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Does Prior Infection with Varicella-Zoster Virus Influence Risk of Adult Glioma?

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To evaluate a possible association between varicella-zoster virus infection and glioma, the authors asked adults with glioma (n = 462) whose tumors were diagnosed between August 1, 1991, and March 31, 1994, and age-, sex-, and ethnicity-matched controls (n = 443) about their histories of chickenpox or shingles. Cases were significantly less likely than controls to report a history of either chickenpox (odds ratio = 0.4, 95% confidence interval (CI) 0.3-0.6) or shingles (odds ratio = 0.5, 95% CI 0.3-0.8). To obtain serologic support for these findings, the authors conducted double-blind enzyme-linked immunosorbent assays for immunoglobulin G antibodies to varicella-zoster virus among 167 self-reporting subjects for whom blood samples were available. Cases and controls reporting no history of chickenpox were equally likely to test positive (73% vs. 75%), but among those reporting a positive history, cases were less likely than were controls to test positive (71% vs. 85%). Despite the misclassification, an odds ratio of 0.6 was obtained using either serologic data (95% CI 0.3-1.3) or reported history of chickenpox (95% CI 0.3-1.1) in this subgroup of subjects. This suggests that adults with glioma were less likely than controls either to have had prior varicella-zoster virus infection or to have an immunoglobulin G antibody response adequate to indicate positivity. Since either explanation suggests novel mechanisms for brain tumor pathogenesis, these findings require corroboration and elaboration.
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American Journal of Epidemiology
Copyright © 1997 by The Johns Hopkins University School of Hygiene and Public Health
All rights reserved
Vol 145, No 7
Printed in US A.
A BRIEF ORIGINAL CONTRIBUTION
Does Prior Infection with Varicella-Zoster Virus Influence Risk of Adult
Glioma?
Margaret Wrensch,
1
Adriana Weinberg,
2
John Wiencke,
1
Helen Masters,
2
Rei Muke,
1
Geoffrey Barger,
3
and
Manon Lee
1
To evaluate a possible association between varicella-zoster virus infection and glioma, the authors asked
adults with glioma (n = 462) whose tumors were diagnosed between August 1,1991, and March 31,1994, and
age-,
sex-, and ethnicity-matched controls (n - 443) about their histories of chickenpox or shingles. Cases
were significantly less likely than controls to report a history of erther chickenpox (odds ratio = 0.4, 95%
confidence interval (Cl) 0.3-0.6) or shingles (odds ratio = 0.5, 95% Cl 0.3-0.8). To obtain serologic support for
these findings, the authors conducted double-blind enzyme-linked immunosorbent assays for immunoglobuhn
G antibodies to varicella-zoster virus among 167 serf-reporting subjects for whom blood samples were
available. Cases and controls reporting no history of chickenpox were equally likely to test positive (73% vs.
75%),
but among those reporting a positive history, cases were less likely than were controls to test positive
(71
% vs. 85%). Despite the misclassification, an odds ratio of 0.6 was obtained using either serologic data
(95%
Cl 0.3-1.3) or reported history of chickenpox (95% Cl 0.3-1.1) in this subgroup of subjects. This
suggests that adults with glioma were less likely than controls erther to have had pnor varicella-zoster virus
infection or to have an immunoglobulin G antibody response adequate to indicate positivity. Since either
explanation suggests novel mechanisms for brain tumor pathogenesis, these findings require coiToboration
and elaboration. Am J Epidemiol 1997;145:594-7.
chickenpox; glioma; herpesvirus 3, human
Editor's note: A companion article by Wrensch et
al. appears on page 581 of this issue.
It has long been speculated that infectious agents or
an immunologic response to these agents may play a
role in causing, promoting, or preventing brain tumors
or other cancers (1, 2). Certain viruses are known to
induce glioma in test animals (1). There are intriguing
but inconclusive epidemiologic data linking simian
virus 40 infection with increased incidence of glioblas-
toma multiforme and medulloblastoma (3). Bithell et
al.
(4) reported a statistically significant excess of
children with medulloblastoma born to mothers who
Received for publication February 20, 1996, and In final form
August 2, 1996
Abbreviation: Cl, confidence interval.
1
Department of Epidemiology and Biostatlstics, School of Med-
icine,
University of California, San Francisco, CA
2
Pediatric Infectious Diseases, Diagnostic Virology Laboratory,
University of Colorado Hearth Sciences Center, Denver, CO.
3
Department of Neurology, School of Medicine, Wayne State
University, Detroit, Ml.
Reprint requests to Dr. Margaret Wrensch, Box 0560, University
of California School of Medicine, San Francisco, CA 94143-0560.
had had chickenpox during pregnancy, but the results
were based on only three observed cases, with 0.3
cases expected.
With regard to other infectious agents, Schuman et
al.
(5) showed that astrocytoma patients were signifi-
cantly more likely than controls to have antibodies to
Toxoplasma gondii using the Sabin-Feldman dye test,
and they showed that animals exposed to Toxoplasma
can develop glioma. Ryan et al. (6) could not confirm
this finding in a more recent Australian study; how-
ever, they did not report histologic types for their
subjects, and Schuman et al.'s findings were confined
to astrocytoma.
In the ongoing San Francisco Bay Area Adult Gli-
oma Study, subjects were asked about their histories of
chickenpox and shingles. Both are caused by varicella-
zoster virus, a herpesvirus which is known to have
nervous system involvement (7), and we thought they
might be comparatively memorable infections. Cases
were significantly less likely than controls to report a
history of both chickenpox (odds ratio = 0.4, 95
percent confidence interval (Cl) 0.3-0.6) and shingles
(odds ratio = 0.5, 95 percent Cl 0.3-0.8) (8). In this
report, we present serologic support for the finding
594
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Varicella-Zoster Virus and Adult Brain Cancer 595
that glioma cases were less likely than controls either
to have had varicella-zoster infection or to have anti-
bodies to this virus.
MATERIALS AND METHODS
Details on subject recruitment and interview have
been given elsewhere (8). Briefly, 462 eligible adults
newly diagnosed with glioma in any of six San
Francisco Bay Area Counties between August 1, 1991,
and March 31, 1994, participated; 443 age-, sex-, and
ethnicity-matched controls were obtained through ran-
dom digit dialing. Participation rates were 82 percent
for cases and 63 percent for controls. In-person struc-
tured interviews asked about personal and familial
medical history, demographic factors, and potential
brain tumor risk factors.
Blood sample collection was undertaken partway
through the study. Up to 30 ml of blood was collected
from 187 cases and 169 controls in heparinized green-
topped tubes. Whole blood was stored at 70°C and
was transported frozen using dry ice.
Because the blood specimens were obtained primar-
ily for polymorphism analyses, serologic studies were
conducted only on a sample of available blood speci-
mens.
The subsample originally included all subjects
with a negative history of chickenpox and a random
sample of 43 percent of those with a positive history.
Upon specimen retrieval, insufficient blood remained
for serologic studies from 16 glioma cases with a
negative chickenpox history. Consequently, to pre-
serve the observed association between chickenpox
history and glioma, an additional 13 glioma cases with
a positive chickenpox history were deleted from sero-
logic studies.
Serologic analysis was performed using the Vari-
cella STAT enzyme-linked immunoassay (BioWhit-
taker, Walkersville, Maryland) according to the man-
ufacturer's instructions, with modified criteria of
interpretation. Briefly, test sera and controls were di-
luted at 1:20 and added to antigen-coated wells in a
microtiter plate. Bound antibodies were revealed with
peroxidase-conjugated anti-human immunoglobulin G
and colorimetric substrate. Absorbances measured
with a spectrophotometer were used to calculate the
varicella index for each serum sample by dividing the
absorbance of the test serum well by the absorbance of
the manufacturer's positive control. Based on a previ-
ous study (9), a varicella index £ 0.9 indicated the
absence of specific antibodies; a varicella index S: 1.2
indicated immunity; and a varicella index greater than
0.9 but less than 1.2 was reported as borderline, be-
cause it did not correlate with immunity nor did it
exclude past infection. As performed, this test has 87
percent sensitivity and 91 percent specificity in com-
parison with cell-mediated immunity (9). Serologic
analysis was conducted blind to both case-control sta-
tus and reported history of chickenpox.
All odds ratios comparing cases with controls were
adjusted for age using the SAS Logistic procedure (10).
RESULTS
History of chickenpox among all subjects and
those sampled for blood and serologic analysis
Table 1 compares the odds ratios for a reported
history of chickenpox among all subjects, as well as
among subjects from whom a blood sample was ob-
tained, those selected for serologic study, and those for
whom adequate blood specimens remained for sero-
logic study. Among subjects from whom blood was
obtained, a significant negative association between
chickenpox history and glioma persisted (table 1). As
TABLE 1. History of chickenpox among glioma cases and controls, San Franctsoo Bay Area Adult
Glioma Study, 1991-1995
All subjects
All subjects from whom blood
was obtained
Subsample selected for
serologic studies^
Subsample with sufficient blood
available for serologic
studies^
Ca
No.wSti
posUve
history
267
138
59
45
No.wtth
negative
history
114
49
49
33
Controls
No.wBh
positive
history
348
141
61
61
No wBh
negative
hfstoiy
66
28
28
28
OR'.t
0.4
0.5
0.5
0.6
95%
a*
0.3-0.6
0.3-0.8
0.3-0.9
0.3-1.1
* OR, odds ratio; Cl, confidence interval,
t Adjusted for individual year of age.
i See text for explanation of sampling strategy. These subsamples were specifically chosen to have similar
odds ratios for a reported history of chickenpox as that found in all subjects from whom blood was obtained.
Am J
Epidemiol
Vol. 145, No. 7, 1997
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596 Wrensch et al.
stated above, the subsamples selected for serologic
analysis were chosen to be representative of the per-
sons from whom blood was obtained and to preserve
the observed negative association between chickenpox
history and glioma.
Serologic results for immunoglobulin G
antibodies to varicella-zoster virus
The odds ratio for the presence of immunoglobulin
G antibodies to varicella-zoster virus for glioma cases
versus controls was 0.6 (table 2). This is the same
magnitude of association as that found for reported
history of chickenpox, despite rather substantial mis-
classification (table 3); the overall sensitivity of a
reported chickenpox history using immunoglobulin G
as the standard was 65 percent (84/129), and the
specificity was 43 percent (13/30). The proportions of
cases and controls without a history of chickenpox
who were antibody-positive were very similar (73
percent and 75 percent, respectively). However, 85
percent of history-positive controls but only 71 percent
of history-positive cases were antibody-positive.
Prior chemotherapy and radiation did not appear to
explain the lower prevalence of immunoglobulin G
antibodies to varicella-zoster virus among glioma
cases versus controls. Twelve percent (2/17) of
antibody-negative and 27 percent (15/56) of antibody-
positive glioma patients reported prior chemo-
therapy, while 82 percent (14/17) of antibody-
negative and 89 percent (50/56) of antibody-positive
patients reported radiation therapy. Two antibody-
negative cases received chemotherapy 6 or 11 days
before the blood drawing. Seven antibody-positive
cases had chemotherapy on the day of blood drawing;
the other eight had chemotherapy 4-81 days before
blood collection. The average number of days between
the last radiation treatment and the blood drawing was
150 for antibody-negative cases and 140 for antibody-
positive cases.
DISCUSSION
Although there was substantial misclassification be-
tween self-reported history of chickenpox and the
presence of immunoglobulin G antibodies to varicella-
zoster virus, the nature of the misclassification was
such that the odds ratio for glioma cases versus con-
trols for history of chickenpox was very similar to the
odds ratios for positive antibodies to varicella-zoster
virus.
This appears to be the first time the inverse
association with varicella-zoster virus antibodies has
been reported; because power was limited, we choose
to interpret the finding cautiously.
However, because the serologic data support the
statistically significant results for reported histories of
chickenpox and shingles (8), it is worth considering
the implications of the finding of a negative associa-
tion between glioma and varicella-zoster virus infec-
tion or antibodies to varicella-zoster virus. One possi-
bility for an effect of this size is confounding;
however, given the general ubiquity of the varicella-
zoster virus, it is difficult to imagine what the con-
founding factors might be. Possible effects of increas-
ing age on loss of antibody were accounted for through
age adjustment with logistic analyses.
Another possibility is that having a brain tumor
depresses serum immunoglobulin levels, such that it
would be more difficult to detect any immunoglobulin
G in cases compared with controls. On the contrary,
one recent study (11) found serum immunoglobulin G
levels to be significantly higher in glioma cases than in
controls. The comparability of that study group to the
present series is unclear; neither the origin of the
control group nor the treatments received by cases
were reported. The data from this current study indi-
cate that prior radiation or chemotherapy treatments
would not be likely explanations for reduced levels of
immunoglobulin G among the glioma cases.
People with glioma may be less likely than controls
to have a history of a wide variety of infections, but
the evidence is scant. In a report by Schlehofer et al.
TABLE 2. Presence of Immunoglobultn G antibodies to varicella-zoster virus among gDoma
controls, San Francisco Bay Area Adult Glioma Study, 1991-1995
and
ImmunoglobuBn Q
antfcocttesto
varicella-rosier
virus
Negative
Positive
Borderline
Total
Ce
Mo.
17
56
5
78
ises
%
21.8
71.8
6.4
100
No
13
73
3
89
Controls
%
14.6
82.0
3.4
100
OR'.t
(95%CI»)
1.0
0.6(0.3-1.3)
* OR, odds ratio; Cl, confidence interval.
fOdds ratios for positive versus negative antibodies to varicella-zoster virus (borderline results were
considered missing data), adjusted for incividuai year of age. If borderline results are considered positive, OR -
0.6, 95% Cl 0.3-1.3; if borderline results are considered negative, OR
•=
0.5, 95% Cl
0.3-1.1.
Am J Epidemiol Vol. 145, No. 7, 1997
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Varicella-Zoster Virus and Adult Brain Cancer 597
TABLE 3. Presence of Immunoglobulin G antibodies to varicella-zoster virus by reported history of chickenpox, San Francisco
Bay Area Adult Qlloma Study, 1991-1995
Immunogtobuln Q
antibodies to
varicela-zoster
vfrus
Negative
Positive
Borderline
Total
NegaUva history ot cNckerpox
Qfloma cases
No.
7
24
2
33
%
21.2
72.7
6.1
100
No.
6
21
1
28
Controls
%
21.4
75.0
3.6
100
Alls»t>jects
No.
13
45
3
61
%
21.3
73.8
4.9
100
Positive history of chictenpox
Qioma cases
No.
10
32
3
45
%
22.2
71.1
6.7
100
No.
7
52
2
61
Controb
%
11.5
85.2
3.3
100
Afl subjects
No.
17
84
5
106
%
16.0
79.3
4.7
100
(12),
adults with newly diagnosed primary brain tu-
mors were less likely than were population-based con-
trols to report colds or infections during the 5 years
prior to interview. The result showed a dose response,
with a lower odds ratio (odds ratio = 0.3, 95 percent
CI 0.1-0.8) for brain tumors appearing among those
reporting three or more colds or infections per year
than among those reporting 1-2 colds or infections per
year (odds ratio = 0.8). The results also were very
similar for men and women. Data on prior infections
were not reported separately for glioma and meningi-
oma. Schlehofer et al. interpreted this finding as indi-
cating that general activation of the immune system
might play a role in influencing these tumors. The
implication seems to be that cancer cells, in general,
might be more readily destroyed with a heightened
immune system. In partial support of this contention,
Abel et al. (13) reported a decreased history of prior
colds and several childhood infections, including
chickenpox, among newly diagnosed cancer patients
(stomach, colorectal, breast, and ovarian carcinoma)
compared with controls. They thoroughly discussed
the previous literature on infections and cancer risk.
Hypotheses have included either that infections de-
crease the chance of cancer development or kill exist-
ing cancer cells; alternatively, infections may be less
likely to arise in individuals who are more susceptible
to cancer or who are developing cancer. Reporting
bias by cases, diminishing the reported severity of
their prior illnesses, was also suggested. However, this
bias could not explain the present serologic findings.
Another, more speculative explanation is that if a virus
or viruses with some cross-reactivity to varicella-
zoster virus influence glioma development, individu-
als with stronger immunity to varicella-zoster virus
might be less susceptible to glioma.
Clearly, the role of viral and other infections in brain
tumor etiology requires further epidemiologic investi-
gation. This is especially important given the ex-
tremely poor prognosis of most brain cancers and the
paucity of available knowledge with which to develop
meaningful preventive strategies. Our results suggest
that self-reported history of chickenpox is an unreli-
able indicator of serologic positivity. In addition to the
need for replication of these results, it would be valu-
able to compare glioma cases and controls for anti-
bodies to herpes simplex virus, cytomegalovirus, and
Epstein-Barr virus. Herpes simplex virus is another
herpesvirus that establishes latency in the nervous
system, while cytomegalovirus and Epstein-Barr virus
are herpesviruses that infect the central nervous sys-
tem without establishing latency.
ACKNOWLEDGMENTS
This work was supported by grants RO1CA52689 and
RO3CA57220 from the National Institutes of Health.
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... To date, seven viruses have been accepted to be tumor-initiating in humans. These include Epstein As first suggested by Wrensch et al. (1997) 10 and later replicated in more extensive analyses within the Glioma International Case-Control Study (GICC) 12 Cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6), but with discordant results 11,[13][14][15] . ...
... To date, seven viruses have been accepted to be tumor-initiating in humans. These include Epstein As first suggested by Wrensch et al. (1997) 10 and later replicated in more extensive analyses within the Glioma International Case-Control Study (GICC) 12 Cytomegalovirus (CMV) and human herpesvirus-6 (HHV-6), but with discordant results 11,[13][14][15] . ...
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Background Multiple studies have implicated infections in glioma susceptibility, but the evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study we leveraged genetic predictors of antibody response to 10 viral antigens to investigate the relationship and glioma risk and survival. Methods Genetic reactivity scores (GRS) for each antigen were derived from genome-wide significant (p<5x10-8) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution using data from 3418 glioma patients and 8156 controls. Results Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were suggestively associated with glioma risk and survival (unadjusted p<0.05). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild type gliomas (Odds ratio ORZEBRA=0.91, p=0.007 / ORMCV=1.11, p=0.005). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR=1.09, p=0.04) and improved survival (Hazard ratio HR=0.86, p=0.01). HLA-DQA1*03:01 was significantly associated with decreased risk of glioma overall (OR=0.85, p=3.96x10-4) after multiple testing adjustment. Conclusion This first systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may also inform applications of antiviral based therapies in the treatment of glioma.
... 16 However, only a limited number of pathogens have been examined as potential risk factors for glioma in human studies. Infections with varicella zoster, the neurotropic virus causing chicken pox, has been consistently inversely associated with glioma risk, 17,18 while cytomegalovirus (CMV) has been demonstrated in some but not all studies to be present in glioma tumors, potentially consistent with an etiologic role. 19,20 Toxoplasma gondii (T gondii) is a common parasite that infects warm blooded animals including humans 21 and to which 20% to 50% of the global population is exposed. ...
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... This observation agrees with a clinical study in which 8 out of 15 patients with highgrade glioma who presented with low-to-no CMV DNA present despite testing positive for CMV-specific IgG [13]. Earlier studies by Wrensch et al. [39,40] described Survival of the patients with GBM based on the CMV-and EBV-specific IFNγ production. Kaplan-Meier curve shows the overall survival of GBM patients with detectable IFNγ response. ...
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Glioma is a highly fatal cancer with prognostically significant molecular subtypes and few known risk factors. Multiple studies have implicated infections in glioma susceptibility, but evidence remains inconsistent. Genetic variants in the human leukocyte antigen (HLA) region modulate host response to infection and have been linked to glioma risk. In this study, we leveraged genetic predictors of antibody response to 12 viral antigens to investigate the relationship with glioma risk and survival. Genetic reactivity scores (GRSs) for each antigen were derived from genome-wide-significant (p < 5 × 10⁻⁸) variants associated with immunoglobulin G antibody response in the UK Biobank cohort. We conducted parallel analyses of glioma risk and survival for each GRS and HLA alleles imputed at two-field resolution by using data from 3,418 glioma-affected individuals subtyped by somatic mutations and 8,156 controls. Genetic reactivity scores to Epstein-Barr virus (EBV) ZEBRA and EBNA antigens and Merkel cell polyomavirus (MCV) VP1 antigen were associated with glioma risk and survival (Bonferroni-corrected p < 0.01). GRSZEBRA and GRSMCV were associated in opposite directions with risk of IDH wild-type gliomas (ORZEBRA = 0.91, p = 0.0099/ORMCV = 1.11, p = 0.0054). GRSEBNA was associated with both increased risk for IDH mutated gliomas (OR = 1.09, p = 0.040) and improved survival (HR = 0.86, p = 0.010). HLA-DQA1∗03:01 was significantly associated with decreased risk of glioma overall (OR = 0.85, p = 3.96 × 10⁻⁴) after multiple testing adjustment. This systematic investigation of the role of genetic determinants of viral antigen reactivity in glioma risk and survival provides insight into complex immunogenomic mechanisms of glioma pathogenesis. These results may inform applications of antiviral-based therapies in glioma treatment.
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Diffuse gliomas are the most common primary malignant brain tumors in adults. Many studies analyzed their epidemiology, such as the incidence and mortality. Moreover, the identification of their risk factors is still controversial and to date we have only a few accepted and confirmed risk factors. In the last few years, many molecular markers have been analyzed and correlated to the prognosis of gliomas. We performed a review aiming to collect and clarify data on epidemiology, risk factors and prognostic factors regarding glioma patients. We performed a comprehensive literature review of research studies focusing on epidemiology of gliomas and their risk factors. At the same time, we collected studies analyzing the most important and validated prognostic factors in glioma patients. Glioblastoma represents the most common primary malignant brain tumor with an incidence rate of 3.23 per 100,000 population. Diffuse astrocytoma and oligodendroglioma tend to peak in young adults with a median age of 46 and 43 years, respectively). Overall, the incidence rate of gliomas is higher in male patients than in females. Rates of overall survival vary widely, ranging from 5 year survival rates of 94.7% for pilocytic astrocytoma to 6.8% for glioblastoma. About 5% of gliomas can be classified as familial and associated with hereditary syndromes, such as the Li-Fraumeni, the Turcot and neurofibromatosis. Ionizing radiation remains the only ascertained environmental risk factor associated with glioma. In addition to the clinical characteristics, such as the age, performance status and the extent of resection, also mutational status of some genes such as IDH, TERT, CDKN2A and the MGMT methylation status can be correlated with the glioma patient survival. Gliomas represent rare tumors and can be defined as a heterogenous group of primitive brain tumors. In recent years, new data emerged regarding the etiology of these tumors as well as the knowledge of new prognostic factors.
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Glioma is an aggressive neoplasm of the brain with poorly understood etiology. A limited number of pathogens have been examined as glioma risk factors, but data from prospective studies with infection status determined before disease are lacking. Herpesviruses comprise a large family of DNA viruses that infect humans and are linked to a range of chronic diseases. We conducted a prospective evaluation of the association between antibody to 6 human herpesviruses and glioma risk in the Janus Serum Bank (Janus) and the Cancer Prevention Study‐II (CPS‐II). In Janus and CPS‐II, the risk for glioma was not related to seroprevalence of herpes simplex virus‐1, varicella zoster virus, or human herpes viruses 6A or 6B. In Janus, seropositivity to either the Epstein Barr virus (EBV) EA[D] or VCAp18 antigen was associated with a lower risk of glioma (ORs: 0.55 [95%CI 0.32‐0.94] and 0.57 [95%CI 0.38‐0.85]). This inverse association was consistent by histologic subtype and was observed for gliomas diagnosed up to two decades following antibody measurement. In Janus, seropositivity to at least one of three examined cytomegalovirus (CMV) antigens (pp150, pp52, pp28) was associated with an increased risk of non‐glioblastoma (OR: 2.08 [95%CI 1.07‐4.03]). This association was limited to tumors diagnosed within 12 years of antibody measurement. In summary, we report evidence of an inverse association between exposure to EBV and glioma. We further report that CMV exposure may be related to a higher likelihood of the non‐glioblastoma subtype. This article is protected by copyright. All rights reserved.
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This article reviews the current epidemiology of central nervous system tumors. Population-level basic epidemiology, nationally and internationally, and current understanding of germline genetic risk are discussed, with a focus on known and well-studied risk factors related to the etiology of central nervous system tumors.
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Glioma is an aggressive primary tumor of the brain with a poorly understood etiology. We studied the association of 4 human polyomaviruses (HPyV)—JC virus (JCV), BK virus (BKV), human polyomavirus 6 (HPyV6), and Merkel cell polyomavirus (MCPyV) with glioma risk within the Cancer Prevention Study II in the US (CPS-II) and the Janus Serum Bank in Norway. Cohort participants subsequently diagnosed with glioma from the CPS-II (n = 37) and Janus Serum Bank (n = 323), a median of 6.9 and 15.4 years after blood collection, respectively, were matched to individual controls on age, sex, and date of blood draw. Serum antibodies to the major viral capsid protein (VP1) were used to establish infection history for each polyomavirus. Odds ratios (ORs) and 95% confidence intervals (CIs) were estimated using conditional logistic regression. In the Janus Serum Bank, MCPyV infection was associated with a higher risk of glioma overall (OR: 1.56; 95% CI 1.10, 2.19). A modest, nonsignificant positive association with MCPyV infection was also observed in CPS-II (OR: 1.29; 95% CI 0.54, 3.08). In both cohorts, glioma risk was not significantly related to infection with JCV, BKV or HPyV6. The present study suggests that MCPyV infection may increase glioma risk.
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Brain and other central nervous system tumors are a significant cause of morbidity and mortality, causing nearly 15,000 deaths per year in the United States alone. Epidemiologic studies have helped elucidate aspects of brain tumor etiology by tracking patterns of tumor incidence and mortality and by identifying potential risk factors for tumor development. With respect to glioma, the most common primary malignant brain tumor, incidence rates are elevated among men and individuals of Caucasian ethnicity. High-dose ionizing radiation has been established as a major risk factor for glioma development, and evidence has accumulated that a history of allergies and atopy is inversely associated with glioma risk. Recognized genetic risk factors for glioma include both rare germline mutations underlying several familial cancer syndromes and 25 single-nucleotide polymorphisms as of the most recent and largest genome-wide association study to date. Here, the current state of knowledge on brain tumor epidemiology and etiology is discussed, with an emphasis on glioma and meningioma in adults. Key challenges and open questions in the field are highlighted.
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The possibility of an association between virus infections during pregnancy and subsequent malignant disease in the child has been investigated using retrospective data from the Oxford Survey of Childhood Cancers. Such an association appears to exist for influenza, chickenpox, and possibly rubella. For influenza and rubella the estimated risk is small; the data do not permit an estimate to be made directly in the case of chickenpox. It is suggested that there may be a specific association between maternal chickenpox and tumours of the nervous system.It is important to emphasize that, even if the relative risk associated with these viruses is fairly large, the number of cases of childhood cancer and leukaemia actually attributable to them is probably very small.
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Immunoglobulin level in the sera of 62 patients with intracranial space occupying lesions was assayed using the radial immunodiffusion method. Serum IgM levels showed a highly significant increase in all types of brain tumour when compared to controls. Serum IgG levels were also increased in benign as well as malignant cases. Serum IgA levels were high only in benign cases. Hence, increased serum Ig levels may be of prognostic value in these cases.
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This is an account of cancer epidemiology. The second edition has been expanded and contains new material on cancer biology, molecular epidemiology, preventive strategies and specific types and sites of cancer.
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Several diseases and medical treatments are discussed as risk factors for the development of brain tumors. A population-based case-control study in the Rhein-Neckar-Odenwald area (containing 1.3 million inhabitants) of Germany was established to investigate this question. A total of 226 patients (cases) with primary brain tumors (International Classification of Diseases, ninth edition, classes 191, 191.1, and 192.0) and 418 control subjects (controls) were interviewed using a standardized questionnaire over a period of 2 years. No association was seen for head injuries, hereditary diseases, family history, and radiographic examination of the head and teeth. However, more cases than controls had had meningitis (relative risk [RR], 2.7; 95% confidence interval [CI], 0.9 to 8.6) or epilepsy (RR, 2.6; 95% CI, 0.6 to 11.7). The RR was decreased for those who had allergic diseases (RR, 0.7; 95% CI, 0.5 to 1.0), diabetes (RR, 0.7; 95% CI, 0.3 to 1.8), and infections and colds (RR, 0.3; 95% CI, 0.1 to 0.8).
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The association between the frequency of manifest infectious diseases and cancer risk was investigated in a case-control study at Heidelberg, FRG. A total of 255 cases with carcinomas of the stomach, colon, rectum, breast, and ovary, as well as 255 population controls and 230 hospital controls were interviewed using a standard questionnaire. Controls were matched to the cases for age, sex, and region of residence at the time of the interview. A history of common colds or gastroenteric influenza prior to the interview was found to be associated with a decreased cancer risk. Thus the odds ratios for "three or more common colds per year (on average)" versus "no common cold within the last 5 years prior to the interview" were 0.18 (95% CI = 0.05-0.69) and 0.23 (95% CI = 0.06-0.89) relative to population controls and hospital controls, respectively. There was no apparent relationship between childhood infections or other diseases reported in the earlier history, and cancer risk. While the findings are supported by previous studies and fit well into the results of other fields of cancer research, a conclusive interpretation and biological explanation cannot yet be given.
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Experimental viral infections are described which cause malformations of the developing nervous system. These include influenza virus infection of chick embryos causing defects in neural tube closure and flexion, parvovirus infections of rodents and cats resulting in a granuloprival cerebellar malformation, and myxovirus infections of rodents inducing stenosis of the aqueduct of Sylvius. In each experimental model the pathogenesis of the malformation is different, but in each the resultant noninflammatory malformation bears resemblances to malformations in man considered to have a genetic basis.
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The possible association between prior infection with the protozoan Toxoplasma gondii and development of brain tumours was investigated as part of two Australian population-based case-control studies of adult brain tumours. One study, based in Adelaide, South Australia, collected blood from 73 subjects with glioma, 53 subjects with meningioma and 348 controls. The other study, based in Melbourne, Victoria, collected blood from 44 subjects with glioma and 67 controls. All tumours had been verified histologically. IgG antibodies to T. gondii were measured using Enzyme Linked Immunosorbent Assay (ELISA) techniques. In both the centre-specific and combined analyses, there was no difference between subjects with glioma and controls in the prevalence of antibody test-positivity (35% test-positive in glioma versus 33% in controls, age-, sex- and centre-adjusted odds ratio (OR) = 1.00, 95% confidence interval (CI): 0.64-1.56). In the Adelaide study, there was a statistically significant increased risk of meningioma associated with antibody test-positivity (47% test-positive in meningioma versus 31% in controls, P = 0.02, adjusted OR = 2.09, 95% CI: 1.14-3.83). Our results do not support the hypothesis that antibody positivity to T. gondii is a risk factor for glioma, but suggest that it might be associated with meningioma.
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We evaluated an enzyme-linked immunoassay (EIA; BioWhittaker) and a latex agglutination (LA; Becton Dickinson) for varicella-zoster virus (VZV) antibody determination, using cell-mediated immunity (CMI) as a "gold standard." VZV EIA had a sensitivity, specificity, positive predictive value, and negative predictive value of 87, 91, 87, and 91%, respectively, compared with CMI. Correlation was excellent except when the varicella index was 0.9 to 1.2. We defined sera with varicella indices of 0.9 to 1.2 as indeterminate. LA had a sensitivity, specificity, positive predictive value, and negative predictive value of 96, 91, 97, and 90%, respectively, compared with EIA. LA reactivity only at a 1:2 dilution did not correlate with CMI, but sera reactive at dilutions of > or = 1:8 indirectly did. We defined indeterminate sera as those reactive at 1:2 and nonreactive at 1:8. EIA and LA were equivalent for determining VZV immune status, and both methods required modified criteria of interpretation to increase their specificity.