Article

Circulating 25-Hydroxyvitamin D and Risk of Esophageal and Gastric Cancer Cohort Consortium Vitamin D Pooling Project of Rarer Cancers

National Cancer Institute, Bethesda, Maryland 20852, USA.
American journal of epidemiology (Impact Factor: 5.23). 07/2010; 172(1):94-106. DOI: 10.1093/aje/kwq121
Source: PubMed

ABSTRACT

Upper gastrointestinal (GI) cancers of the stomach and esophagus have high incidence and mortality worldwide, but they are
uncommon in Western countries. Little information exists on the association between vitamin D and risk of upper GI cancers.
This study examined the association between circulating 25-hydroxyvitamin D (25(OH)D) and upper GI cancer risk in the Cohort
Consortium Vitamin D Pooling Project of Rarer Cancers. Concentrations of 25(OH)D were measured from 1,065 upper GI cancer
cases and 1,066 age-, sex-, race-, and season-of blood draw–matched controls from 8 prospective cohort studies. In multivariate-adjusted
models, circulating 25(OH)D concentration was not significantly associated with upper GI cancer risk. Subgroup analysis by
race showed that among Asians, but not Caucasians, lower concentrations of 25(OH)D (<25 nmol/L) were associated with a statistically
significant decreased risk of upper GI cancer (reference: 50–<75 nmol/L) (odds ratio = 0.53, 95% confidence interval: 0.31,
0.91; P trend = 0.003). Never smokers with concentrations of <25 nmol/L showed a lower risk of upper GI cancers (odds ratio = 0.55,
95% confidence interval: 0.31, 0.96). Subgroup analyses by alcohol consumption produced opposing trends. Results do not support
the hypothesis that interventions aimed at increasing vitamin D status would lead to a lower risk of these highly fatal cancers.

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American Journal of Epidemiology
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Vol. 172, No. 1
DOI: 10.1093/aje/kwq121
Advance Access publication:
June 18, 2010
Original Contribution
Circulating 25-Hydroxyvitamin D and Risk of Esophageal and Gastric Cancer
Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Christian C. Abnet*, Yu Chen, Wong-Ho Chow, Yu-Tang Gao, Kathy J. Helzlsouer, Loı
¨
cLe
Marchand, Marjorie L. McCullough, James M. Shikany, Jarmo Virtamo, Stephanie J. Weinstein,
Yong-Bing Xiang, Kai Yu, Wei Zheng, Demetrius Albanes, Alan A. Arslan, David S. Campbell, Peter
T. Campbell, Richard B. Hayes, Ronald L. Horst, Laurence N. Kolonel, Abrah am M. Y. Nomura,
Mark P. Purdue, Kirk Snyder, and Xiao-Ou Shu
* Correspondence to Dr. Christian C. Abnet, Division of Cancer Epidemiology and Genetics, National Cancer Institute, Executive
Plaza South, Suite 320, 6120 Executive Boulevard, Bethesda, MD 20852 (e-mail: christian.abnet@nih.gov).
Initially submitted October 23, 2009; accepted for publication April 12, 2010.
Upper gastrointestinal (GI) cancers of the stomach and esophagus have high incidence and mortality
worldwide, but they are uncommon in Western countries. Little information exists on the association
between vitam in D and risk of upper GI cancers. This study examined the association b etween circulating
25-hydroxyvitamin D (25(OH)D) and upp er GI cancer risk in the Cohort Consortium Vitamin D Pooling Project
of Rarer Cancers. Concentrati ons of 25(OH)D were measured from 1,065 upper GI cancer cases and 1,066
age-, sex-, race-, and season-of blood draw–matched controls from 8 prospective cohort studies. In multivariate-
adjusted models, circulating 25(OH)D concentration was not significantly associated with upper GI cancer
risk. Subgroup analysis by race showed that among Asians, but not Caucasians, lower concentrations of
25(OH)D (<25 nmol/L) were associated with a statistically significant decreased risk of upper GI cancer (reference:
50–<75 nmol/L) (odds ratio ¼ 0.53, 95% confidence interval: 0.31, 0.91; P trend ¼ 0.003). Never smokers with
concentrations of <25 nmol/L showed a lower risk of upper GI cancers (odds ratio ¼ 0.55, 95% confidence interval:
0.31, 0.96). Subgroup analyses by alcohol consumption produced opposing trends. Results do not support the
hypothesis that interventions aimed at increasing vitamin D status would lead to a lower risk of these highly fatal
cancers.
case-control studies; cohort studies; esophageal neoplasms; prospective studies; stomach neoplasms; vitamin D
Abbreviations: CI, confidence interval ; ESCC, esophag eal squamous cell carcinoma; GI, gastrointestinal; 25(OH)D,
25-hydroxyvitamin D; OR, odds ratio; VDPP, C ohort Consortium Vitamin D Pooling Project of Rarer Cancers.
Upper gastrointestinal (GI) cancers of the stomach and
esophagus have high incidence and mortality worldwide,
but they are uncommon in Western countries. Few epidemi-
ologic studies have examined the association between vita-
min D and risk of upper GI cancers of the esophagus or
stomach. The major source of vitamin D for most people
is generation through the skin during exposure to ultraviolet
B radiation, whereas diet contributes little, especially
among those who do not consume vitamin D–fortified prod-
ucts or oily fish. Vitamin D can be antiproliferative in cells
of the skin, colon, breast, and prostate, among others, and
may also limit proinflammatory stresses (1).
Ecologic studies in the United States (2) and elsewhere
(3) have suggested an inverse correlation between estimated
ultraviolet exposure and upper GI cancer rates. However,
ecologic studies are principally hypothesis generating and
provide the weakest evidence because of the lack of indi-
vidual data on exposure and disease. In contrast, another
study reported a higher risk of second primary cancers in
internal organs, including the esophagus and stomach, after
94 Am J Epidemiol 2010;172:94–106
Page 1
a first diagnosis of nonmelanoma skin cancer, but these
associations seemed limited to countries with lower ultravi-
olet exposure and did not show specificity by cancer site (4).
Another study built an index from factors that predict higher
serum 25-hydroxyvitamin D (25(OH)D) concentrations
(dietary and supplemental vitamin D, skin pigmentation,
adiposity, geographic region of residence, and leisure-
time physical activity) and found that index values that
predict higher vitamin D status were associated with a sta-
tistically significant lower risk of esophageal cancer and a
non-statistically-significant lower risk of stomach cancer
(5). This index, however, included exposures that may affect
cancer risk independent from their association with vitamin
D status.
Observational studies with individual exposure metrics
have produced mixed results. Case-control studies of upper
GI cancer examining dietary and/or supplemental vitamin D
have reported that higher vitamin D intake is associated with
lower risk of esophageal squamous cell carcinoma (ESCC)
(6), is associated with increased risk of gastric cancer (7), or
had no association with gastric cancer (8). A prospective
cohort study from China showed that higher serum
25(OH)D concentrations were associated with higher risk
of ESCC but had no association with risk of gastric cancer
(9). Another study in the same population showed that
higher 25(OH)D concentrations were associated with
higher risk of squamous dysplasia, the precursor lesion for
ESCC (10).
The current study examined the association between cir-
culating 25(OH)D concentration and upper GI cancer risk in
a nested case-control study combining gastric and esopha-
geal cancer cases and matched controls from 8 prospective
cohort studies from China, Finland, and the United States as
part of the Cohort Consortium Vitamin D Pooling Project of
Rarer Cancers (VDPP). To maximize power, total upper GI
cancer was the primary outcome.
MATERIALS AND METHODS
Study design and population
A detailed description of the cohorts and methods used in
the VDPP is provided in the paper by Gallicchio et al. (11).
The upper GI cancer analyses included esophageal and gas-
tric cancer cases from the following 8 cohorts: the Alpha-
Tocopherol, Beta-Carotene Cancer Prevention Study
(ATBC); CLUE; the Cancer Prevention Study II (CPS-II)
Nutrition Cohort; the Multiethnic Cohort Study (MEC); the
New York University Women’s Health Study (NYU-WHS);
the Prostate, Lung, Colorectal and Ovarian Cancer Screening
Trial (PLCO); the Shanghai Men’s Health Study (SMHS);
and the Shanghai Women’s Health Study (SWHS). The num-
ber of subjects and other information for each cohort are
given in Table 1.
Tumor location and histologic coding methods varied by
study and included the International Classification of Dis-
eases, Ninth Revision; Internat ional Statistical Classifica-
tion of Diseases and Related Health Problems, Tenth
Revision; and country-specific methods. For the Interna-
tional Statistical Classification of Diseases and Related
Health Problems, Tenth Revision, cases with epithelial tu-
mors located in the esophagus (codes C152–159), gastric
cardia (code C160), body of the stomach (codes C161–
166), and overlapping and not otherwise specified locations
(codes C168–169) were included. Cases were matched to
controls who were alive and cancer free at the time of case
diagnosis. Controls were matched within cohorts to cases on
age at blood collection (61 year), sex, race/ethnicity (Asian/
black/Caucasian/other), and calendar day of blood draw
(630 days).
Of the 1,077 cases initially identified, 12 were excluded
because of a diagnostic date before blood draw (n ¼ 2),
ineligible histology (n ¼ 5), failed 25(OH)D assay (n ¼ 1),
Table 1. Characteristics of Participants, by Cohort, in the Investigation of Upper
Gastrointestinal Cancer Within the Cohort Consortium Vitamin D Pooling Project of Rarer
Cancers
Cohort
No. of
Cases
No. of
Controls
Median Years From
Blood Collection to
Cancer Diagnosis
(Interquartile Range)
Median Circulating 25(OH)D, nmol/L
(Interquartile Range)
Cases Controls
ATBC 416 417 8.7 (5.1–13.1) 30.8 (20.0–43.3) 31.5 (19.6–46.8)
CLUE 88 88 10.6 (5.5–16.5) 59.3 (45.4–81.7) 61.5 (45.4–80.9)
CPS-II 40 40 1.9 (1.4–3.8) 58.4 (46.6–71.4) 58.2 (46.6–69.0)
MEC 82 82 2.2 (1.1–3.4) 47.8 (33.6–66.3) 47.0 (34.5–64.8)
NYU-WHS 27 27 11.8 (7.0–16.2) 41.0 (26.3–51.3) 38.6 (28.7–51.3)
PLCO 99 99 5.5 (2.9–6.9) 56.7 (42.4–68.3) 55.8 (41.1–68.5)
SMHS 131 131 1.7 (0.9–2.9) 41.8 (29.6–57.5) 39.0 (29.5–53.6)
SWHS 182 182 4.6 (2.5–6.6) 36.6 (24.3–47.5) 35.1 (24.7–45.7)
Total 1,065 1,066 5.3 (2.4–9.1) 39.4 (26.3–56.1) 39.3 (26.1–56.3)
Abbreviations: ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CPS-II,
Cancer Prevention Study II Nutrition Cohort; MEC, Multiethnic Cohort Study; NYU-WHS, New
York University Women’s Health Study; 25(OH)D, 25-hydroxyvitamin D; PLCO, Prostate, Lung,
Colorectal and Ovarian Cancer Screening Trial; SMHS, Shanghai Men’s Health Study; SWHS,
Shanghai Women’s Health Study.
Circulating 25(OH)D and Upper GI Cancer Risk 95
Am J Epidemiol 2010;172:94–106
Page 2
and lack of an adequate control (n ¼ 4), leaving 1,065 cases
and 1,066 controls for analysis. Case and control numbers
are uneven because 1 subject was simultaneously diag-
nosed with esophageal and stomach cancer and was
matched to 2 different controls. In disease-stratified analy-
ses, this subject was included for both cancer sites but only
once in the total upper GI cancer analyses. Any upper
GI cancer was the main outcome to maximize power, but
subgroup analyses were conducted based on organ and his-
tology, where possible, including all esophageal cancer
(n ¼ 265), ESCC (n ¼ 142), esophageal adenocarcinoma
(n ¼ 104), all gastric cancers (n ¼ 784), gastric cardia
adenocarcinoma (n ¼ 135), and gastric noncardia adeno-
carcinoma (n ¼ 428).
Measurement of circulating 25(OH)D
Circulating (serum or plasma) 25(OH)D concentrations
were assayed by using a direct, competitive chemilumines-
cence immunoassay using the DiaSorin LIAISON 25 OH
Vitamin D TOTAL Assay (11, 12). Coefficients of variation
for duplicate serum/plasma aliquots included in all laboratory
sample batches were calculated by using the 2 masked stan-
dards provided by the National Institute of Standards and
Technology (NIST): level 1 (~60 nmol/L) and level 2
(~35 nmol/L). Interbatch and intrabatch coefficients of vari-
ation for level 1 samples were 12.7% and 9.3%, respectively;
interbatch and intrabatch coefficients of variation for level 2
samples were 13.6% and 11.0%, respectively. For all primary
analyses, a priori categories were used based on clinically
defined cutpoints: <25, 25–<37.5, 37.5–<50, 50–<75,
75–<100, and 100 nmol/L. The category 50–<75 nmol/L
was chosen as the reference because it encompasses the mean
for subjects in the National Health and Nutrition Examination
Survey (13). For some subgroup analyses, alternative con-
structs were used, including considering the <25 nmol/L
category as the referent group (to aid interpretability) and
using log-transformed continuous 25(OH)D (to potentially
maximize power and simplify presentation).
Statistical analyses
All statistical analyses were carried out at Information
Management Services, Inc. (Silver Spring, Maryland) by
Table 2. Selected Characteristics of Cases and Controls in the Investigation of Upper Gastrointestinal Cancer
Within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Characteristic
Cases (N 5 1,065) Controls (N 5 1,066)
P Value
a
No. %
Median
(Interquartile
Range)
No. %
Median
(Interquartile
Range)
Age at blood draw, years 61 (55–67) 61 (55–66) Matched
Sex
Female 290 27 290 27 Matched
Male 775 73 776 73
Race/ethnic group
Caucasian 647 61 649 61 Matched
Black 30 3 30 3
Asian 350 33 349 33
Other 35 3 36 3
Missing 3 <12<1
Cigarette smoking
Never 305 29 344 32 0.0001
Quit >15 years ago 85 8 107 10
Quit 10–15 years ago 62 6 40 4
Quit 1–<10 years ago 39 4 28 3
Current, <20 cigarettes/
day
214 20 250 23
Current, 20 cigarettes/
day
352 33 291 27
Missing 8 <16<1
Alcohol intake, g/day
None 406 38 426 40 0.13
>0–14 284 27 316 30
>14–28 120 11 120 11
>28 153 14 122 11
Missing 102 10 82 8
Table continues
96 Abnet et al.
Am J Epidemiol 2010;172:94–106
Page 3
using SAS software, versions 9.1.3 and 9.2 (SAS Institute,
Inc., Cary, North Carolina), and meta analyses were con-
ducted by using the R function MiMa (14). Reported P
values were derived from 2-sided tests, and those <0.05
were considered statistically significant.
Conditional logistic regression models were used for the
primary analyses of the association between circulating
25(OH)D and upper GI cancer risk, whereas unconditional
models were used for stratified models. Estimated odds ra-
tios and 95% confidence intervals were calculated by using
the 6 clinically defined categories in models without further
adjustment and in multivariate-adjusted models. Trend tests
of the overall association were conducted by using a 1
degree-of-freedom test with subjects assigned a value of
1–6 based on their 25(OH)D category. Conditional and
unconditional models (data not shown) produced similar
results. Models using cohort- and season-specific quartiles
produced results similar to those using the clinically defined
cutpoints (data not shown).
Potential confounding variables assessed included ciga-
rette smoking, alcohol drinking, educational attainment (as
a proxy for socioeconomic status), body mass index, and
history of gastric surgery where available. Bivariate analy-
ses to test for independent associations between potentially
confounding variables and both case status (conditional lo-
gistic regression) and circulating 25(OH)D concentrations
among controls (linear regression) based on the Wald test
were conducted. Variables with an independent association
with both case status and circulating 25(OH)D concentra-
tion (P < 0.10), as well as those with known associations
with cancer risk from previous studies, were retained; then,
a parsimonious final model was built with a forward selec-
tion and backward elimination procedure, looking for
changes in the 25(OH)D betas of 6 10%. Body mass index
was excluded as a confounder and therefore the multivariate
models included cigarette smoking, alcohol drinking, edu-
cation, and history of gastric surgery as categorized in
Table 2. For variables for which data were missing,
Table 2. Continued
Characteristic
Cases (N 5 1,065) Controls (N 5 1,066)
P Value
a
No. %
Median
(Interquartile
Range)
No. %
Median
(Interquartile
Range)
Education
Less than high school 440 41 384 36 0.0062
Completed high school 157 15 164 15
Vocational school 211 10 202 19
Some college 160 15 186 18
College graduate 47 4 71 7
Graduate studies 40 4 51 5
Missing 10 1 8 1
Body mass index, kg/m
2
25.3 (22.9–28.2) 25.3 (23.1–28.1) 0.51
History of gastric surgery
No 620 58 758 71 0.0003
Yes 41 4 16 2
Missing 404 38 292 27
Season of blood draw
Winter 560 53 556 52 0.55
Summer 505 47 510 48
Serum 25(OH)D
concentration,
nmol/L
39.4 (26.3–56.1) 39.1 (25.8–56.7) 0.90
Serum 25(OH)D
concentration
category, nmol/L
<25 241 22.7 252 23.6 0.97
25–<37.5 248 23.2 239 22.4
37.5–<50 224 21.0 223 20.9
50–<75 249 23.4 252 23.6
75–<100 83 7.8 77 7.2
100 20 1.9 23 2.2
Abbreviation: 25(OH)D, 25-hydroxyvitamin D.
a
Wald test from conditional logistic regression, excluding subjects with missing data.
Circulating 25(OH)D and Upper GI Cancer Risk 97
Am J Epidemiol 2010;172:94–106
Page 4
including history of gastric surgery (data missing for 38% of
cases and 27% of controls), ethnicity, smoking, alcohol
drinking, and education (missing for 1% of subjects), a cat-
egorical variable to account for missingness was included.
Unconditional models included both the matching and ad-
ditional adjustment variables.
Stratified analyses were conducted by season (summer
(June–November)/winter (December–May)), sex, organ, or-
gan and histology, smoking (never/ever), alcohol drinking (4
categories), and length of follow-up (<2 years, 2 years).
Models stratified on alcohol drinking did not include some
adjusting variables because of small cell counts. We found
no differences by follow-up time (data not shown). Stratified
analysis by age, body mass index, physical activity, and
follow-up time were conducted by using long-transformed
continuous concentrations. Seasonally adjusted 25(OH)D
concentrations were created by using the residuals after re-
gression against week of blood draw using the local poly-
nomial regression (loess) method. These results were
similar to the non-seasonally-adjusted results and are not
shown in this paper.
In addition to the pooled analysis described above,
a meta-analysis approach was also used (14). For each
cohort separately, with 50–<75 nmol/L as the referent
category, odds ratios and 95% confidence intervals for
subjects in the bottom (<25 nmol/L) category and for the
top 2 categories combined (75 nmol/L) were estimated.
Pooled estimates of effect using inverse-variance-weighted
random-effects models were calculated and statistical
heterogeneity assessed by Q and I
2
statistics.
RESULTS
Table 1 presents the number of cases and controls from
each cohort, the median time from blood draw to case di-
agnosis, and the median (interquartile range) circulating
25(OH)D concentration by cohort. Median follow-up time
ranged from 1.7 years in the Shanghai Men’s Health Study
to 11.8 years in the New York University Women’s Health
Study. The Alpha-Tocopherol, Beta-Carotene Cancer Pre-
vention Study had the lowest median 25(OH)D concentra-
tion at 31.5 nmol/L among controls, whereas CLUE had the
highest at 61.5 nmol/L. Median concentrations by cohort
varied based on the sex ratios, ethnic makeup, seasons of
blood collection, and other factors. The predictors of
25(OH)D concentration in the VDPP cohorts were evaluated
separately (15).
Table 2 shows subject characteristics by case status. Com-
pared with controls, upper GI cancer cases reported signif-
icantly more cigarette smoking and less education, and they
were more likely to report a history of gastric surgery. Cases
and controls did not differ in body mass index and were
comparable regarding matching factors.
Median circulating 25(OH)D concentration did not differ
significantly (P ¼ 0.90) between upper GI cancer cases and
controls—39.4 nmol/L (interquartile range: 26.3–56.1) and
39.1 nmol/L (interquartile range: 25.8–56.7), respectively
(Table 2). Furthermore, the distribution of cases and con-
trols did not differ across the 6 categories of 25(OH)D
(P ¼ 0.97).
Table 3 presents the results of primary analyses of the
association between circulating 25(OH)D concentration
and risk of upper GI cancer overall, by season and by sex.
Multivariate adjustment for potentially confounding factors
had little impact on the estimates. In the overall analysis and
in all subgroupings presented here, no association between
25(OH)D concentration and risk of upper GI cancer was
observed. No stratum showed statistically significant asso-
ciations for individual categories or trend tests. Further sub-
dividing into 4 strata according to sex and season also
showed no significant associations (data not shown).
Subgroup analyses by organ site and histology are shown
in Table 4. No associations were observed for total esopha-
geal cancer or when subdivided into the 2 histologic types
ESCC and esophageal adenocarcinoma. Total gastric cancer
showed no association, but when divided into the 2 primary
gastric subsites, cardia and noncardia stomach, an increased
risk of gastric noncardia cancer with higher circulating
25(OH)D concentration was observed. Compared with the
reference group (50–<75 nmol/L), those in the higher cat-
egory (75–<100 nmol/L) were at statistically significantly
higher risk (odds ratio (OR) ¼ 2.00, 95% confidence inter-
val (CI): 1.03, 3.91. The test for trend across categories was
P ¼ 0.083.
Among never smokers, those in the lowest category of
25(OH)D concentrations were at lower risk of upper GI
cancer compared with the reference group (OR ¼ 0.55,
95% CI: 0.31, 0.96), with a statistically significant test for
trend (P ¼ 0.004). No statistically significant associations
were observed among ever smokers (Table 4).
In models stratified on alcohol drinking, some differences
were found (Table 4). Subjects consuming more than 14 g
of alcohol a day showed higher risk of upper GI cancer at
lower vitamin D concentrations, whereas an opposite trend
appeared to be present among those who did not drink
alcohol.
Associations varied by race (Table 5), but sufficient num-
bers to examine models separately were available for only
Asians and Caucasians. Among Asians, a statistically sig-
nificant decreased risk of upper GI cancer was observed
with lower concentrations, with a significant trend across
categories of 25(OH)D concentration (P ¼ 0.003). For ex-
ample, subjects in the lowest category (<25 nmol/L) had
a 47% (95% CI: 9, 69) lower risk of upper GI cancer than
those in the referent group (50–<75 nmol/L). To simplify
interpretation, models were also fit by using the lowest cat-
egory as the referent. The odds ratio estimates for increas-
ing 25(OH)D categories were 1.0 (reference), 0.94 (95% CI:
0.60, 1.48), 0.96 (95% CI: 0.59, 1.56), 1.88 (95% CI: 1.10,
3.22), 3.56 (95% CI: 1.39, 9.14), and 1.85 (95% CI: 0.44,
7.75). Although sample sizes became sparse, further strat-
ification by season or by sex found significant trend tests in
all subgroups of Asians except women alone. Among Cau-
casians, no statistically significant associations were ob-
served between circulating 25(OH)D and risk of upper GI
cancer overall or in groups defined by sex or season. Strat-
ified analyses among the overall population by age, body
mass index, physical activity, and follow-up time showed
no evidence that the associations differed by these strata
(Table 6).
98 Abnet et al.
Am J Epidemiol 2010;172:94–106
Page 5
Table 3. Odds Ratios and 95% Confidence Intervals for the Association Between Circulating 25(OH)D and Risk of Upper Gastrointestinal Cancer Overall and by Season or Sex Within the
Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Circulating 25(OH)D, nmol/L
P
trend
<25 25–<37.5 37.5–<50 50–<75
a
75–<100 100
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
95%
CI
All subjects
b
241 252 248 239 224 223 249 252 83 77 20 23
Crude 0.96 0.72, 1.28 1.04 0.80, 1.37 1.02 0.79, 1.33 1.0 1.09 0.76, 1.57 0.88 0.45, 1.70 0.79
Multivariate
adjusted
0.90 0.65, 1.24 1.03 0.76, 1.39 0.92 0.69, 1.23 1.0 1.17 0.79, 1.75 0.81 0.39, 1.69 0.54
All subjects,
winter
c
183 202 161 136 105 110 83 80 24 25 4 3
Crude 0.89 0.60, 1.32 1.16 0.78, 1.74 0.93 0.62, 1.42 1.0 0.96 0.50, 1.84 1.20 0.24, 5.94 0.71
Multivariate
adjusted
0.87 0.57, 1.31 1.13 0.74, 1.72 0.89 0.58, 1.38 1.0 0.82 0.41, 1.65 0.97 0.17, 5.43 0.81
All subjects,
summer
c
58 50 87 103 119 113 166 172 59 52 16 20
Crude 1.18 0.75, 1.87 0.86 0.60, 1.25 1.07 0.76, 1.51 1.0 1.17 0.76, 1.81 0.83 0.41, 1.69 1.00
Multivariate
adjusted
0.90 0.55, 1.46 0.79 0.53, 1.17 0.98 0.68, 1.40 1.0 1.30 0.82, 2.06 0.83 0.40, 1.74 0.23
Men
b
177 190 176 152 149 155 190 193 63 65 20 21
Crude 0.95 0.68, 1.33 1.19 0.86, 1.63 0.99 0.72, 1.34 1.0 0.97 0.64, 1.47 0.95 0.48, 1.89 0.85
Multivariate
adjusted
0.89 0.61, 1.31 1.23 0.85, 1.76 0.87 0.62, 1.24 1.0 1.03 0.65, 1.64 0.88 0.41, 1.89 0.97
Women
b
64 62 72 87 75 68 59 59 20 12 0 2
Crude 0.98 0.55, 1.73 0.79 0.46, 1.34 1.10 0.66, 1.83 1.0 1.83 0.81, 4.14 0.39
Multivariate
adjusted
0.88 0.47, 1.65 0.78 0.44, 1.38 0.96 0.56, 1.67 1.0 1.79 0.74, 4.33 0.34
Abbreviations: CI, confidence interval; 25(OH)D, 25-hydroxyvitamin D; OR, odds ratio.
a
Reference category.
b
Conditional logistic regression models were matched on cohort, race, sex, and date of blood draw without or with further adjustment for alcohol drinking, smoking, education, and history of gastric surgery.
c
Unconditional logistic regression models were adjusted for the matching factors cohort, race, sex, and date of blood draw without or with further adjustment for alcohol drinking, smoking, education, and history of gastric surgery.
Circulating 25(OH)D and Upper GI Cancer Risk 99
Am J Epidemiol 2010;172:94–106
Page 6
Table 4. Odds Ratios and 95% Confidence Intervals
a
for the Association Between Circulating 25(OH)D and Risk of Upper Gastrointestinal Cancer by Organ, Organ Subsite, Histology, and
Smoking Status Within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Circulating 25(OH)D, nmol/L
P
trend
<25 25–<37.5 37.5–<50 50–<75
b
75–<100 100
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
95%
CI
Esophageal, all 54 44 42 51 56 53 76 79 26 28 11 9
Multivariate
adjusted
1.07 0.55, 2.10 0.70 0.38, 1.30 1.04 0.60, 1.80 1.0 0.98 0.48, 1.98 1.06 0.37, 3.05 0.80
Esophageal,
ESCC
44 32 24 37 33 29 32 33 7 8 2 3
Multivariate
adjusted
1.38 0.53, 3.57 0.49 0.20, 1.22 1.16 0.50, 2.66 1.0 0.96 0.23, 3.92 0.68 0.076, 6.02 0.77
Esophageal, EADC 8 10 15 11 19 20 36 38 17 18 9 6
Multivariate
adjusted
0.61 0.47, 3.96 1.36 0.47, 3.96 0.95 0.39, 2.28 1.0 1.10 0.43, 2.83 1.17 0.30, 4.45 0.70
Gastric, all 183 202 201 187 164 167 171 165 56 49 9 14
Multivariate
adjusted
0.77 0.55, 1.08 0.99 0.71, 1.36 0.88 0.64, 1.22 1.0 1.11 0.70, 1.77 0.65 0.26, 1.62 0.25
Gastric, cardia 34 40 29 33 29 23 32 25 9 9 2 5
Multivariate
adjusted
0.64 0.26, 1.62 0.70 0.29, 1.71 1.12 0.46, 2.71 1.0 0.65 0.18, 2.32 0.12 0.011, 1.25 0.88
Gastric, noncardia 103 115 115 116 99 96 86 87 35 19 1 6
Multivariate
adjusted
0.74 0.47, 1.17 0.87 0.56, 1.35 0.91 0.59, 1.41 1.0 2.00 1.03, 3.91 0.10 0.01, 0.99 0.083
Never smoker
c
51 58 65 89 69 88 86 79 27 25 7 5
Multivariate
adjusted
0.55 0.31, 0.96 0.47 0.28, 0.78 0.56 0.35, 0.90 1.0 1.24 0.63, 2.44 1.47 0.41, 5.30 0.004
Ever smoker
c
189 194 183 147 151 134 162 171 54 52 13 18
Multivariate
adjusted
1.02 0.72, 1.45 1.38 0.98, 1.95 1.20 0.85, 1.69 1.0 1.07 0.67, 1.69 0.68 0.30, 1.49 0.49
Nondrinker
d
93 107 98 117 85 98 98 82 25 16 5 5
Multivariate
adjusted
0.75 0.48, 1.16 0.70 0.46, 1.07 0.72 0.47, 1.09 1.0 1.32 0.66, 2.66 0.88 0.24, 3.16 0.081
Drinks >0–14 g/day
of alcohol
c
66 75 57 65 55 59 68 78 33 30 5 8
Multivariate
adjusted
0.94 0.57, 1.53 0.95 0.57, 1.57 1.02 0.62, 1.68 1.0 1.19 0.65, 2.17 0.72 0.22, 2.34 0.64
Drinks >14 g/day
of alcohol
d
65 57 76 45 60 51 53 64 14 14 5 8
Multivariate
adjusted
1.42 0.83, 2.45 2.06 1.20, 3.54 1.39 0.81, 2.38 1.0 0.96 0.43, 2.14 0.69 0.21, 2.27 0.034
Missing data for
alcohol
drinking
d
17 13 17 12 23 14 29 27 10 14 5 2
Multivariate
adjusted
1.30 0.48, 3.56 1.36 0.49, 3.79 1.54 0.64, 3.70 1.0 0.65 0.24, 1.74 2.37 0.42, 13.37 0.55
Abbreviations: CI, confidence interval; EADC, esophageal adenocarcinoma; ESCC, esophageal squamous cell carcinoma; 25(OH)D, 25-hydroxyvitamin D; OR, odds ratio.
a
Unconditional logistic regression models were adjusted for the matching factors cohort, race, sex, and date of blood draw, with further adjustment for alcohol drinking, smoking, education, and history of gastric surgery. The adjustments for
models stratified on alcohol drinking are given in footnote c.
b
Reference category.
c
The test for interaction with smoking was statistically significant, P ¼ 0.015.
d
Unconditional logistic regression models were adjusted for the matching factors race, sex, and date of blood draw, without further adjustment. The test for interaction with drinking was statistically significant, P ¼ 0.0025.
100 Abnet et al.
Am J Epidemiol 2010;172:94–106
Page 7
Table 5. Odds Ratios and 95% Confidence Intervals
a
for the Association Between Circulating 25(OH)D and Risk of Upper Gastrointestinal Cancer by Ethnic Group, by Season and Sex
Within Ethnic Group, Within the Cohort Consortium Vitamin D Pooling Project of Rarer Cancers
Circulating 25(OH)D, nmol/L
P
trend
<25 25–<37.5 37.5–<50 50–<75
b
75–<100 100
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
No.
of
Cases
No.
of
Controls
OR
95%
CI
No.
of
Cases
No.
of
Controls
OR
95%
CI
Asians, all 67 71 92 111 73 88 88 63 24 11 6 5
Multivariate
adjusted
0.53 0.31, 0.91 0.50 0.31, 0.80 0.51 0.32, 0.82 1.0 1.89 0.78, 4.60 0.99 0.25, 3.91 0.003
Asians, winter 52 55 60 63 31 37 25 12 7 5 1 0
Multivariate
adjusted
0.29 0.11, 0.73 0.29 0.12, 0.72 0.27 0.10, 0.69 1.0 0.76 0.13, 4.30 0.049
Asians, summer 15 16 32 48 42 51 63 51 17 6 5 5
Multivariate
adjusted
0.79 0.34, 1.83 0.57 0.31, 1.05 0.67 0.37, 1.21 1.0 3.24 1.03, 10.17 1.06 0.23, 4.91 0.027
Asians, men 19 24 41 45 26 42 51 37 18 9 6 4
Multivariate
adjusted
0.46 0.20, 1.08 0.57 0.29, 1.12 0.38 0.19, 0.78 1.0 2.05 0.70, 6.01 1.28 0.28, 5.91 0.014
Asians, women 48 47 51 66 47 46 37 26 6 2 0 1
Multivariate
adjusted
0.65 0.31, 1.34 0.51 0.26, 1.01 0.68 0.34, 1.33 1.0 2.01 0.35, 11.48 0.16
Caucasians, all 155 167 140 115 134 115 150 172 54 62 14 18
Multivariate
adjusted
0.98 0.67, 1.44 1.43 0.98, 2.08 1.28 0.89, 1.84 1.0 1.07 0.68, 1.69 0.81 0.37, 1.79 0.69
Caucasians,
winter
119 140 93 67 71 65 51 58 16 16 3 3
Multivariate
adjusted
0.98 0.58, 1.65 1.73 1.00, 2.97 1.25 0.72, 2.17 1.0 1.00 0.41, 2.40 0.77 0.11, 5.28 0.98
Caucasians,
summer
36 27 47 48 63 50 99 114 38 46 11 15
Multivariate
adjusted
1.06 0.54, 2.10 1.09 0.63, 1.90 1.37 0.83, 2.27 1.0 1.07 0.62, 1.85 0.78 0.32, 1.91 0.57
Caucasians,
men
149 159 127 102 114 101 132 146 42 54 14 17
Multivariate
adjusted
0.94 0.63, 1.40 1.40 0.93, 2.10 1.20 0.81, 1.77 1.0 0.91 0.55, 1.51 0.85 0.37, 1.90 0.73
Caucasians,
women
6 8 13 13 20 14 18 26 12 8 0 1
Multivariate
adjusted
0.80 0.17, 3.71 1.71 0.50, 5.92 1.42 0.46, 4.38 1.0 2.95 0.76, 11.46 0.73
Abbreviations: CI, confidence interval; 25(OH)D, 25-hydroxyvitamin D; OR, odds ratio.
a
Unconditional logistic regression models were adjusted for the matching factors cohort, race, sex, and date of blood draw, with further adjustment for alcohol drinking, smoking, education, and history of gastric surgery, as appropriate within
strata. The test for interaction with ethnicity was statistically significant, P ¼ 0.0021.
b
Reference category.
Circulating 25(OH)D and Upper GI Cancer Risk 101
Am J Epidemiol 2010;172:94–106
Page 8
Models for each of the 4 specific cancer outcomes that
were simultaneously stratified on ethnicity, smoking, or
alcohol drinking had small numbers and produced most risk
estimates with wide confidence intervals (data not shown).
These results were similar to those presented in that low
vitamin D concentrations were associated with lower risk
of noncardia gastric cancer in Asians and lower risk of
esophageal adenocarcinoma in whites. In contrast, risk of
ESCC was nonsignificantly higher with lower concentra-
tions in whites and Asians.
Finally, the association between circulating 25(OH)D
concentration and upper GI cancer risk was examined by
using a meta-analysis framework. Figure 1 shows the odds
ratio in each cohort separately comparing those in the <25
nmol/L group with the referent group of 50–<75 nmol/L
and those in the 75 nmol/L group compared with the
same group. For subjects with circulating concentrations
of <25 nmol/L, most estimates were below unity, and the
summary odds ratio across cohorts was 0.89 (95% CI: 0.47,
1.66), although there was some heterogeneity in these esti-
mates (I
2
¼ 39%; P ¼ 0.14). The estimate for the Alpha-
Tocopherol, Beta-Carotene Cancer Prevention Study cohort
appeared to differ from the rest in showing significantly
increased risk (OR ¼ 1.85, 95% CI: 1.06, 3.21). For subjects
with circulating concentrations of 75 nmol/L, risk esti-
mates centered on unity with an odds ratio across cohorts
of 1.06 (95% CI: 0.67, 1.68) and little heterogeneity (I
2
¼
9%; P ¼ 0.36).
DISCUSSION
This study examined the association between circulating
25(OH)D concentrations and upper GI cancer risk in a
combined analysis nested in 8 prospective cohort studies.
Overall, no association between circulating 25(OH)D
concentration and risk of upper GI cancers was observed.
Surprisingly, in models stratified by race/ethnic group or
smoking, there was evidence of a protective association with
lower vitamin D status and cancer risk. In models stratified
on alcohol drinking, 2 opposing trends were evident. For
subjects reporting no alcohol consumption, having a lower
concentration of circulating vitamin D was associated with
lower cancer risk; for those reporting consumption of more
than 14 g of alcohol a day, lower concentrations were asso-
ciated with higher risk of cancer. Among Asians, most of
whom participated in the 2 Shanghai cohorts of Han Chi-
nese, and among never smokers, the risk of cancer was
statistically significantly lower for subjects with circulating
concentrations of <50 nmol/L compared with those with
higher concentrations. Specifically, compared with a circu-
lating 25(OH)D concentration of 50–75 nmol/L, a range that
encompasses the mean for subjects in the National Health
and Nutrition Examination Survey, the odds ratio for Asian
subjects with a circulating concentration of <25 nmol/L was
0.53 (95% CI: 0.31, 0.91).
Similarly, for never smokers, the same contrast produced
an odds ratio of 0.55 (95% CI: 0.31, 0.96). The estimate in
the Alpha-Tocopherol, Beta-Carotene Cancer Prevention
Study cohort, whose members were all active smokers, ap-
peared to differ from that in the other cohorts, showing that
subjects in the lowest 25(OH)D category had higher risk of
upper GI cancer (OR ¼ 1.85, 95% CI: 1.06, 3.21). This
finding is consistent with the possibility that smoking status
may modify the association of vitamin D with upper GI
cancer risk. All these stratified estimates should be inter-
preted with caution because these stratifications also altered
the primary outcomes examined (e.g., more ESCC among
the alcohol drinkers), and it altered the relative representa-
tion of different cohorts (e.g., all Alpha-Tocopherol, Beta-
Carotene Cancer Prevention Study subjects were among the
ever smokers). However, these subgroup analyses strongly
suggest that each disease subtype should be examined sep-
arately in large studies to clarify these potential interactions.
To our knowledge, only 2 previous studies have tested the
association between circulating vitamin D status and risk of
upper GI cancer, and both were conducted in China and
examined Han Chinese (9, 10). In a prospective study, a se-
rum 25(OH)D concentration of <20 nmol/L compared
with >48 nmol/L conveyed a significantly reduced risk of
0.56 for ESCC in men but showed no association among
women. In contrast, there was no evidence of association
with risk of gastric cancer in either sex in that study. A
subsequent cross-sectional study in the same population
showed lower risk of esophageal squamous dysplasia, the
preneoplastic lesion for ESCC, with lower serum 25(OH)D
status. The results of the present study among Asian partic-
ipants, most of whom were Han Chinese, were similar re-
garding the direction of association. Our sample size among
Asians was too small to test for distinct associations by
Table 6. Odds Ratios and 95% Confidence Intervals for the
Association Between Circulating 25(OH)D
a
and Risk of Upper
Gastrointestinal Cancer by Selected Strata Within the Cohort
Consortium Vitamin D Pooling Project of Rarer Cancers
OR 95% CI
Age at blood draw, years
61 1.07 0.84, 1.36
>61 1.06 0.80, 1.39
Body mass index, kg/m
2
<25 1.00 0.77, 1.30
25–<30 1.28 0.94, 1.74
30 0.82 0.47, 1.43
Physical activity
Sedentary 0.97 0.73, 1.30
Light 0.98 0.69, 1.38
Moderate 1.60 0.85, 3.00
Vigorous 1.10 0.63, 1.91
Follow-up time, years
<2 1.19 0.83, 1.71
2 1.04 0.84, 1.28
Abbreviations: CI, confidence interval; 25(OH)D, 25-hydr oxyvitamin D;
OR, odds ratio.
a
Modeled as 1 log unit of 25(OH)D in unconditional logistic regres-
sion models adjusted for the matching factors cohort, race, sex, and
date of blood draw, with further adjustment for alcohol drinking, smok-
ing, education, and history of gastric surgery, as appropriate within
strata.
102 Abnet et al.
Am J Epidemiol 2010;172:94–106
Page 9
0.125 0.25 0.50 1 2
48
Odds Ratio
Cohort OR (95% CI) Cases Controls
ATBC 1.11 (0.43, 2.85)
CLUE 0.85 (0.33, 2.18) 3
CPS-II 1.51 (0.19, 12.0)
MEC 0.61 (0.17, 2.17)
NYU-WHS
PLCO 0.72 (0.25, 2.04)
SMHS/SWHS 3.76 (1.07, 13.2)
18
26
8
11
18
19
25
0
7
15
19
4
Overall 1.06 (0.67, 1.68)
B)
Decreased Risk Increased Risk
Upper GI Cancer
0.125 0.25 0.50 1 2 4 8
Odds Ratio
Cohort OR (95% CI)
Cases Controls
ATBC 1.85 (1.06, 3.21)
CLUE 0.37 (0.05, 2.78)
CPS-II 0.62 (0.01, 45.7)
MEC 0.61 (0.17, 2.22)
NYU-WHS
PLCO 0.77 (0.13, 4.67)
SMHS/SWHS 0.65 (0.35, 1.20)
148
2
1
14
4
66
153
6
1
13
3
71
Overall 0.89 (0.47, 1.66)
A)
Decreased Risk Increased Risk
Upper GI Cancer
Figure 1. Forest plots for the meta-analysis of the association between circulating 25-hydroxyvitamin D (25(OH)D) and the risk of esophageal and gastric cancer within the Cohort Consortium
Vitamin D Pooling Project of Rarer Cancers. Risk estimates, by cohort, for subjects with circulating 25(OH)D concentrations of A) <25 nmol/L and B) 75 nmol/L compared with the referent group
(50–<75 nmol/L). Odds ratios (ORs) and 95% confidence intervals (CIs) were derived from conditional logistic regression models. The boxes show the odds ratios, the bars show the 95%
confidence intervals, and the size of each box is inversely proportional to the variance of the log odds ratio estimate in each cohort. The overall estimates (diamonds) were derived from a meta-
analysis using random-effects modeling. No estimates are given for the NYU-WHS because of small numbers in the exposed group. For the <25 nmol/L comparison, I
2
was 39%; for the 75
nmol/L comparison, I
2
was 9%. ATBC, Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study; CPS-II, Cancer Prevention Study II Nutrition Cohort; GI, gastrointestinal; MEC, Multiethnic
Cohort Study; NYU-WHS, New York University Women’s Health Study; PLCO, Prostate, Lung, Colorectal and Ovarian Cancer Screening Trial; SMHS/SWHS, Shanghai Men’s Health Study/
Shanghai Women’s Health Study.
Circulating 25(OH)D and Upper GI Cancer Risk 103
Am J Epidemiol 2010;172:94–106
Page 10
cancer type, but the adverse association was apparent in both
sexes, a finding that differs from the previous report (9).
Studies of other cancer sites in the VDPP have also ob-
served an association between higher vitamin D status and
increased cancer risk. As in a previous study of the Alpha-
Tocopherol, Beta-Carotene Cancer Prevention Study cohort
alone (16), higher vitamin D status was associated with in-
creased risk of pancreatic cancer. Here, a 2-fold increase in
risk was seen for subjects with a 25(OH)D concentration
of >100 nmol/L (17). In addition, the analysis of non-
Hodgkin lymphoma suggested an association of increased
risk with higher vitamin D status in women (18).
As in all observational epidemiologic studies, the results
of this analysis should be interpreted with caution because
unmeasured or poorly measured confounders could obscure
the true association. Furthermore, the significant differences
we observed were apparent only in subgroups. However, the
magnitude of the estimated risks in these subgroups and the
observed dose-response associations were such that any un-
measured factor would need to have a strong association
with upper GI cancer risk and also be well correlated with
vitamin D status to confound the associations observed.
One possible source of confounding not included in our
pooled analysis study was occupation. Some jobs that con-
vey lower socioeconomic status, which may increase the
risk of upper GI cancers, may also entail more sun expo-
sure. This potential confounding by occupation was ex-
plored in the Shanghai cohorts (data not shown), but
these analyses did not suggest that occupational differ-
ences would explain the adverse association among
Asians. Other potential confounders were considered in
the analyses. Among Asian controls in the VDPP, alcohol
consumption and vitamin D intake (primarily from fish)
was associated with higher circulating 25(OH)D, whereas
current smoking was associated with significantly lower
circulating 25(OH)D (15). Because the models were ad-
justed for alcohol consumption and cigarette smoking,
and because smoking was correlated with lower 25(OH)D
concentration, confounding by smoking is unlikely to explain
the association among Asians.
Several biologic rationales have been postulated for pos-
sible adverse associations between higher vitamin D status
and increased cancer risk, including induction of phase I
metabolizing enzymes under certain conditions (19), which
may be relevant in some populations. Second, the vitamin D
pathway can have both proliferative and antiproliferative
effects on preneoplastic lesions in an organ-specific manner.
In cells molecularly similar to esophageal squamous dyspla-
sia in their ratio of E-cadherin to osteopontin, vitamin D
may stimulate cell proliferation; in cells molecularly similar
to colon polyps in their ratio of E-cadherin to osteopontin,
vitamin D appears to be antiproliferative (20). However,
these hypotheses remain speculative. Alternatively, vitamin
D status may change with occult cancer such that reverse
causation contributes to the apparent adverse association.
Future analyses of these cohorts are warranted because the
relatively short median follow-up in the Shanghai Men’s
Health Study, a major contributor of the Asian subjects in
the analysis, leaves open the possibility that occult cancers
influenced vitamin D concentrations.
This study has several strengths. The combination of mul-
tiple populations from diverse geographic locations pro-
vided a wide distribution of exposure to circulating
25(OH)D concentrations. Using 8 cohorts supplied a rela-
tively large sample size for these cancers in a prospective
study. Furthermore, all samples were measured by using the
same methods in a single facility. Weaknesses of the study
include combining cancers with some disparate risk factors
under a single outcome of upper GI cancer, although anal-
yses were also conducted by cancer type. In addition, data
on several potential confounding risk factors, including
Helicobacter pylori status for gastric cancer and history of
gastroesophageal reflux disease for esophageal adenocarci-
nomas, were not available. However, no data suggest that
these factors are related to vitamin D status and could con-
found results.
In this combined analysis of 8 prospective cohorts, no
overall association between circulating 25(OH)D concentra-
tion and risk of upper GI cancers was observed. In subgroup
analyses, an adverse association between higher vitamin D
status and upper GI cancer risk for Asians and for never
smokers, and opposing trends in subgroups defined by alco-
hol consumption, suggested that the association may differ
by major risk factors for upper GI cancer or among individ-
uals with different risk-factor profiles for upper GI cancer. In
summary, these results do not support the hypothesis that
interventions aimed at increasing vitamin D status would
lead to lower risk of these highly fatal cancers.
ACKNOWLEDGMENTS
Author affiliations: Department of Chronic Disease Pre-
vention, National Institute for Health and Welfare, Helsinki,
Finland (Jarmo Virtamo); Department of Environmental
Medicine, New York University School of Medicine, New
York, New York (Alan A. Arslan, Yu Chen, Richard B.
Hayes); Department of Obstetrics and Gynecology, New
York University School of Medicine, New York, New York
(Alan A. Arslan); Department of Medicine, New York Uni-
versity School of Medicine, New York, New York (Yu
Chen); New York University Cancer Institute, New York,
New York (Alan A. Arslan, Yu Chen, Richard B. Hayes);
Epidemiology Research Program, American Cancer Soci-
ety, Atlanta, Georgia (Peter T. Campbell, Marjorie L.
McCullough); Department of Epidemiology, Shanghai Can-
cer Institute, Shanghai, People’s Republic of China
(Yu-Tang Gao, Yong-Bing Xiang); Department of Preven-
tive Medicine, University of Alabama at Birmingham,
Birmingham, Alabama (James M. Shikany); Division of
Cancer Epidemiology and Genetics, National Cancer Insti-
tute, Bethesda, Maryland (Christian C. Abnet, Demetrius
Albanes, Wong-Ho Chow, Mark P. Purdue, Kai Yu,
Stephanie J. Weinstein); Epidemiology Program, Cancer Re-
search Center of Hawaii, University of Hawaii, Honolulu,
Hawaii (Laurence N. Kolonel, Loı
¨
c Le Marchand, Abraham
M. Y. Nomura); Heartland Assays, Inc., Ames, Iowa (Ronald
L. Horst); Information Management Services, Inc., Silver
Spring, Maryland (David S. Campbell, Kirk Snyder);
104 Abnet et al.
Am J Epidemiol 2010;172:94–106
Page 11
Department of Epidemiology, The Johns Hopkins Bloomberg
School of Public Health, Baltimore, Maryland (Kathy J.
Helzlsouer); The Prevention and Research Center, The
Weinberg Center for Women’s Health and Medicine,
Mercy Medical Center, Baltimore, Maryland (Kathy J.
Helzlsouer); and Division of Epidemiology, Department
of Medicine, Vanderbilt Epidemiology Center, Vanderbilt-
Ingram Cancer Center, Vanderbilt University School of
Medicine, Nashville, Tennessee (Xiao-Ou Shu, Wei Zheng).
This work was supported by the Extramural Research
Program of the National Institutes of Health, Division of
Cancer Control and Population Sciences, National Cancer
Institute (NCI) (Bethesda, Maryland) and the Intramural
Research Program of the National Institutes of Health, Di-
vision of Cancer Epidemiology and Genetics, NCI. The
New York University Women’s Health Study was supported
by the NCI (grant R01 CA098661). The Multiethnic Cohort
Study was supported by the NCI (grants R37 CA54281, P01
CA33619, R01 CA063464, and N01-PC35137). The Shang-
hai Men’s Health Study was supported by the NCI (grant
R01 CA82729). The Shanghai Women’s Health Study was
supported by the NCI (grants R37 CA70867 and N02-CP-
11010-66). The Prostate, Lung, Colorectal and Ovarian
Cancer Screening Trial was supported by contracts from
the NCI to the University of Colorado, Denver, Colorado
(grant N01-CN-25514); Georgetown University, Washing-
ton, DC (grant N01-CN-25522); the Pacific Health Research
Institute, Honolulu, Hawaii (grant N01-CN-25515); the
Henry Ford Health System, Detroit, Michigan (grant N01-
CN-25512); the University of Minnesota, Minneapolis,
Minnesota (grant N01-CN-25513); Washington University,
St. Louis, Missouri (grant NO1-CN-25516); the University
of Pittsburgh, Pittsburgh, Pennsylvania (grant N01-CN-
25511); the University of Utah, Salt Lake City, Utah (grant
N01-CN-25524); the Marshfield Clinic Research Founda-
tion, Marshfield, Wisconsin (grant N01-CN-25518); the
University of Alabama, Birmingham, Alabama (grant
NO1-CN-75022); Westat, Inc., Rockville, Maryland (grant
N01-CN-25476); and the University of California, Los An-
geles, Los Angeles, California (grant NO1-CN-25404). The
Alpha-Tocopherol, Beta-Carotene Cancer Prevention Study
was supported by funding provided by the Intramural Re-
search Program of the NCI and US Public Health Service
contracts (N01-CN-45165, N01-RC-45035, N01-RC-
37004). CLUE was supported by the National Institute on
Aging (grant U01 AG018033) and the NCI (grants R01
CA105069, K07 CA73790). The participation of CLUE
investigators was also supported by an NCI contract
awarded to Mercy Medical Center through the University
of Hawaii (Honolulu, Hawaii). The Cancer Prevention
Study II Nutrition Cohort was supported by the American
Cancer Society (Atlanta, Georgia).
The authors thank Dr. Karen Phinney of the National
Institute of Standards and Technology for providing
the SRM 972 Vitamin D in Human Serum used in this
work.
Members of the VDPP Upper GI Writing Committee:
Christian C. Abnet, Yu Chen, Wong-Ho Chow, Yu-Tang
Gao, Kathy J. Helzlsouer, Loı
¨
c Le Marchand, Marjorie L.
McCullough, James M. Shikany, and Xiao-Ou Shu.
This report is based at least in part on information pro-
vided by the Maryland Cancer Registry, Maryland Depart-
ment of Health and Mental Hygiene.
Dr. Ronald L. Horst is the President and Chief Executive
Officer of Heartland Assays, Inc.
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  • Source
    • "As differences by calcium status for liver cancer could be due to chance, replication in future studies are needed to confirm these findings. Although a number of studies have investigated associations between serum vitamin D levels and various cancers (Garland and Garland, 1980; Chen et al, 2007; Li et al, 2007; Abbas et al, 2008; Ahn et al, 2008; Abnet et al, 2010; Jenab et al, 2010; StolzenbergSolomon et al, 2010), little epidemiologic data for vitamin D and liver cancer are available, despite the important role of the liver in metabolising the circulating form of vitamin D. Supporting a possible association, vitamin D has been shown to inhibit liver carcinogenesis in cell lines and several animal models (Ghous et al, 2008), for example, vitamin D has been shown to reduce the number of chromosomal aberrations and double-strand breaks (Saha et al, 2001) as well as prevent cellular proliferation (Pourgholami et al, 2000; Caputo et al, 2003). For liver disease, results from existing epidemiologic studies, each modest in size, are mixed. "
    [Show abstract] [Hide abstract] ABSTRACT: C-reactive protein (CRP) is a marker of systemic inflammation that has been associated with the incidence and prognosis for a number of different cancers. Recent data suggest that CRP may be a prognostic factor for liver cancer and cirrhosis. However, few long-term studies are available. We prospectively examined associations between serum CRP and subsequent risk of liver cancer incidence or chronic liver disease mortality in a nested case-control study performed in the Linxian Nutrition Intervention Trials cohort. Baseline serum CRP was measured for 220 incident liver cancer cases, 276 participants who died of chronic liver disease, and 1,018 age-, sex-, and trial-matched controls. Unconditional logistical regression models were used to estimate ORs and 95% confidence intervals (CI). Compared with the lowest quartile, subjects in the fourth quartile of serum CRP had a higher risk of liver cancer incidence (OR, 1.63; 95% CI, 1.06-2.51), with a significant Ptrend across quartiles (P = 0.01). The association with liver cancer was only significant among men (Q4 vs. Q1; OR, 2.00; 1.10-3.62), but not among women (Q4 vs. Q1; OR, 1.15; 0.60-2.22). For chronic liver disease deaths, the corresponding risk estimate in men and women was 2.95 (1.90-4.57), with a monotonic trend (P < 0.001). Higher serum CRP concentrations at baseline were associated with subsequent incidence of liver cancer and death from chronic liver disease. Our findings suggest that levels of systemic inflammation may serve as a long-term marker of liver cancer and liver disease. Cancer Epidemiol Biomarkers Prev; 24(2); 1-7. ©2015 AACR. ©2015 American Association for Cancer Research.
    Full-text · Article · Sep 2013 · British Journal of Cancer
  • Source
    • "Upper gastrointestinal (UGI) cancers (gastric and esophagus cancer) constitute a major health problem worldwide (1). Although a decreasing incidence of gastric cancer has been observed during the last decades, it remains the fourth most common cancer worldwide and the second leading cause of cancer-related death (2, 3). "
    [Show abstract] [Hide abstract] ABSTRACT: The present study aimed to evaluate the prevalence of positive family history of these cancers in a large population-based sample of Tehran province, capital of Iran. Upper gastrointestinal (UGI) cancers (gastric and esophagus cancer) constitute a major health problem worldwide. A family history of cancer can increase the risk for developing cancer and recognized as one of the most important risk factors in predicting personal cancer risk. This study designed as a cross-sectional survey in general population (2006-2007) of Tehran province. Totally 7,300 persons (age > = 20 years) sampled by random sampling on the basis of the list of postal, of whom 6,700 persons agreed to participate (response rate 92%). Respondents were asked if any first-degree (FDR) or second-degree (SDR) relatives had gastric or esophageal cancer. Totally, 6,453 respondents (48% male) entered to the study. The mean age of responders with positive FH was significantly higher than those with negative FH (P < 0.05). In total, 341 respondents (5.3%) reporting a history of UGI cancers in their relatives, 134(2.1%) in FDRs, and 207(3.2%) in SDRs. Our findings showed that the reported prevalence of FH of UGI cancers was relatively low and varied by specific respondent characteristics such as age and sex. However, the estimates of prevalence presented here are likely to be conservative compared with actual prevalence because of self-reported data gathering.
    Full-text · Article · Feb 2012 · Gastroenterology and hepatology from bed to bench
  • Source
    • "Results were debatable, and consistent associations have only been demonstrated in colorectal cancer [12,13]. The Cohort Consortium Vitamin D Pooling Project of Rarer Cancers have suggested that circulating 25(OH)D concentration was not significantly associated with upper GI cancer risk, but analysis on race subgroup in that study showed that among Asians, lower concentrations of 25(OH)D were associated with a statistically significant decreased risk of upper GI cancer [14]. A prospective study built an index from factors that predicted higher vitamin D status were statistically significantly associated with a lower risk of esophageal cancer and non-statistically-significantly with a lower risk of stomach cancer [15]. "
    [Show abstract] [Hide abstract] ABSTRACT: Results from large epidemiologic studies on the association between vitamin D and gastric cancer are controversial. Vitamin D significantly promotes apoptosis in the undifferentiated gastric cancer cell, but the prognostic effects of its levels are unknown. 197 gastric carcinoma patients who received treatment in the cancer centre of Sun Yat-sen University from January 2002 to January 2006 were involved in the study. The stored blood drawn before any treatment was assayed for 25-hydroxyvitamin D levels. The clinicopathologic data were collected to examine the prognostic effects of vitamin D. The mean vitamin D levels of the 197 gastric patients was 49.85 ± 23.68 nmol/L, among whom 114(57.9%) were deficient in Vitamin D(< 50 nmol/L), 67(34%) were insufficient (50-75 nmol/L) and 16(8.1%) were sufficient (> 75 nmol/L). Clinical stage (P = 0.004) and lymph node metastasis classification (P = 0.009) were inversely associated with vitamin D levels. The patients with high vitamin D levels group (≥ 50 nmol/L) had a higher overall survival compared with the low vitamin D levels group (< 50 nmol/L)(P = 0.018). Multivariate analysis indicated that vitamin D levels were an independent prognostic factor of gastric cancer (P = 0.019). Vitamin D deficiency may be associated with poor prognosis in gastric cancer.
    Full-text · Article · Jan 2012 · Journal of Translational Medicine
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