184. Wrensch M, Weinberg A, Wiencke J, et al: Does prior infec-
tion with varicella-zoster virus influence risk of adult glioma?
Am J Epidemiol 145:594–597, 1997
185. Wrensch M, Weinberg A, Wiencke J, et al: Prevalence of anti-
bodies to four herpesviruses among adults with glioma and
controls.
Am J Epidemiol 154:161–165, 2001
186. Wrensch M, Weinberg A, Wiencke J, et al: History of chick-
enpox and shingles and prevalence of antibodies to varicella-
zoster virus and three other herpesviruses among adults with
glioma and controls.
Am J Epidemiol 161:929–938, 2005
187. Yang P, Kollmeyer TM, Buckner K, et al: Polymorphisms in
GLTSCR1 and ERCC2 are associated with the development
of oligodendrogliomas.
Cancer 103:2363–2372, 2005
188. Yuspa SH, Shields PG: Etiology of cancer: chemical factors,
in De Vita J, Hellman VTS (eds):
Cancer: Principles and
Practice of Oncology.
Philadelphia: Lippincott Williams &
Wilkins, 2001, pp 179–193
189. Zheng PP, Hop WC, Sillevis Smitt PA, et al: Low-molecular
weight caldesmon as a potential serum marker for glioma.
Clin Cancer Res 11:4388–4392, 2005
190. Zheng T, Cantor KP, Zhang Y, et al: Occupational risk factors
for brain cancer: a population-based case-control study in Io-
wa.
J Occup Environ Med 43:317–324, 2001
191. Zhu A, Shaeffer J, Leslie S, et al: Epidermal growth factor
receptor: an independent predictor of survival in astrocytic
tumors given definitive irradiation.
Int J Radiat Oncol Biol
Phys 34:
809–815, 1996
Manuscript received September 15, 2005.
Accepted in final form October 18, 2005.
This work was supported by the following grants from the Na-
tional Cancer Institute: No. R01CA52689 (Margaret Wrensch, Prin
-
cipal Investigator), No. P50CA097257 (Mitchel Berger, Principal
Investigator), and No. R03CA103379 (Judith Schwartzbaum, Prin
-
cipal Investigator).
Address reprint requests to: Margaret Wrensch, Ph.D., Depart
-
ment of Neurological Surgery, 44 Page Street, Suite 503, University
of California, San Francisco, California 94102. email: wrensch@itsa.
ucsf.edu.
Neurosurg. Focus / Volume 19 / November, 2005
Molecular epidemiology of gliomas in adults
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