Best Practice & Research Clinical Gastroenterology 31 (2017) 509e517

Contents lists available at ScienceDirect

Best Practice & Research Clinical Gastroenterology

journal homepage: https://ees.elsevier.com/ybega/default.asp

Alcohol, smoking and risk of oesophago-gastric cancer

Jing Dong a, b, Aaron P. Thrift a, b, *
a
Section of Epidemiology and Population Sciences, Department of Medicine, Baylor College of Medicine, Houston, TX, USA
b
Dan L Duncan Comprehensive Cancer Center, Baylor College of Medicine, Houston, TX, USA

a r t i c l e i n f o a b s t r a c t

Article history: Oesophago-gastric cancers (oesophageal and gastric cancers) are common, highly fatal cancers. Oeso-
Received 20 July 2017 phageal squamous cell carcinoma (OSCC) and oesophageal adenocarcinoma (OAC) are the two main
Received in revised form histological subtypes of oesophageal cancer. Globally, OSCC remains the most common histological
18 August 2017
subtype of oesophageal cancer, with the highest burden occurring along two geographic belts, one from
Accepted 3 September 2017
north central China through the central Asian republics to northern Iran, and one from eastern to
southern Africa. In Western countries, the incidence of OAC has increased dramatically over the past 40
Keywords:
years. OAC is now the most common subtype of oesophageal cancer in the United States, United
Alcohol
Smoking
Kingdom, and Australia. Approximately 90% of gastric cancers are adenocarcinoma, with the majority of
Oesophageal neoplasms cases diagnosed in Eastern Asia, Eastern Europe, and some Latin American countries. Smoking is an
Stomach cancers established risk factor for both oesophageal (OSCC and OAC) and gastric cancers. Alcohol consumption,
however, is strongly associated with increased risk of OSCC and probably increases the risk of gastric
cancer, but is not associated with OAC. Here, we review the current epidemiological evidence on asso-
ciations between alcohol consumption, smoking and the risk of developing oesophago-gastric cancer,
and emphasize the importance of focusing efforts on controlling the worldwide burden of oesophago-
gastric cancer by reducing alcohol and tobacco use.
© 2017 Elsevier Ltd. All rights reserved.

1. Introduction and 400,000 deaths from oesophageal cancer occur annually.

Oesophago-gastric cancer refers to cancers of the oesophagus or
the stomach. Globally, oesophageal and gastric cancers are com-
mon, highly fatal cancers with overall mortality to incidence ratios
greater than 0.75. Alcohol and smoking, alone and in combination,
are associated with increased risks of cancers at various sites. Here,
we review the current epidemiological evidence on associations
between alcohol consumption, smoking and the risk of developing
oesophago-gastric cancer (Table 1).
2. Oesophageal cancer
According to the most recent world estimates, 456,000 new
cases of oesophageal cancer (representing 3.2% of all cancers cases)
Abbreviations: BEACON, Barrett's and Esophageal Adenocarcinoma Consortium;
BO, Barrett's oesophagus; OAC, Oesophageal adenocarcinoma; OSCC, Oesophageal
squamous cell carcinoma.
* Corresponding author. Dan L Duncan Comprehensive Cancer Center, Baylor
College of Medicine, One Baylor Plaza, MS: BCM305, Houston, TX 77030, USA.
E-mail address: aaron.thrift@bcm.edu (A.P. Thrift).
Oesophageal cancer is therefore responsible for about five percent
of all deaths from cancer worldwide and is the eighth most com-
mon cancer worldwide in 2012 [1]. However, a marked geograph-
ical variation exists in both the incidence and mortality rates for
oesophageal cancer [1]. The highest incidence rates of oesophageal
cancer are seen along two geographic belts, one from north central
China through the central Asian republics to northern Iran, and one
from eastern to southern Africa. Despite many recent advances in
diagnosis and treatment, the prognosis for persons diagnosed with
oesophageal cancer is poor. The average overall 5-year survival rate
for person diagnosed with oesophageal cancer in developed
countries remains <20% [2].
There are two main histological subtypes of oesophageal cancer:
oesophageal squamous cell carcinoma (OSCC) and oesophageal
adenocarcinoma (OAC). The aetiologies of OSCC and OAC are very
different [3]. Globally, OSCC remains the most common histological
subtype of oesophageal cancer, representing ~87% of all oesopha-
geal cancer cases diagnosed worldwide in 2012. While this is due
largely to high incidence rates in many developing countries, the
incidence rates for OSCC are significantly higher than the rates for
OAC in 90% of all countries presented in the International Agency

http://dx.doi.org/10.1016/j.bpg.2017.09.002
1521-6918/© 2017 Elsevier Ltd. All rights reserved.
510 J. Dong, A.P. Thrift / Best Practice & Research Clinical Gastroenterology 31 (2017) 509e517
Table 1
Summary of the associations between alcohol consumption and smoking and the risk of oesophago-gastric cancer.
Risk factor Cancer Type
Alcohol Consumption Oesophageal cancer
Gastric cancer
Smoking Oesophageal cancer
Gastric cancer
Smoking cessation > 10 years Oesophageal cancer
Gastric cancer
Multiplicative effects Oesophageal cancer
Gastric cancer
0, no association; þ, low to moderate increase in risk; þþ, moderate to high increase in risk; þþþ, high increase in risk; -, low to moderate inverse association; - -, moderate to
high inverse association; - - -, strong inverse association.
for Research on Cancer GLOBOCAN project (Fig. 1). The highest
burden of OSCC occur in developing countries, such as Eastern/
South-East Asia, sub-Saharan Africa and Central Asia [4]. Howev-
er, the highest burden of OAC occurs in Northern and Western
Europe, Northern America and Oceania [4,5]. Over the past 40
years, there has been a dramatic shift in the epidemiology of
oesophageal cancer in Western populations. The incidence of OSCC
has decreased, while the incidence of OAC has increased sharply in
most Western countries [6,7]. As described in detail below, studies
have consistently shown that alcohol consumption and smoking
are the main risk factors for OSCC; however, while smoking is
associated with increased risk of OAC, there is no association be-
tween alcohol consumption and the risk of OAC [8].
2.1. Oesophageal squamous cell carcinoma
OSCC occurs mostly in flat cells lining the upper two-thirds of
the oesophagus [8]. During the period when rates of OAC were
increasing dramatically in many Western populations, rates of
OSCC declined in these same populations. Worldwide, 398,000 new
cases of OSCC were diagnosed in 2012 (278,000 in men, 120,000 in
women) with highest incidence in Eastern/South-East Asia (8.8 per
100,000 persons), followed by sub-Saharan Africa (5.1 per 100,000
persons) and Central Asia (4.7 per 100,000 persons) (Fig. 2) [4].
Approximate 80% of OSCC cases (315,000 cases) occurred in the
Central and South-East Asian region, especially in China - the
country alone accounted for 53% of the global burden of OSCC cases.
The overall burden of OSCC in the United States is low, with higher
incidence rates observed among African Americans than among
Caucasians [4,9].
The regional distributions of OSCC roughly mirror the rates of
alcohol consumption and smoking. China, the country with the
highest incidence rates for OSCC, consumes the most cigarettes per
person; an estimated 45% of men and 2% of women in China are
current smokers (The Tobacco Atlas, http://www.tobaccoatlas.org/
topic/cigarette-use-globally/). Studies from high-incidence re-
gions in Africa also suggest that alcohol consumption and smoking
contribute substantially to the high burden of OSCC in that region
[10,11]. In Western populations, heavy alcohol consumption and
smoking are the main risk factors for OSCC, such that alcohol
consumption and smoking have been estimated to account for 80%
and 40% of OSCC cases in men and women, respectively [12]. The
declining incidence of OSCC in many Western populations is
thought to be due to the decreasing consumption of alcohol and
Subtype Magnitude of risk
Barrett's oesophagus (precursor) 0
Oesophageal adenocarcinoma 0
Oesophageal squamous cell carcinoma þþ
þ
Barrett's oesophagus (precursor) þ
Oesophageal adenocarcinoma þ
Oesophageal squamous cell carcinoma þþ
þþ
Barrett's oesophagus (precursor) 0
Oesophageal adenocarcinoma -
Oesophageal squamous cell carcinoma —
—
Barrett's oesophagus (precursor) 0
Oesophageal adenocarcinoma 0
Oesophageal squamous cell carcinoma þþþ
þ
lower rates of smoking.
2.1.1. Risk associated with alcohol consumption
Epidemiological studies have consistently linked higher alcohol
consumption with increased risk of OSCC, and reported a strong
dose-response relationship [13e15]. Compared to people who have
never consumed alcohol, the risk of OSCC is three to five times
higher among people who have ever consumed alcohol [14,16]. A
pooled analysis of individual level data from 7 studies (5 case-
control and 2 cohort studies) participating in the International
Barrett's and Oesophageal Adenocarcinoma Consortium (BEACON)
found increased risk for OSCC associated with increasing numbers
of drink-years [13]. Compared to lifelong non-drinkers of alcohol,
the risk of OSCC among persons who reported consuming 3-<5, 5-
<7 and
7 drinks per day were 5-fold (Odds Ratio [OR], 4.56; 95%
confidence interval [CI], 2.32e8.96), 7-fold (OR, 7.17; 95% CI,
2.98e17.25) and 10-fold (OR, 9.62; 95% CI, 4.26e21.71) higher,
respectively. In their meta-analysis of 40 case-control studies and
12 cohort studies, Islami et al. showed that moderate and high
alcohol drinking were associated with an increased risk of OSCC in
studies conducted in both Asian (Relative Risk [RR], 2.17; 95% CI,
1.58e2.96; RR, 4.02; 95% CI 2.76e5.83; respectively) and non-Asian
(RR, 2.34; 95% CI, 1.90e2.88; RR, 5.73; 95% CI, 4.41e7.44; respec-
tively) countries [15]. These associations were also present among
never-smokers (RR, 1.54; 95% CI, 1.09e2.17 for moderate, and RR,
3.09; 95% CI, 1.75e5.46 for high intakes) [15]. While for light alcohol
drinking, increased OSCC risk was observed only for studies con-
ducted in Asian countries (RR, 1.63; 95% CI, 1.20e2.22), however, a
dose-response relationship between alcohol consumption and the
risk of OSCC was observed in both Asian and non-Asian countries
[15]. Another meta-analysis of 34 studies from Asia, Europe and
South America assessed the effect of alcohol consumption on the
risk of OSCC and found no differences in the effect of association by
race [17].
Studies investigating associations with specific types of alco-
holic beverages (e.g., beer, wine, etc.) have shown inconsistent
patterns of association. In several large studies, heavy consumption
of beer or liquor has been associated with significantly increased
risks of OSCC [14], whereas in populations where beer consumption
was much lower than other types of alcoholic beverages, an inverse
association with beer has been observed [18]. A J-shaped rela-
tionship has been observed with wine consumption, where the
risks were lower among those consuming less than three drinks per
day on average and then shifted towards a significantly increased
 J. Dong, A.P. Thrift / Best Practice & Research Clinical Gastroenterology 31 (2017) 509e517 511

Fig. 1. Age standardized incidence rates for histological subtypes of oesophageal cancer in (A) men, and (B) women, worldwide in 2012.

risk among heavier wine drinkers [14,18,19].
2.1.2. Risk associated with smoking
Ever smoking, regardless of dose, is strongly associated with
increased risk of OSCC. The risk of OSCC increases linearly with
increasing duration and intensity of smoking [20e22]. In the pro-
spective Netherland Cohort Study, compared to never smokers,
current smokers had over two-fold higher risk of developing OSCC
(RR, 2.63; 95% CI, 1.47e4.69). Furthermore, there was a strong dose-
response relationship between pack-years of smoking and risk of
OSCC [16]. This is supported by findings from multiple case-control
studies that found that the risk of OSCC among smokers is three to
five times higher than that among never smokers. These same
studies found that more cigarettes per day for shorter duration
were less deleterious than fewer cigarettes per day for longer
duration [13,20]. Several studies have also reported that stronger
tobacco products (such as cigarettes with high-tar or dark tobacco)
are associated with higher risks for OSCC compared to the effect of
filter-tipped cigarettes on OSCC risk [23,24]. Increased risk of OSCC
was also found to be associated with secondhand smoking, and the
effects of secondhand smoking on OSCC were stronger among
never smokers [25]. In a meta-analysis of 20 studies, cigarette
smoking increased the risk of OSCC in a dose-dependent way [26].
2.1.3. Effect of smoking cessation on risk
The causal link between smoking and OSCC has also been sup-
ported by evidence of significant risk reductions among former
smokers compared with current smokers. In their recent meta-
analysis of 41 studies of OSCC, Wang et al. [27] found that the
risk of OSCC for former smokers compared with non-smokers (RR,
2.05; 95% CI, 1.71e2.45) was significantly lower than the risk for
current smokers (RR, 4.18; 95% CI, 3.42e5.12). Importantly, when
512 J. Dong, A.P. Thrift / Best Practice & Research Clinical Gastroenterology 31 (2017) 509e517
Fig. 2. Age-standardized rates (World) of incident cases of (A) and (C) oesophageal adenocarcinoma, (B) and (D) oesophageal squamous cell carcinoma, worldwide in 2012.
compared to current smokers, the risk of OSCC among former
smokers decreased linearly with increasing duration of smoking
cessation. While the greatest impact of smoking cessation was seen
among individuals that quit smoking >20 years ago (vs. current
smokers, RR, 0.34; 95% CI, 0.25e0.47) and their risk of OSCC was not
different to non-smokers (vs. current smokers, RR, 0.22; 95% CI,
0.18e0.28), the positive impact of smoking cessation was seen
already within 5 years of smoking cessation (vs. current smokers:
quit smoking 5e9 years ago, RR, 0.59; 95% CI, 0.47e0.75; quit
smoking 10e20 years ago, RR, 0.42; 95% CI, 0.34e0.51) [27].
2.1.4. Risk associated with combined alcohol consumption and
smoking
The joint effects of alcohol consumption and smoking on the risk
of OSCC appear to be multiplicative [16,18e22,24,28], with heavy
smokers who also drink heavily having especially high risk for
OSCC [16,18e20,24,28]. In their prospective cohort study, Steevens
et al. [16] found that the risk of OSCC among current smokers who
consumed >15 g/day of ethanol was 8-fold higher than among
never smokers who consumed 0e5 g/day of ethanol (RR, 8.05; 95%
CI, 3.89e16.60). On the other hand, compared to the same low risk
group (never smokers who consumed 0e5 g/day of ethanol), the
risk of OSCC among never smokers who consumed >15 g/day of
ethanol was only 4-fold higher (RR, 3.74; 95% CI, 1.25e11.20).
Likewise, in a case-control study conducted in Australia, the risk of
OSCC among current smokers who consume on average
420 g/
week of alcohol had over 20-fold higher risk than never smokers
who were lifelong non-drinkers (OR, 21.87; 95% CI, 3.90e122.49)
[14]. The positive synergistic effect of alcohol consumption and
smoking for OSCC was confirmed in a recent meta-analysis of five
population based case-control or cohort studies [29].
2.1.5. Other risk factors
In addition to alcohol consumption and smoking, certain sub-
stances in the diet, exposure to chemicals (polycyclic aromatic
hydrocarbons and nitrosamine), low socioeconomic status, and
drinking very hot beverages are associated with increased risk of
OSCC. Conversely, use of certain medications (including aspirin and
nonsteroidal anti-inflammatory drugs) and high intakes of fruit and
vegetables and consumption of monosaturated fatty acids are
associated with lower risk of OSCC [30]. For example, in their meta-
analysis of 16 studies comprising 3566 OSCC cases and 12,240
controls, Andrici and Eslick [31] found that consumption of hot food
and beverages was associated with over two-fold higher risk of
OSCC (OR, 2.29; 95% CI, 1.79e2.93). A report on dietary factors and
cancer prevention published by the World Cancer Research Fund/
American Institute for Cancer Research (WCRF/AICR) stated citrus
fruits may decrease the risk of OSCC (highest vs. lowest intake: RR,
0.65; 95% CI, 0.47e0.89) [32].
2.2. Oesophageal adenocarcinoma and Barrett's oesophagus
Forty years ago OSCC was responsible for >90% of the cases of
oesophageal cancer in the United States. However, since the early
1970s, the incidence of OAC has increased greatly in the United
States such that OAC is now the most common subtype of oeso-
phageal cancer in the United States, representing 80% of cases [33].
Among white men in the United States, the annual incidence of OAC
has increased 10-fold (from 0.6 per 100,000 to 6.0 per 100,000)
since 1973 [34]. Similar increases in incidence have been observed
in most Western populations [7]. In 2012, there were 52,000 new
cases of OAC diagnosed worldwide (41,000 in men, 11,000 in
women). The highest incidence of OAC were found in Northern and
Western Europe (1.9 per 100,000 persons), Northern America (1.9
per 100,000 persons) and Oceania (1.7 per 100,000 persons), while
the regions with highest incidence of OSCC had the lowest inci-
dence of OAC, such as Eastern and South-Eastern Asia (0.4 per
100,000 persons) and sub-Saharan Africa (0.3 per 100,000 persons)
(Fig. 2) [4].
OAC typically develops in the lower third of the oesophagus [8].
Barrett's oesophagus (BO), a condition in which the normal squa-
mous mucosa of the oesophagus is replaced by columnar intestinal
epithelium, is the only known precursor lesion for OAC. The devel-
opment of OAC can be characterized by a progression from BO to
 J. Dong, A.P. Thrift / Best Practice & Research Clinical Gastroenterology 31 (2017) 509e517
dysplasia and ultimately invasive carcinoma. BO is present in up to
15% of individuals with frequent symptoms of gastro-oesophageal
reflux disease (GORD), and in 1e2% of the general adult popula-
tion [35]. Compared to the general population, patients with BO
have at least 10-fold higher risk for OAC. Consequently, the current
approach to the prevention and control of OAC therefore relies on
upper endoscopy with biopsy to identify BO among individuals with
frequent symptoms of GORD, followed by regular endoscopic sur-
veillance in an effort to identify BO patients with neoplastic pro-
gression before they progress to invasive OAC.
2.2.1. Risk associated with alcohol consumption
Unlike OSCC, where alcohol is a known strong risk factor, alcohol
consumption is not associated with increased risk of OAC. The ma-
jority of studies have found no overall association between alcohol
consumption and OAC. After 16.3 years of follow-up, the prospective
Netherland Cohort Study did not observe a statistically significant
association between alcohol consumption and OAC (RR, 1.04; 95% CI,
0.54e2.02) [16]. In a pooled analysis of 11 studies participating in
BEACON (involving 1821 patients with OAC and 10,854 population-
based controls), no increase was observed in the risk of OAC among
ever alcohol consumers [36]. Furthermore, the risk of OAC did not
increase with increasing levels of alcohol consumption (5-<7
drinks/day, OR, 0.93; 95% CI, 0.66e1.31;
7 drinks/day, OR, 0.97; 95%
CI, 0.68e1.36) or with duration (40-<50 years, OR, 0.74; 95% CI,
0.49e1.10;
50 years, OR, 0.71; 95% CI, 0.48e1.05) when compared
with lifelong non-drinkers of alcohol. Similar results have been
observed for risk of BO. A pooled analysis of five case-control studies
participating in BEACON (involving 1169 patients with BO and 1282
population-based controls) showed alcohol consumption was not
associated with increased risk of BO (any vs. none, OR, 0.77; 95% CI,
0.60e1.00) [37]. Furthermore, a prospective cohort study of 411
patients with BO found no association between alcohol consump-
tion and the risk of progression to OAC [38]. A recent meta-analysis
of 11 studies also reported no association between alcohol con-
sumption and risk of neoplastic progression from BO to OAC (RR,
1.17; 95% CI, 0.93e1.48) [39]. In contrast, in studies examining as-
sociations with beverage-specific alcohol consumption reported
some evidence for an inverse association between wine consump-
tion and risks of OAC [36] and BO [37].
2.2.2. Risk associated with smoking
Epidemiological studies have consistently found a strong asso-
ciation between smoking and OAC, with risk increasing linearly with
duration and cumulative exposure. The prospective Netherlands
Cohort Study consisting of 145 OAC cases after 16.3 years of follow-
up (from among 120,852 participants at baseline) showed that cur-
rent smokers had a RR of 1.67 for developing OAC (95% CI, 1.01e2.77)
[16]. In a pooled analysis of 12 studies participating in BEACON
(involving 1540 OAC patients and 9453 population-based controls
from 10 case-control and 2 cohort studies), the risk of OAC was twice
as high among ever smokers as it was among never smokers (OR,
1.96; 95% CI, 1.64e2.34) [40]. Furthermore, a strong dose-response
association was observed between increasing pack-years of smok-
ing and risk of OAC (P-trend among ever smokers < 0.001) [40].
The strength of the association between smoking and BO is less
clear than for OAC. A pooled analysis of five case-controls studies in
BEACON (involving 1059 BE patients and 1143 population-based
controls) found that ever smoking was associated with increased
risk of BO (OR, 1.67; 95% CI, 1.04e2.67) [41]. However, there was no
dose-dependent relationship with cumulative exposure (P-trend
among ever smokers ¼ 0.193). Importantly, the summary risk esti-
mate from this pooled analysis was affected by significant between-
study heterogeneity. While some studies report an increased risk of
BO for ever smokers [42,43], there was no association between
513
smoking and BO in other studies [44e46]. There is however
increasing evidence to suggest that smoking may promote progres-
sion to OAC in patients with BO [38,47,48]. In the Seattle Barrett's
Oesophagus Study, the risk of OAC in patients with BO increased
linearly with increasing duration of exposure (P-trend ¼ 0.05) and
pack-years of exposure (P-trend ¼ 0.04). Compared with never
smokers, the risk of progression from BO to OAC was 2-fold higher
among those in the highest tertile of cumulative smoking exposure
(
36 pack-years vs. never smokers, HR, 2.29; 95% CI, 1.04e5.07) [38].
Similarly, in their study among BO patients in the Northern Ireland
Barrett's Oesophagus Registry, Coleman et al. [47] found that smok-
ing was associated with almost 2-fold higher risk of neoplastic pro-
gression to OAC or high-grade dysplasia, as compared with never-
smokers (current vs. never, HR, 1.85; 95% CI, 1.18e2.91). Similar
findings were reported in a study of smoking and neoplastic pro-
gression in BO patients from the UK National Barrett's Oesophagus
Registry [48].
2.2.3. Effect of smoking cessation on risk
In contrast to that seen for OSCC, there is only a small difference
in the magnitude of risk for OAC associated with smoking for former
and current smokers. In their meta-analysis of 23 studies of OAC,
Wang et al. [27] reported relative risks of 1.66 (95% CI, 1.48e1.85)
and 2.34 (95% CI, 2.04e2.69) for former smokers and current
smokers, respectively, compared with non-smokers. Furthermore,
the positive impact of smoking cessation is seen much later for OAC.
Compared to current smokers, smoking cessation >20 years ago was
associated with almost 30% lower risk of OAC (RR, 0.72; 95% CI,
0.52e1.01); however, there was no reduction in risk of OAC among
those that quit smoking <20 years ago (vs. current smokers: quit
smoking 5e9 years ago, RR, 0.87; 95% CI, 0.58e1.30; quit smoking
10e20 years ago, RR, 0.95; 95% CI, 0.78e1.15) [27].
2.2.4. Risk associated with combined alcohol use and smoking
Unlike OSCC, neither prospective cohorts nor case-control
studies observed interactions between alcohol consumption and
smoking on the risks of OAC and BO. For example, current smokers
who also consumed alcohol did not show statistically significant
increased risk of OAC (P > 0.05 in all stratum) in a cohort study with
16.3 years of follow-up [16].
2.2.5. Other risk factors
Epidemiological studies have identified frequent or persistent
symptoms of GORD and obesity as strong risk factors for OAC and
BO. A pooled analysis of individual level data from five large
population-based case-control studies participating in BEACON
found a strong, dose-dependent relationship between frequency of
GORD symptoms and OAC, with five-fold and eight-fold increased
risk associated with at least weekly and daily symptoms, respec-
tively [49]. Similar results were observed for BO [50]. In their meta-
analyses, Singh et al. [51] found that obesity, especially central
adiposity, is associated with two-to three-fold increased risks of
OAC and BO. However, there is no evidence that GORD or obesity
interacts with smoking to confer higher risks for OAC and BO
[40,52]. Higher intake of fruits and vegetables are associated with
lower risks of OAC and BO [44], while use of aspirin and non-aspirin
nonsteroidal anti-inflammatory drugs lower risk of OAC [53], but
not BO [54].
3. Gastric cancer
In 2012, 952,000 new cases of gastric cancer were diagnosed
worldwide (representing 6.8% of all cancer cases diagnosed in 2012)
[1]. Gastric cancer is the third most common cause of cancer-related
death worldwide, accounting for 723,000 deaths in 2012
514 J. Dong, A.P. Thrift / Best Practice & Research Clinical Gastroenterology 31 (2017) 509e517
(representing 8.8% of all cancer-related deaths in 2012) [1].
Approximately 90% of gastric cancers are adenocarcinoma, which
arises from the glands of the most superficial layer, or the mucosa, of
the stomach. Gastric cancer can be subdivided into gastric cardia
(roughly the top inch of the stomach) and gastric non-cardia cancer
by anatomic demarcations. Gastric cancer incidence has consider-
able geographic variation. The majority of cases are diagnosed in
Eastern Asia (Korea, Mongolia, Japan, and China, with rates between
40 and 60 per 100,000 persons), Eastern Europe (~35 per 100,000
persons), and some Latin American countries, especially Central
America and the Andean Region, with rates between 20 and 30 per
100,000 persons [55,56] (Fig. 3). Some of the lowest incidence rates
are found in African countries (0.6e3.0 per 100,000 persons) and
North America (5e6 per 100,000 persons) [55]. Globally, gastric
cancer incidence has declined over the past 4-5 decades [57]. This is
believed to be partly due to the decrease in prevalence of Heli-
cobacter pylori infection, the predominant risk factor for gastric
cancer. However, the incidence of gastric cardia adenocarcinoma
has remained stable or increased, at least in Western countries [58].
While findings from studies examining the association with alcohol
consumption have been inconsistent, recent evidence suggests a
modest positive association with gastric cancer risk. Conversely,
smoking is an established causal risk factor for gastric cancer.
3.1. Risk associated with alcohol consumption
The available information on the association between alcohol
consumption and risk of gastric cancer is contradictory. While some
large prospective cohort studies have reported no significant as-
sociation between alcohol consumption and the risk of gastric
(gastric cardia and/or non-cardia) cancer, including studies among
European [16,19] and Asian [59] populations, others have reported
positive associations with alcohol consumption [60,61]. Based on
the results of their recent meta-analysis, the World Cancer
Fig. 3. Estimated age-standardized rates (World) of incident cases, gastric cancer, worldwide in 2012.
Research Fund concluded that alcohol probably increases the risk of
gastric cancer [62]. Although the primary analysis showed no sta-
tistically significant association with alcohol consumption (RR per
10 g per day, 1.02; 95% CI, 1.00e1.04), after removing one study that
reported especially high intakes of alcohol, the association with
alcohol consumption did reach statistical significance (RR, 1.03; 95%
CI, 1.01e1.04). Among men, they showed that risk of gastric cancer
increased by 3% per 10 g per day increase in alcohol consumption
(RR, 1.03; 95% CI, 1.01e1.05). There was however no association
between alcohol consumption and risk of gastric cancer among
women (RR, 1.02; 95% CI, 0.90e1.15). Finally, in their non-linear
analysis, they found that the dose-response association with
gastric cancer risk was statistically significant at higher levels of
alcohol intake (i.e., >45 g of alcohol per day) [62].
3.2. Risk associated with smoking
Cigarette smoking was designated a cause of gastric cancer by
the International Agency for Research on Cancer in 2002. Smoking
is associated with increased risk of both gastric cardia and non-
cardia cancers. A prospective study conducted in the United
States among 474,606 participants found that compared with never
smokers, current smokers were at increased risk of both gastric
cardia (HR, 2.86; 95% CI, 1.73e4.70) and gastric non-cardia (HR,
2.04; 95% CI, 1.32e3.16) cancers [19]. The population attributable
risk for ever smoking was 47% and 19% for gastric cardia and non-
cardia cancer, respectively [19]. Similar results were observed in a
prospective study in The Netherlands (120,852 participants), with a
risk estimate of 1.40 (95% CI, 0.86e2.27) for former smoking and
1.60 (95% CI, 0.96e2.66) for current smoking associated with gastric
cardia cancer; and 1.47 (95% CI, 1.11e1.96) for former smoking and
1.86 (95% CI, 1.40e2.48) for current smoking associated with gastric
non-cardia cancer [16]; and in a prospective study in China (18,244
men), with a HR of 1.59 (95% CI, 1.27e1.99) [60]. A recent meta-
 J. Dong, A.P. Thrift / Best Practice & Research Clinical Gastroenterology 31 (2017) 509e517
analysis from the Consortium on Health and Aging: Network of
Cohorts in Europe and the United States (CHANCES) included 19
population-based prospective cohort studies with 897,021 Euro-
pean and American adults, and reported smoking status was
associated with higher incidence and mortality of gastric cancer
[63]. The current smokers significantly advanced the risk of gastric
cancer by 5.6 years compared with never smokers [63].
3.3. Effect of smoking cessation on risk
As noted above, compared to non-smokers, the risk of gastric
cancer for former smokers is similar to that seen for current
smokers. However, in the prospective Netherland Cohort Study, the
risk of gastric cardia adenocarcinoma and gastric non-cardia
adenocarcinoma both declined for smokers who had stopped for
periods of <10, 10 to 20, or
20 years (P for trend < 0.05) [16]. In
their recent meta-analysis of individual level data from 19
population-based cohorts participating in the Consortium on
Health and Aging: Network of Cohorts in Europe and the United
States (CHANCES), Ordonez-Mena et al. [63] found that individuals
who quit smoking
20 years ago had significantly lower risk of
gastric cancer compared with current smokers (HR, 0.69; 95% CI,
0.51e0.93). In addition, quitting smoking significantly delayed the
risk of death from gastric cancer up to 5.6 years compared with
those who did not quit smoking [63].
3.4. Risk associated with combined alcohol use and smoking
Compared with persons who neither drank alcohol nor smoked
cigarettes, heavy drinkers who also smoked cigarettes had statis-
tically significant 2-fold increased risk of gastric cancer, however,
no significant interaction between alcohol consumption and
smoking was observed (P for interaction ¼ 0.15) [60]. No interaction
between alcohol consumption and smoking on the risk of gastric
cancer was also reported by a prospective study in Japan [59]. In the
2015 Continuous Update Project, the World Cancer Research Fund
found that among never smokers individuals in the highest cate-
gory of alcohol intake had 23% increased risk of gastric cancer (RR,
1.23; 95% CI, 1.03e1.46) compared to those in the lowest category of
intake. Among ever smokers, individuals in the highest category of
alcohol intake had 84% increased risk of gastric cancer (RR, 1.84;
95% CI, 1.43e2.36) compared to those in the lowest category of
alcohol intake [62].
3.5. Other risk factors
H. pylori infection is the main cause of gastric cancer, accounting
for approximately 89% of distal gastric cancer cases worldwide
[64e66]. There is also evidence that H. pylori infection interacts
with smoking to confer especially high risk for gastric cancer [67].
Other factors associated with increased risk for gastric cardia and
non-cardia cancers include low socioeconomic status, physical
inactivity, and radiation exposure; while obesity and GORD
symptoms are associated with increased risk of gastric cardia
cancer only [68]. A report published by the WCRF/AICR stated that
non-starchy vegetables and fruits probably protect against gastric
cancer [69]. A high salt diet has been associated with a higher risk
for gastric cancer [69], and salt may act synergistically with H. pylori
infection to confer higher risk for gastric cancer [70,71]. Diets high
in nitroso compounds may also be associated with increased risk
for gastric cancer [69]. Conversely, use of aspirin, nonsteroidal anti-
inflammatory drugs and statins may lower risk for gastric cancer
[68].
515
Conflicts of interest
None to declare.
Financial support
Jing Dong is supported by a Research Training Grant from the
Cancer Prevention and Research Institute of Texas (CPRIT;
RP160097).
Summary
Both oesophageal cancer and gastric cancer remain common
cancers, and they remain the focus of clinical, epidemiologic, and
translational research. Previous studies have established smoking
as a dominant risk factor for both cancer types. Alcohol consump-
tion is a known strong risk factor for OSCC and probably increases
the risk of gastric cancer; however, alcohol consumption is not
associated with increased risk of OAC. These findings emphasize
the importance of focusing efforts on controlling the worldwide
burden of oesophago-gastric cancer by reducing alcohol con-
sumption and avoiding smoking. For current smokers, smoking
cessation can substantially lower their future risk of developing
oesophago-gastric cancer. Further studies are needed to under-
stand the biological mechanisms involved in the development of
oesophago-gastric cancer among individuals who consume alcohol
and tobacco.
Practice points
 Smoking is an important risk factor for oesophago-gastric can-
cer, while the role of alcohol consumption in gastric cancer re-
mains controversial.
 Reducing tobacco use and smoking cessation should continue to
be strongly encouraged, and smoking cessation strategies
should be considered for patients with Barrett's oesophagus.
 Excess alcohol consumption should be avoided, especially for
smokers.
Research agenda
 More large prospective studies are needed to determine the
associations between alcohol consumption and gastric cancer,
and present the beverage-specific effects.
 Studies of the biological mechanisms involved in the develop-
ment of oesophago-gastric cancer among individuals consume
alcohol and tobacco are needed.
References
[1] Ferlay J, Soerjomataram I, Dikshit R, Eser S, Mathers C, Rebelo M, et al. Cancer
incidence and mortality worldwide: sources, methods and major patterns in
GLOBOCAN 2012. Int J Cancer 2015;136:E359e86.
[2] Thrift AP. The epidemic of oesophageal carcinoma: where are we now? Cancer
Epidemiol 2016;41:88e95.
[3] Kamangar F, Chow WH, Abnet CC, Dawsey SM. Environmental causes of
esophageal cancer. Gastroenterol Clin North Am 2009;38:27e57.
[4] Arnold M, Soerjomataram I, Ferlay J, Forman D. Global incidence of oeso-
phageal cancer by histological subtype in 2012. Gut 2015;64:381e7.
[5] Lepage C, Drouillard A, Jouve JL, Faivre J. Epidemiology and risk factors for
oesophageal adenocarcinoma. Dig Liver Dis 2013;45:625e9.
[6] Siegel RL, Miller KD, Jemal A. Cancer statistics, 2016. CA Cancer J Clin 2016;66:
7e30.
[7] Thrift AP, Whiteman DC. The incidence of esophageal adenocarcinoma con-
tinues to rise: analysis of period and birth cohort effects on recent trends. Ann
Oncol 2012;23:3155e62.
[8] Enzinger PC, Mayer RJ. Esophageal cancer. N Engl J Med 2003;349:2241e52.
[9] Baquet CR, Commiskey P, Mack K, Meltzer S, Mishra SI. Esophageal cancer
516 J. Dong, A.P. Thrift / Best Practice & Research Clinical Gastroenterology 31 (2017) 509e517
epidemiology in blacks and whites: racial and gender disparities in incidence,
mortality, survival rates and histology. J Natl Med Assoc 2005;97:1471e8.
[10] Okello S, Churchill C, Owori R, Nasasira B, Tumuhimbise C, Abonga CL, et al.
Population attributable fraction of Esophageal squamous cell carcinoma due
to smoking and alcohol in Uganda. BMC Cancer 2016;16:446.
[11] Sewram V, Sitas F, O'Connell D, Myers J. Tobacco and alcohol as risk factors for
oesophageal cancer in a high incidence area in South Africa. Cancer Epidemiol
2016;41:113e21.
[12] Pandeya N, Olsen CM, Whiteman DC. Sex differences in the proportion of
esophageal squamous cell carcinoma cases attributable to tobacco smoking
and alcohol consumption. Cancer Epidemiol 2013;37:579e84.
[13] Lubin JH, Cook MB, Pandeya N, Vaughan TL, Abnet CC, Giffen C, et al. The
importance of exposure rate on odds ratios by cigarette smoking and alcohol
consumption for esophageal adenocarcinoma and squamous cell carcinoma in
the Barrett's Esophagus and Esophageal Adenocarcinoma Consortium. Cancer
Epidemiol 2012;36:306e16.
[14] Pandeya N, Williams G, Green AC, Webb PM, Whiteman DC. Alcohol con-
sumption and the risks of adenocarcinoma and squamous cell carcinoma of
the esophagus. Gastroenterology 2009;136:1215e24.
[15] Islami F, Fedirko V, Tramacere I, Bagnardi V, Jenab M, Scotti L, et al. Alcohol
drinking and esophageal squamous cell carcinoma with focus on light-
drinkers and never-smokers: a systematic review and meta-analysis. Int J
Cancer 2011;129:2473e84.
[16] Steevens J, Schouten LJ, Goldbohm RA, van den Brandt PA. Alcohol con-
sumption, cigarette smoking and risk of subtypes of oesophageal and gastric
cancer: a prospective cohort study. Gut 2010;59:39e48.
[17] Prabhu A, Obi KO, Rubenstein JH. Systematic review with meta-analysis: race-
specific effects of alcohol and tobacco on the risk of oesophageal squamous
cell carcinoma. Aliment Pharmacol Ther 2013;38:1145e55.
[18] Zambon P, Talamini R, La Vecchia C, Dal Maso L, Negri E, Tognazzo S, et al.
Smoking, type of alcoholic beverage and squamous-cell oesophageal cancer in
northern Italy. Int J Cancer 2000;86:144e9.
[19] Freedman ND, Abnet CC, Leitzmann MF, Mouw T, Subar AF, Hollenbeck AR,
et al. A prospective study of tobacco, alcohol, and the risk of esophageal and
gastric cancer subtypes. Am J Epidemiol 2007;165:1424e33.
[20] Pandeya N, Williams GM, Sadhegi S, Green AC, Webb PM, Whiteman DC.
Associations of duration, intensity, and quantity of smoking with adenocar-
cinoma and squamous cell carcinoma of the esophagus. Am J Epidemiol
2008;168:105e14.
[21] Gammon MD, Schoenberg JB, Ahsan H, Risch HA, Vaughan TL, Chow WH, et al.
Tobacco, alcohol, and socioeconomic status and adenocarcinomas of the
esophagus and gastric cardia. J Natl Cancer Inst 1997;89:1277e84.
[22] Vaughan TL, Davis S, Kristal A, Thomas DB. Obesity, alcohol, and tobacco as
risk factors for cancers of the esophagus and gastric cardia: adenocarcinoma
versus squamous cell carcinoma. Cancer Epidemiol Biomarkers Prev 1995;4:
85e92.
[23] Nasrollahzadeh D, Kamangar F, Aghcheli K, Sotoudeh M, Islami F, Abnet CC,
et al. Opium, tobacco, and alcohol use in relation to oesophageal squamous
cell carcinoma in a high-risk area of Iran. Br J Cancer 2008;98:1857e63.
[24] Castellsague X, Munoz N, De Stefani E, Victora CG, Castelletto R, Rolon PA,
et al. Independent and joint effects of tobacco smoking and alcohol drinking
on the risk of esophageal cancer in men and women. Int J Cancer 1999;82:
657e64.
[25] Rafiq R, Shah IA, Bhat GA, Lone MM, Islami F, Boffetta P, et al. Secondhand
smoking and the risk of esophageal squamous cell carcinoma in a high inci-
dence region, Kashmir, India: a case-control-observational study. Med Baltim
2016;95, e2340.
[26] Chung CS, Lee YC, Wang CP, Ko JY, Wang WL, Wu MS, et al. Secondary pre-
vention of esophageal squamous cell carcinoma in areas where smoking,
alcohol, and betel quid chewing are prevalent. J Formos Med Assoc 2010;109:
408e21.
[27] Wang Q-L, Xie S-H, Li W-T, Lagergren J. Smoking cessation and risk of
esophageal cancer by histological type: systematic review and meta-analysis.
J Natl Cancer Inst 2017;109(12). djx115.
[28] Lagergren J, Bergstrom R, Lindgren A, Nyren O. The role of tobacco, snuff and
alcohol use in the aetiology of cancer of the oesophagus and gastric cardia. Int
J Cancer 2000;85:340e6.
[29] Prabhu A, Obi KO, Rubenstein JH. The synergistic effects of alcohol and tobacco
consumption on the risk of esophageal squamous cell carcinoma: a meta-
analysis. Am J Gastroenterol 2014;109:822e7.
[30] Thrift AP, Pandeya N, Whiteman DC. Esophageal cancer: epidemiology and
risk factors. In: Eslick GD, editor. Esophageal cancer: epidemiology, diagnosis
and treatment; 2012. p. 7e28.
[31] Andrici J, Eslick GD. Hot food and beverage consumption and the risk of
esophageal cancer: a meta-analysis. Am J Prev Med 2015;49:952e60.
[32] Vingeliene S, Chan DS, Aune D, Vieira AR, Polemiti E, Stevens C, et al. An
update of the WCRF/AICR systematic literature review on esophageal and
gastric cancers and citrus fruits intake. Canc Causes Contr 2016;27:837e51.
[33] Pohl H, Welch HG. The role of overdiagnosis and reclassification in the marked
increase of esophageal adenocarcinoma incidence. J Natl Cancer Inst 2005;97:
142e6.
[34] Vaughan TL, Fitzgerald RC. Precision prevention of oesophageal adenocarci-
noma. Nat Rev Gastroenterol Hepatol 2015;12:243e8.
[35] Ronkainen J, Aro P, Storskrubb T, Johansson SE, Lind T, Bolling-Sternevald E,
et al. Prevalence of Barrett's esophagus in the general population: an
endoscopic study. Gastroenterology 2005;129:1825e31.
[36] Freedman ND, Murray LJ, Kamangar F, Abnet CC, Cook MB, Nyren O, et al.
Alcohol intake and risk of oesophageal adenocarcinoma: a pooled analysis
from the BEACON Consortium. Gut 2011;60:1029e37.
[37] Thrift AP, Cook MB, Vaughan TL, Anderson LA, Murray LJ, Whiteman DC, et al.
Alcohol and the risk of Barrett's esophagus: a pooled analysis from the In-
ternational BEACON Consortium. Am J Gastroenterol 2014;109:1586e94.
[38] Hardikar S, Onstad L, Blount PL, Odze RD, Reid BJ, Vaughan TL. The role of
tobacco, alcohol, and obesity in neoplastic progression to esophageal adeno-
carcinoma: a prospective study of Barrett's esophagus. PLoS One 2013;8,
e52192.
[39] Lou Z, Xing H, Li D. Alcohol consumption and the neoplastic progression in
Barrett's esophagus: a systematic review and meta-analysis. PLoS One 2014;9,
e105612.
[40] Cook MB, Kamangar F, Whiteman DC, Freedman ND, Gammon MD,
Bernstein L, et al. Cigarette smoking and adenocarcinomas of the esophagus
and esophagogastric junction: a pooled analysis from the international BEA-
CON consortium. J Natl Cancer Inst 2010;102:1344e53.
[41] Cook MB, Shaheen NJ, Anderson LA, Giffen C, Chow WH, Vaughan TL, et al.
Cigarette smoking increases risk of Barrett's esophagus: an analysis of the
Barrett's and Esophageal Adenocarcinoma Consortium. Gastroenterology
2012;142:744e53.
[42] Smith KJ, O'Brien SM, Green AC, Webb PM, Whiteman DC. Study of Digestive
H. Current and past smoking significantly increase risk for Barrett's esoph-
agus. Clin Gastroenterol Hepatol 2009;7:840e8.
[43] Edelstein ZR, Farrow DC, Bronner MP, Rosen SN, Vaughan TL. Central adiposity
and risk of Barrett's esophagus. Gastroenterology 2007;133:403e11.
[44] Anderson LA, Watson RG, Murphy SJ, Johnston BT, Comber H, Mc Guigan J,
et al. Risk factors for Barrett's oesophagus and oesophageal adenocarcinoma:
results from the FINBAR study. World J Gastroenterol 2007;13:1585e94.
[45] Kubo A, Levin TR, Block G, Rumore G, Quesenberry Jr CP, Buffler P, et al.
Cigarette smoking and the risk of Barrett's esophagus. Canc Causes Contr
2009;20:303e11.
[46] Thrift AP, Kramer JR, Richardson PA, El-Serag HB. No significant effects of
smoking or alcohol consumption on risk of Barrett's esophagus. Dig Dis Sci
2014;59:108e16.
[47] Coleman HG, Bhat S, Johnston BT, McManus D, Gavin AT, Murray LJ. Tobacco
smoking increases the risk of high-grade dysplasia and cancer among patients
with Barrett's esophagus. Gastroenterology 2012;142:233e40.
[48] Ramus JR, Gatenby PA, Caygill CP, Watson A, Winslet MC. The relationship
between smoking and severe dysplastic disease in patients with Barrett's
columnar-lined oesophagus. Eur J Cancer Prev 2012;21:507e10.
[49] Cook MB, Corley DA, Murray LJ, Liao LM, Kamangar F, Ye W, et al. Gastro-
esophageal reflux in relation to adenocarcinomas of the esophagus: a pooled
analysis from the Barrett's and Esophageal Adenocarcinoma Consortium
(BEACON). PLoS One 2014;9, e103508.
[50] Taylor JB, Rubenstein JH. Meta-analyses of the effect of symptoms of gastro-
esophageal reflux on the risk of Barrett's esophagus. Am J Gastroenterol
2010;105:1730e7.
[51] Singh S, Sharma AN, Murad MH, Buttar NS, El-Serag HB, Katzka DA, et al.
Central adiposity is associated with increased risk of esophageal inflamma-
tion, metaplasia, and adenocarcinoma: a systematic review and meta-anal-
ysis. Clin Gastroenterol Hepatol 2013;11:1399e412.
[52] Whiteman DC, Sadeghi S, Pandeya N, Smithers BM, Gotley DC, Bain CJ, et al.
Combined effects of obesity, acid reflux and smoking on the risk of adeno-
carcinomas of the oesophagus. Gut 2008;57:173e80.
[53] Zhang S, Zhang XQ, Ding XW, Yang RK, Huang SL, Kastelein F, et al. Cyclo-
oxygenase inhibitors use is associated with reduced risk of esophageal
adenocarcinoma in patients with Barrett's esophagus: a meta-analysis. Br J
Cancer 2014;110:2378e88.
[54] Thrift AP, Anderson LA, Murray LJ, Cook MB, Shaheen NJ, Rubenstein JH, et al.
Nonsteroidal anti-inflammatory drug use is not associated with reduced risk
of Barrett's esophagus. Am J Gastroenterol 2016;111:1528e35.
[55] Correa P. Gastric cancer: overview. Gastroenterol Clin North Am 2013;42:
211e7.
[56] Tsukanov VV, Butorin NN, Maady AS, Shtygasheva OV, Amelchugova OS,
Tonkikh JL, et al. Helicobacter pylori infection, intestinal metaplasia, and
gastric cancer risk in eastern Siberia. Helicobacter 2011;16:107e12.
[57] Forman D, Burley VJ. Gastric cancer: global pattern of the disease and an
overview of environmental risk factors. Best Pract Res Clin Gastroenterol
2006;20:633e49.
[58] Camargo MC, Anderson WF, King JB, Correa P, Thomas CC, Rosenberg PS, et al.
Divergent trends for gastric cancer incidence by anatomical subsite in US
adults. Gut 2011;60:1644e9.
[59] Sasazuki S, Sasaki S, Tsugane S. Japan Public Health Center Study G. Cigarette
smoking, alcohol consumption and subsequent gastric cancer risk by subsite
and histologic type. Int J Cancer 2002;101:560e6.
[60] Moy KA, Fan Y, Wang R, Gao YT, Yu MC, Yuan JM. Alcohol and tobacco use in
relation to gastric cancer: a prospective study of men in Shanghai, China.
Cancer Epidemiol Biomarkers Prev 2010;19:2287e97.
[61] Everatt R, Tamosiunas A, Kuzmickiene I, Virviciute D, Radisauskas R,
Reklaitiene R, et al. Alcohol consumption and risk of gastric cancer: a cohort
study of men in Kaunas, Lithuania, with up to 30 years follow-up. BMC Cancer
2012;12:475.
[62] World Cancer Research Fund International/American Institute for Cancer
 J. Dong, A.P. Thrift / Best Practice & Research Clinical Gastroenterology 31 (2017) 509e517
Research. Continuous update project report: diet, nutrition, physical activity
and stomach cancer. 2016. wcrf.org/stomach-cancer-2016.
[63] Ordonez-Mena JM, Schottker B, Mons U, Jenab M, Freisling H, Bueno-de-
Mesquita B, et al. Quantification of the smoking-associated cancer risk with
rate advancement periods: meta-analysis of individual participant data from
cohorts of the CHANCES consortium. BMC Med 2016;14:62.
[64] Gonzalez CA, Megraud F, Buissonniere A, Lujan Barroso L, Agudo A, Duell EJ,
et al. Helicobacter pylori infection assessed by ELISA and by immunoblot and
noncardia gastric cancer risk in a prospective study: the Eurgast-EPIC project.
Ann Oncol 2012;23:1320e4.
[65] Lochhead P, El-Omar EM. Helicobacter pylori infection and gastric cancer. Best
Pract Res Clin Gastroenterol 2007;21:281e97.
[66] Plummer M, Franceschi S, Vignat J, Forman D, de Martel C. Global burden of
gastric cancer attributable to Helicobacter pylori. Int J Cancer 2015;136:
487e90.
517
[67] Gonzalez CA, Pera G, Agudo A, Palli D, Krogh V, Vineis P, et al. Smoking and the
risk of gastric cancer in the European prospective investigation into cancer
and nutrition (EPIC). Int J Cancer 2003;107:629e34.
[68] Karimi P, Islami F, Anandasabapathy S, Freedman ND, Kamangar F. Gastric
cancer: descriptive epidemiology, risk factors, screening, and prevention.
Cancer Epidemiol Biomarkers Prev 2014;23:700e13.
[69] World Cancer Research Fund/American Institute for Cancer Research. Food,
nutrition, physical activity, and the prevention of cancer: a global perspective.
Washington DC: AICR; 2007.
[70] Toyoda T, Tsukamoto T, Hirano N, Mizoshita T, Kato S, Takasu S, et al. Syn-
ergistic upregulation of inducible nitric oxide synthase and cyclooxygenase-2
in gastric mucosa of Mongolian gerbils by a high-salt diet and Helicobacter
pylori infection. Histol Histopathol 2008;23:593e9.
[71] Loh JT, Torres VJ, Cover TL. Regulation of Helicobacter pylori cagA expression
in response to salt. Cancer Res 2007;67:4709e15.