Cancer

Epidemiology,
Biomarkers
Review & Prevention

Gastric Cancer: Descriptive Epidemiology, Risk Factors,

Screening, and Prevention
Parisa Karimi1, Farhad Islami4,6, Sharmila Anandasabapathy5, Neal D. Freedman3, and Farin Kamangar2,6

Abstract
Less than a century ago, gastric cancer was the most common cancer in the United States and perhaps
throughout the world. Despite its worldwide decline in incidence over the past century, gastric cancer remains
a major killer across the globe. This article reviews the epidemiology, screening, and prevention of gastric
cancer. We first discuss the descriptive epidemiology of gastric cancer, including its incidence, survival,
mortality, and trends over time. Next, we characterize the risk factors for gastric cancer, both environmental
and genetic. Serologic markers and histological precursor lesions of gastric cancer and early detection of
gastric cancer using these markers are reviewed. Finally, we discuss prevention strategies and provide
suggestions for further research. Cancer Epidemiol Biomarkers Prev; 23(5); 700–13.
2014 AACR.

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Introduction the stomach, and leiomyosarcomas, which arise from the
Less than a century ago, gastric cancer was the most muscles surrounding the mucosa.
common cancer in the United States and perhaps through- A popular classification by Lauren stratifies gastric
out the world. Although it is no longer the most common cancer adenocarcinomas into two major histologic types:
cancer worldwide, gastric cancer remains the second diffuse and intestinal (2). These two types not only look
leading cause of cancer-related mortality worldwide and different under the microscope, but also differ in gender
the most prevalent cancer in Eastern Asia (1). This article ratio, age at diagnosis, and other epidemiologic features
discusses the epidemiology and prevention of gastric (3).
cancer, reviewing both classic studies and the new find- The stomach is divided into several anatomic subsites,
ings that have been added to the literature over the past including the cardia (roughly the top inch of the stomach),
few years. fundus, body, pylorus, and the antrum. These areas are
distinguished by anatomic demarcations, histologic dif-
ferences, or both. Most relevant to this paper is the dis-
Some Terminology tinction between adenocarcinomas arising from the cardia
The large majority (approximately 90%) of gastric can- (cardia gastric cancer) and other parts of the stomach
cers are adenocarcinomas, which arise from the glands of (noncardia gastric cancer), as they have different epide-
the most superficial layer, or the mucosa, of the stomach. miologic patterns and causes.
Therefore, if not specified otherwise, our discussion of
gastric cancer mainly pertains to adenocarcinomas. There Incidence, Mortality, and Burden
are, however, other types of cancer arising from the Each year approximately 990,000 people are diagnosed
stomach, including mucosa-associated lymphoid tissue with gastric cancer worldwide, of whom about 738,000 die
lymphomas, which originate from the lymphoid tissue of from this disease (4), making gastric cancer the fourth
most common incident cancer and the second most com-
mon cause of cancer death (5). Gastric cancer also causes
Authors' Affiliations: 1Johns Hopkins Bloomberg School of Public Health; one of the highest cancer burdens, as measured by dis-
2
Department of Public Health Analysis, School of Community Health and
Policy, Morgan State University, Baltimore; 3Division of Cancer Epidemi- ability-adjusted life years lost (6).
ology and Genetics, National Cancer Institute, NIH, Bethesda, Maryland; Gastric cancer incidence rates vary wildly between men
4
Institute for Transitional Epidemiology, Mount Sinai School of Medicine; and women and across different countries. Rates are 2- to
5
Division of Gastroenterology, Department of Medicine, Mount Sinai Med-
ical Center, New York, New York; and 6Digestive Oncology Research 3-folds higher in men than women (4). Comparing
Center, Digestive Disease Research Institute, Tehran University of Medical nations, the highest incidence rates are observed in East
Sciences, Tehran, Iran
Asia, East Europe, and South America, whereas the lowest
Corresponding Author: Farin Kamangar, Professor and Chairman, rates are observed in North America and most parts of
Department of Public Health Analysis, School of Community Health and
Policy, Morgan State University, 4530 Portage Avenue, Room 302, Balti- Africa (7). For example, the annual age-standardized
more, MD 21251. Phone: 301-655-9280; Fax: 443-885-8309; E-mail: gastric cancer incidence rates per 100,000 in men are
farin.kamangar@morgan.edu 65.9 in Korea versus 3.3 in Egypt (5). In the United States,
doi: 10.1158/1055-9965.EPI-13-1057 the incidence is relatively low, particularly in Whites, with

2014 American Association for Cancer Research. an estimated incidence rate per 100,000 of 7.8 and 3.5 in

700 Cancer Epidemiol Biomarkers Prev; 23(5) May 2014

 Gastric Cancer

non-Hispanic White men and women, respectively (8).

Table 1. Some prominent risk factors for gastric
Rates also vary across races. For example, in the United
cardia and noncardia cancers
States, rates are higher in Latinos (13.9 per 100,000 in men
and 8.2 per 100,000 in women) than in non-Hispanic White
populations (8). Indigenous populations, particularly Risk factors for gastric cancer
Inuits in circumpolar region and Maoris in New Zealand, Cardia Noncardia
suffer from high rates of gastric cancer (9). Age Age
Male sex Male sex
Trends Tobacco smoking Tobacco smoking
Gastric cancer incidence rates have been on the Race Race
decline in most parts of the world (10, 11). In United Family history Family history
States, for example, the incidence rates decreased by Low physical activity Low physical activity
1.7% for men and 0.8% for women annually from 1992 to Fiber intake Fiber intake
2010 (12). A major exception to these decreasing trends Radiation Radiation
is that cardia gastric cancer rates have remained stable — H. pylori
or increased (13, 14), at least in Western countries. Such — Low socioeconomic status
— High intake of salty and smoked food

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contrasting trends for cardia and noncardia gastric
cancer may result from distinct etiologies. Unlike for — Low consumption of fruits and
noncardia gastric cancer, Helicobacter pylori does not vegetables
seem to be a risk factor for cardia gastric cancer in Obesity —
Western countries (15), so its decline in prevalence GERD —
would not be expected to affect cardia gastric cancer
rates. In contrast, obesity and gastroesophageal reflux
seem to be the risk factors for cardia but not noncardia Demographic and Environmental Risk Factors
gastric cancer. Obesity has been increasing in preva-
Gastric cancer is a multifactorial disease, and both
lence in Western countries (16), which may contribute to
environmental and genetic factors have a role in its etiol-
the rates of cardia gastric cancer. Finally, improvements
ogy. Some of these risk factors, such as age and sex are not
in classification of tumors of the stomach might have
modifiable, whereas others such as smoking and H. pylori
contributed to an apparent increased rate of gastric
infection potentially are.
cardia adenocarcinoma (17).
Risk factors for cancers arising from cardia and non-
Other exceptions to the overall decreasing rates of
cardia regions of the stomach may be different (Table 1).
gastric cancer have been recently noted. For example, an
Common risk factors for both cardia and noncardia
increased incidence among young White populations in
gastric cancer include older age, male sex, tobacco
the United States has been recently reported (18) but these
smoking, radiation, and family history. Intake of aspirin
findings may need further confirmation.
and statins may prevent against both of these cancers.
Although race is a risk factor for each, the direction
Survival differs by site. In the United States, Whites are more
Since 1970s, there have been notable improvements in likely to acquire cardia gastric cancer, whereas Hispa-
the relative 5-year survival rates for gastric cancer, for nics are more likely to be diagnosed with noncardia
example, from 15% in 1975 to 29% in 2009 in the United gastric cancer. Factors associated with cardia gastric
States (8). However, survival rates remain dismal (19). The cancer, but not noncardia gastric cancer, include obesity
overall 5-year relative survival rate is about 20% in most and gastroesophageal reflux disease (GERD). On the
areas of the world, except in Japan, where 5-year survival other hand, risk factors that are exclusive for noncardia
rates of above 70% for stages I and II of gastric cancer have gastric cancer include H. pylori infection (at least in
been reported (20). Such high survival rates may be due to Western countries), low socioeconomic status, and per-
effectiveness of mass screening programs in Japan or, haps dietary factors such as low consumption of fruits
alternatively, perhaps due to overdiagnosis, that is, the and vegetables and high intake of salty and smoked
identification of localized cancers by screening programs food.
which would not have progressed to invasive cancer or
caused mortality (21). Age
Recent studies suggest that survival may be better in The incidence rate of gastric cancer rises progressively
patients with gastric cancer tumors that harbor Ebstein– with age. Of the cases diagnosed between 2005 and 2009 in
Barr virus, which constitute approximately 9% of tumors the United States, approximately 1% of cases occurred
(22). Survival is poorer among smokers, as they are more between the ages of 20 years and 34 years, whereas 29%
likely to develop subsequent primary cancers of the stom- occurred between 75 years and 84 years (25). During this
ach (23) and may also die of other complications of period, the median age at diagnosis of gastric cancer was
smoking (24). 70 years (25).

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 Karimi et al.

Male sex Helicobacter pylori

Compared with females, males have a higher risk of In their pivotal letter published in Lancet, the two dis-
both cardia (5-fold) and noncardia gastric cancer (2-fold; coverers of the H. pylori presciently noted that: "[the
ref. 26). The reasons for such differences are not clear. bacteria] may have a part to play in other poorly under-
Environmental or occupational exposures may play a role. stood, gastritis-associated diseases (i.e., peptic ulcer and
For example, men have been historically more likely to gastric cancer)" (40). Significant research over the ensuing
smoke tobacco products, although elevated rates in men two decades established H. pylori as an incontrovertible
seem to persist even in countries where men and women cause of gastric cancer (41), with relative risks of approx-
have similar smoking patterns (27). Alternatively, sex imately 6 for noncardia gastric cancer (42). Certain H. pylori
differences may reflect physiologic differences. Estrogens types, particularly those positive for the virulence factor
may protect against the development of gastric cancer. In cytotoxin-associated gene A (cagA), are more likely to cause
women, delayed menopause and increased fertility may gastric cancer (43–45). H. pylori is estimated to cause 65%
lower the risk of gastric cancer, whereas anti-estrogen to 80% of all gastric cancer cases, or 660,000 new cases
drugs, for example tamoxifen, may increase the rates of annually (42, 46). These numbers may be underestimated,
gastric cancer (28, 29). These hormones may provide as most epidemiologic studies have used ELISA to assess
protection against gastric cancer during the fertile years H. pylori infection, a method that is insufficiently sensitive
of women but their effect is diminished after menopause, for this purpose. More recent studies that have used the

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such that females develop gastric cancer in a manner Western blot assay have found relative risk closer to 21
similar to males, albeit with a 10- to 15-year lag after their (47). It has to be noted that, at least in Western countries,
male counterparts (30, 31). H. pylori is a major risk factor for only noncardia gastric
cancer but not for cardia gastric cancer (42). Decreasing
Cigarette smoking H. pylori prevalence (48, 49), perhaps due to better sanita-
Although the role of smoking in causing several other tion and extensive use of antibiotics, may be a major reason
cancers has long been established, it was not until 2002 for rapid decline in the incidence of noncardia gastric
that the International Agency for Research on Cancer cancer. It is not entirely clear how H. pylori causes gastric
concluded that there was "sufficient" evidence of causality cancer. Two potential pathways are most considered:
between smoking and gastric cancer (32). The reason for indirect action of H. pylori on gastric epithelial cells by
such delay is, in part, that the association between smok- causing inflammation and direct action of the bacteria on
ing and gastric cancer has not been consistent across epithelial cells. H. pylori could also directly modulate
studies, and that the association is not strong. A meta- epithelial cell function through bacterial agents, such as
analysis of cohort studies showed that the risk of gastric CagA. Although the relationship between the two path-
cancer is increased by only 60% (RR:1.6) in male smokers ways is unclear, both pathways seem to work together to
and 20% (RR:1.2) in female smokers compared with never promote gastric cancer development (50).
smokers, and the associations are even weaker in former
smokers (33). Although studies vary, overall the accumu- Low socioeconomic status
lated data suggest that smoking is a risk factor for both At least since the studies of Villerme (51) and Chadwick
cardia and noncardia gastric cancer (33–35). Other forms (52) in the first half of the 19th century, we have known
of tobacco use, such as hookah use, have also been asso- that lower socioeconomic status is associated with higher
ciated with higher risk of gastric cancer (36), although risk of total and cause-specific mortality, including mor-
these associations have not been found in other studies tality from most cancers (53, 54). Gastric cancer and its
(37) and need further confirmation. precursor lesions have been associated with markers of
low socioeconomic status, including low education and
Race low income (55–57). Higher rates of H. pylori infection,
Comparing Whites to other racial groups, cardia higher intake of starchy food, or lower access to fresh food
gastric cancer is approximately twice as common (26), and vegetables may be responsible for the association
whereas noncardia gastric cancer is approximately half between low socioeconomic status and higher risk of
as common (38). The risk of noncardia gastric cancer in gastric cancer (58). The prevalence of H. pylori, particu-
the United States is highest among Asians/Pacific Islan- larly CagA-positive strains, is substantially higher in low-
ders, Blacks, followed by Hispanics, and is least com- income African Americans (59) and may contribute to
mon in Whites (26). The association of race with the higher risks in this group.
incidence of gastric cancer seems to be mediated mostly
via environmental effects, rather than genetic varia- Intake of salty and smoked food
tions. Japan has one of the highest rates of gastric cancer The World Cancer Research Fund/American Institute
incidence in the world (10). After the Japanese migrate for Cancer Research (WCRF/AICR) has concluded that:
to the United States, they maintain very high rates in "Salt, and also salt-preserved foods, are probably causes of
their first generation. However, their rates decline and [gastric cancer]" (60). A 1965 study showed a strong
become similar to those of Americans of European correlation between mortality from stroke and gastric
lineage after two generations (39). cancer across geographic areas and over time, which

702 Cancer Epidemiol Biomarkers Prev; 23(5) May 2014 Cancer Epidemiology, Biomarkers & Prevention
 Gastric Cancer

suggested salt as a risk factor for both (61). Epidemiologic Antioxidant use
and experimental studies supported this hypothesis. A Although intake of vitamin and antioxidants was once
recent meta-analysis of 11 case–control and cohort studies considered to be effective to prevent cancers, well-con-
showed that higher intake of salt increases the risk of ducted randomized trials have generally shown very little
gastric cancer by 22% (62). Also, large cohort studies in or no benefit from their use to prevent gastric cancer or to
Korea have shown that people who tend to prefer salty promote overall health (75, 76). However, dietary supple-
food have higher risk of gastric cancer (63). Salt may mentation may play a preventive role in populations with
increase the risk of gastric cancer through direct damage high rates of gastric cancer and low intake of micronu-
to the gastric mucosa resulting in gastritis or other trients (74, 77).
mechanisms (64).
The role of smoked food in gastric carcinogenesis was Other dietary factors
suggested in the early 1960 (65). Studies in Europe at the Several other dietary factors or patterns have been
time showed that gastric cancer rates were highest in studied in relation to gastric cancer. Studies have sug-
Finland and Iceland, where smoked fish and meat use gested that adherence to Mediterranean diet (78), diets
was very high, which led to a further examination of that may be titled prudent or healthy (79), diets with high
smoked food and their polycyclic aromatic hydrocarbon antioxidant capacity (80), and diets with high fiber content
(PAH) content in gastric carcinogenesis (66). Since then, (81) are associated with lower gastric cancer risk. Con-

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benzo[a]pyrene and other PAHs formed in smoked food versely, diets that have a Western pattern (79) may
have been incriminated in many areas of the world with increase gastric cancer risk. However, these findings need
high gastric cancer rates (67). to be confirmed in future studies.
In addition, certain cooking practices may be associ-
ated with increased risk of gastric cancer. These include Nonsteroidal anti-inflammatory drugs
broiling of meats, roasting, grilling, baking, and deep Current evidence suggests that intake of nonsteroidal
frying in open furnaces, sun drying, curing, and pickling, anti-inflammatory drugs (NSAID) may have an inverse
all of which increase the formation of N-nitroso com- association with gastric cancer risk. Two meta-analyses of
pounds (68). observational studies have shown an inverse association
between aspirin or any other NSAIDs and cardia and
Low consumption of fruits and vegetables noncardia gastric cancer (82, 83), whereas another one
The WCRF/AICR in 2007 commented that: "Non- reported an inverse association of aspirin use with non-
starchy vegetables, including specifically allium vege- cardia gastric cancer but not with cardia gastric cancer
tables, as well as fruits probably protect against gastric (84). The two most-updated meta-analyses (one with 13
cancer" (60). In this report, a 50 g/day intake of allium and the other with 15 studies) reported an inverse asso-
vegetables was associated with a 23% reduction in risk ciation between aspirin use and all gastric cancer (OR ¼
of gastric cancer, a number that was confirmed in a 0.65), with little difference between case–control and
recent meta-analysis (69). Such an association is plau- cohort studies in this regard (85, 86). These two studies
sible, as fruit and vegetables are rich sources of vitamin did not report the results by subsites of gastric cancer.
C, folate, carotenoids, and phytochemicals, which may On the other hand, in a pooled analysis of seven clinical
inhibit carcinogenesis by modulating xenobiotic-metab- trials of daily aspirin use (done originally for prevention
olizing enzymes. of vascular events), the risk of death from gastric cancer
However, despite many years of research and a plau- in the aspirin taking group was not lower than in the
sible hypothesis, the epidemiologic literature remains control group: the HR (95% confidence interval; CI) was
inconsistent (70, 71). WCRF/AICR’s 2007 position of 1.85 (0.81–4.23) for 0 to 5 years of follow-up and 3.09 (0.64–
"probable" protection of gastric cancer by fruit and vege- 14.9) for longer follow-up. These estimates were, how-
tables was a withdrawal from its 1997 position, which ever, based on 36 gastric cancer deaths only (87).
concluded that there was "convincing" evidence. This
change was largely because cohort studies published Statins
between the two reviews did not replicate the strong Two recent meta-analyses (88, 89) suggested that statin
protections that were mostly found in earlier case–control intake was associated with an approximately 30%
studies. Since the publication of WCRF/AICR report, the reduced risk of gastric cancer. However, when a study
results of other large cohort studies have been conflicting, with outlier results was excluded, the risk reduction was
too. Although the one large cohort study found no evi- approximately 15%, which was homogeneous across
dence for protection (72), another one found a statistically studies. Statins have been associated with reduced risk
significant inverse association (73). The results are also of some other cancers, such as esophageal adenocarcino-
mixed for cardia and noncardia gastric cancer. In a high- ma (90), and a host of mechanisms has been suggested for
risk Chinese population, a randomized trial of 7.3 years of a lower risk of cancer associated with statin use (91).
supplementation with garlic extract and oil resulted in a Nevertheless, statins are not associated with a reduced
statistically nonsignificant reduction in gastric cancer risk of all cancer incidence or morality, particularly in
incidence or mortality (74). randomized trials (92). As such, the reduced risk of gastric

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 Karimi et al.

cancer associated with statin use needs to be further A null or an inverse association has been reported for
investigated. GERD and noncardia gastric cancer (100, 101, 104, 106,
110). This may be explained, at least partly, by the
Obesity association between atrophic gastritis and noncardia
Obesity is a growing problem in modern societies and gastric cancer. Severe atrophic gastritis may be associ-
has been associated with a range of diseases, including ated with decreased secretion of gastric acid and lower
the cardia gastric cancer. Compared with individuals risk of GERD (106).
with body mass index (BMI) of <25, individuals with
BMIs of 30 to 35 have a 2-fold, and those with a BMI of Radiation
>40 have a 3-fold risk of cancers of the esophagogastric Long-term follow-up of survivors of Hiroshima and
junctional, including the cardia gastric cancer (93). In Nagasaki established radiation as a risk factor for gastric
contrast, obesity is not a risk factor for noncardia gastric cancer (111). A recent study of survivors of Hodgkin’s
cancer (94). Several mechanisms have been proposed. lymphoma also showed that radiation to the stomach had
Abdominal fat may directly cause GERD, a risk factor a dose–response association with higher risk of gastric
for esophageal cancer and cardia gastric cancer. More- cancer (112). This effect was particularly pronounced in
over, fat is metabolically active and produces numerous those who concomitantly received procarbazine as the
compounds that circulate in the body. These metabolic chemotherapeutic agent, such that those who received

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products, such as insulin-like growth factor and leptin, both high-dose radiation and procarbazine had a 77-fold
have been associated with malignancies, possibly increased risk of subsequent gastric cancer (112). Little
through the induction of progrowth changes in the cell information is available for cardia and noncardia gastric
cycle, decreased cell death, and proneoplastic cellular cancer.
changes (95, 96).
Other potential risk factors
Physical activity A number of other risk factors have been investigated in
A recently published meta-analysis (97) showed a 21% relation to gastric cancer but the results are not convinc-
reduction in gastric cancer risk, comparing individuals ing, at least as of yet. Among these risk factors are poor
who are most active with those who are least active. This oral hygiene and tooth loss (37, 113, 114), opium use
risk reduction was seen for both cardia gastric cancer (20% (36, 115–117), infection with Ebstein–Barr virus (118,
risk reduction) and noncardia gastric cancer (37% risk 119), and eating pickled vegetables (120).
reduction). However, risk reductions were less strong in
high-quality studies. Furthermore, because all included
studies were observational, the potential for confounding Familial Aggregation
should be considered. A positive family history (having a first-degree relative
with gastric cancer) is a risk factor for gastric cancer (121).
Gastroesophageal reflux disease The magnitude of the relative risk differs by country and
GERD is strongly associated with risk of esophageal study, ranging from 2 to 10 (122). Positive family history
adenocarcinoma, with approximately 5- to 7-fold increase could be a risk factor as a result of shared environment, for
in the risk (98). Several studies have also reported statis- example, passing of H. pylori from parents to children, or
tically significant associations between GERD and cardia because of shared genetic factors (123).
gastric cancer (99–103), with increased risks of 2- to 4-folds Studies have shown two patterns of risk change after
in the majority of studies, although not all studies agree migration. First, the risk of gastric cancer in migrants gets
(104–106). closer to that of the population of origin but does not reach
Some investigators have suggested that there might the risk of the host population in the immigrant or the first-
exist two distinct forms of cardia gastric cancer: one generation postmigration; it takes at least two generations
similar to esophageal adenocarcinoma and associated to reach the risk levels of the adopted country (123–125).
with GERD and one similar to noncardia gastric cancer Second, place of birth is perhaps a stronger predictor of
and associated with severe atrophic gastritis and H. pylori gastric cancer risk than current place of residence (126,
infection (103, 107, 108). This pattern, if it truly exists, 127). These findings show the importance of childhood
could explain the null association observed in some exposure in the etiology of gastric cancer, such that
populations. If the association between GERD and cardia migrants do not lose their risk in the generation who
gastric cancer is real, then the mechanism might be similar migrated or their children who migrated with them early
to those for the association between GERD and esoph- in their life. One example of a risk factor that could take a
ageal adenocarcinoma: GERD may cause columnar and couple of generations to modify is that H. pylori infection
intestinal metaplasia with potential progression to ade- usually happens before the age of 10 years (48, 128),
nocarcinoma (109). Alternatively, however, esophageal typically before one migrates. Even when children are
adenocarcinomas are adjacent to and often cross the upper born in the adopted country, they are likely to contract H.
border of the stomach, thus may be misclassified as cardia pylori from parents, older siblings, or other people who
cancers (93, 102). have migrated from their native country (129).

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Genetic Risk Factors and Korean (136) and two in Chinese (137, 138) popula-
Only 1% to 3% of gastric cancer cases arise as a result of tions. In both Japanese and Korean populations, this
inherited syndromes (130), which are briefly discussed in association was much stronger with the diffuse type of
the "Hereditary syndromes" section. The rest are sporadic gastric cancer than with the intestinal type (Table 2). In
gastric cancer cases, for whom no major high-penetrance one of the Chinese studies, a SNP in PSCA was asso-
genes have been discovered. Investigation of genetic risk ciatied with noncardia gastric cancer but not with cardia
factors for sporadic cases is discussed under "Single- gastric cancer (138). The other Chinese study that
nucleotide polymorphisms." reported a positive association included noncardia gas-
tric cancer cases only (137).
Hereditary syndromes Significant associations between SNPs at 1q22, located
These syndromes include hereditary diffuse gastric in Mucin 1, cell surface-associated (MUC1) gene, and
cancer (HDGC), familial adenomatous polyposis (FAP), gastric cancer were reported in the GWAS of Japanese
and Peutz–Jeghers syndrome (PJS). and Korean (136) and two independent GWAS of Chinese
HDGC is a rare, autosomal dominant inherited form populations (137, 138). Meta-analysis of the results from
of gastric cancer, usually with a highly invasive diffuse Japanese and Korean populations identified several other
type tumor, a late presentation, and a poor prognosis SNPs in MUC1 that were significantly associated with
(131). These cancers display a prominent molecular gastric cancer risk (140). These SNPs had stronger asso-

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abnormality, defective intercellular adhesions, which ciations with diffuse type than with intestinal type of
might be the result of loss of expression of the cell gastric cancer. In one of the GWAS in Chinese population,
adhesion protein E-cadherin (132). Approximately positive associations between SNPs in MUC1 and cardia
25% of families with HDGC have inactivating CDH1 and noncardia cancers were similar (138). The other Chi-
germline mutations (132). The penetrance of CDH1 gene nese study that reported a positive association included
mutations is high, with an estimated risk of >80% for noncardia gastric cancer cases only (137). MUC1 encodes
both men and women by the age of 80 years, and the mucin glycoproteins expressed in most epithelial cells,
median age at diagnosis of 38 years. including gastric epithelium.
FAP is an autosomal-dominant colorectal cancer syn- Additional loci have been identified. Two independent
drome, caused by a mutation in the adenomatous poly- GWAS in Chinese reported associations between multiple
posis coli gene (133). Patients with FAP carry a 100% risk variants at 10q23, located in gene PLCE1, and cardia
of colorectal cancer by the age of 35 to 40 years, as well as a gastric cancer risk (138, 139). One of these GWAS did not
high risk of other malignancies, including gastric cancer. include noncardia gastric cancer cases (139). The other one
PJS is a rare autosomal dominant inherited condition, did not find any association between SNPs in PLCE1
characterized by hamartomatous gastrointestinal polypo- region and noncardia gastric cancer (138). Other loci were
sis, and melanin spots on the lips and buccal mucosa (134). found in the Chromosome 20 open reading frame 54
Germline mutation of the LKB1 gene, which encodes a (C20orf54) gene (137, 139), the first intron of PRKAA1
serine/threonine kinase that acts as a tumor suppressor, is (encoding protein kinase, AMP-activated, a-1 catalytic
a cause of PJS. subunit, AMPK) and adjacent to PTGER4 (encoding pros-
taglandin E receptor 4), and the second SNP located in the
Single-nucleotide polymorphisms intron of ZBTB20 (encoding zinc finger and BTB domain
Before the advent and wide use of genome-wide scans, containing protein 20; ref. 137).
hundreds of case–control studies examined candidate The mechanism of action is not yet clear for any of these
polymorphisms (mostly chosen based on biologic plau- polymorphisms. Hopefully, however, these findings will
sibility) in relation to gastric cancer. Although some of lead to mechanistic insights into gastric carcinogenesis.
these associations showed promise, nearly all failed to
replicate. For example, the initially exciting associations
found for polymorphisms in inflammatory genes, in par- Screening
ticular interleukin-1B polymorphisms, were not replicated Screening to detect gastric cancer at its early stages can
in future studies (135), including in genome-wide asso- be done for large masses of the population (mass screen-
ciation studies (GWAS). ing) or for individuals at high risk (opportunistic screen-
In contrast with candidate studies, results from very ing). Although the value of screening mass populations
large GWAS seem to be reproducible (refs. 136–139; Table for gastric cancer remains controversial (141), it has been
2). So far, all GWAS results are from East Asians, includ- provided in some countries with high incidence of gastric
ing Japanese, Korean, and Chinese populations. Howev- cancer, such as Japan, Venezuela, and Chile. In contrast, in
er, results from other populations are expected in the next countries with low incidence of gastric cancer, such as the
few years. United States, this strategy is costly and unwarranted. In
A significant association between single-nucleotide low-risk regions, only people with certain conditions may
polymorphisms (SNP) located in the prostate stem cell benefit from gastric cancer screening, including older
antigen (PSCA) gene and gastric cancer has been individuals with chronic gastric atrophy or pernicious
reported by three independent GWAS: one in Japanese anemia, and patients who have had gastric polyps, partial

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Table 2. Susceptibility loci associated with higher risk of gastric cancer identified in GWAS

SNPs by nearest Case/ Allele-specific

gene (locus) Study Ethnicity Subtype control OR (95% CI) P
PSCA (8q24.3)
rs2294008 (T>C) Sakamoto et al. (136) Japanese — 749/750 1.58 (1.35–1.85) 6.3  109
— — Diffuse 925/1,396 1.67 (1.47–1.90) 2.2  1015
— — Intestinal 599/1,396 1.29 (1.11–1.49) 6.0  104
— Korean Diffuse 454/390 1.91 (1.57–2.33) 6.3  1011
— — Intestinal 417/390 1.37 (1.12–1.69) 0.0017
Abnet et al. (138) Chinese Cardia 1,213/3,302 — 0.53
— — Noncardia 917/3,302 1.27 (1.09–1.47) 1.63  103
Shi et al. (137) Chinese Noncardia 4,294/5,882 1.36 (NR) 2.1  107
rs2976392 (A>G) Sakamoto et al. (136) Japanese —a 749/750 1.62 (1.38–1.89) 1.1  109
— — Diffuse 926/1,397 1.71 (1.50–1.94) 1.5  1016
— — Intestinal 926/1,397 1.29 (1.12–1.49) 5.0  104

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— Korean Diffuse 449/390 1.90 (1.56–2.33) 8.0  1011
— — Intestinal 416/390 1.37 (1.12–1.68) 0.0017
Shi et al. (137) Chinese Noncardia 4,294/5,882 1.35 (NR) 3.7  107
MUC1 (1q22)
rs4072037 (A>G) Abnet et al. (138) Chinese Cardia 1,213/3,302 0.75 (0.62–0.87) 9.5  105
— — Noncardia 917/3,302 0.72 (0.62–0.85) 5.7  105
— — Total 2,240/3,302 0.75 (0.67–0.84) 4.2  107
Shi et al. (137) Chinese Noncardia 4,294/5,882 0.73 (NR) 1.0  104
rs4460629 (C>T) Abnet et al. (138) Chinese Cardia 1,213/3,302 0.74 (0.64–0.86) 1.3  104
— — Noncardia 917/3,302 0.75 (0.64–0.88) 5.4  104
— — Total 2,240/3,302 0.75 (0.67–0.85) 2.3  106
rs2070803 (A>G) Sakamoto et al. (136)b Japanese —a 749/750 1.62 (1.33–1.98) 1.2  106
rs2075570 (G>A) Sakamoto et al. (136)b Japanese —a 749/750 1.65 (1.34–2.02) 9.2  107

PLCE1 (10q23)
rs2274223 (A>G) Wang et al. (139) Chinese Cardia 2,766/11,013 1.55 (1.45–1.66) 1.7  1039
Abnet et al. (138) Chinese Cardia 1,213/3,302 1.57 (1.40–1.76) 4.2  1015
— Noncardia 917/3,302 1.02 (0.86–1.22) 0.15
rs3765524 (C>T) Abnet et al. (138) Chinese Cardia 1,213/3,302 1.56 (1.40–1.75) 7.4  1015
— Noncardia 917/3,302 1.03 (0.87–1.22) 0.16
rs3781264 (T>C) Abnet et al. (138) Chinese Cardia 1,213/3,302 1.60 (1.41–1.81) 1.1  1013
Noncardia 917/3,302 1.18 (0.97–1.42) 0.25
rs11187842 (C>T) Abnet et al. (138) Chinese Cardia 1,213/3,302 1.63 (1.42–1.87) 7.1  1012
— Noncardia 917/3,302 1.17 (0.97–1.42) 0.26
rs753724 (G>T) Abnet et al. (138) Chinese Cardia 1,213/3,302 1.63 (1.42–1.87) 8.0  1012
— Noncardia 917/3,302 1.19 (0.99–1.44) 0.16

C20orf54 (20p13)
rs13042395 (C>T) Shi et al. (137) Chinese Noncardia 4,294/5,882 0.80 (NR) 6.9  104
Wang et al. (139) Chinese Cardia 2,766/11,013 0.91 (0.85–0.97) 3.0  103

PRKAA1, PTGER4 (5p13.1)

rs13361707 (T>C) Shi et al. (137) Chinese Noncardia 4,294/5,882 1.41 (1.32–1.49) 7.6  1029

ZBTB20 (3q13.31)
rs9841504 (C>G) Shi et al. (137) Chinese Noncardia 4,294/5,882 0.76 (0.69–0.83) 1.7  109

Abbreviation: NR, not reported.

a
Only participants included in a part of the study (stage II of the screening study).
b
Another gene in the original paper was mentioned as the nearest gene. Further fine mapping showed that the SNP was located in
MUC1 gene (140). Meta-analysis of the results from Japanese and Korean populations in this study showed more significant
associations between rs2075570 (OR ¼ 1.71; 2.3  1012) and rs2070803 (OR ¼ 1.71; 4.3  1013) and gastric cancer (140).

706 Cancer Epidemiol Biomarkers Prev; 23(5) May 2014 Cancer Epidemiology, Biomarkers & Prevention
 Gastric Cancer

gastrectomy, FAP, and hereditary nonpolyposis colon antibodies suggests the highest risk (150), as it may indi-
cancer (142). cate that atrophy is so severe that it has led to the decline of
Screening may be done using markers of atrophy in the H. pylori populations in the stomach.
stomach (a precursor lesion of gastric cancer), such as
serum pepsinogens or serum ghrelin; or serum antibodies Serum ghrelin
to H. pylori, the main risk factor for gastric cancer; or Ghrelin, a hormone secreted by the gastric mucosa, has
examining the stomach mucosa using methods such as a key role in maintaining energy balance (151). Chronic
barium photofluorography or endoscopy (143). We have inflammation and atrophic gastritis due to H. pylori infec-
reviewed these approaches below. tion may reduce production of ghrelin, thus low serum
ghrelin may indicate higher risk of gastric cancer. This
Photofluorography theory has so far been supported by a case–control and a
Barium studies, including photofluorography, have cohort study, showing a substantial and statistically sig-
been used for gastric cancer screening in Japan since the nificant increased risk of both cardia and noncardia gas-
1960s (143). The Japanese Guidelines for Gastric Cancer tric cancer associated with lower concentrations of ghrelin
Screening, which used data from five case–control and (152, 153). In these studies, serum ghrelin was a predictor
two cohort studies, recommended photofluorography for of gastric cancer independent of serum PGI or PGI/II
both mass screening and opportunistic screening (143). ratio.

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Several studies have shown that the 5-year survival using
these methods could increase approximately from 50% to Gastrin-17
80%. Gastrin-17 (G-17), a peptide hormone synthesized in the
Despite the fact that photofluorography has the best G cells of the gastric antral region, stimulates the secretion
evidence among all methods used to screen for gastric of gastric acid. Therefore, its levels are determined by the
cancer, there is no published randomized trial to assess its health and function of the antrum of the stomach, as well
efficacy. Observational studies used to determine the as by the acid produced from the gastric parietal cells. As
efficacy of photofluorography may be subject to biases such, the interpretation of G-17 levels in relation to gastric
(144). For example, participants in Japanese national mass cancer is not straightforward. When atrophy is predom-
screening programs were more likely to consume more inantly in the corpus, but the antrum is relatively intact,
vegetables, milk, and dietary fiber, and were less likely to lower acid levels produced in the corpus increase the
smoke than the general population (145). When such levels of G-17. However, when atrophy is seen in both
healthier volunteers choose to screen, the results will the antrum and the corpus, G-17 levels may be normal or
favor screening regardless of its real effect. low. Therefore, atrophy of the stomach, a precursor lesion
of the gastric cancer, may result in lower, normal, or
Serum pepsinogens higher levels of G-17. Given that there are very few
Pelayo Correa has suggested a progression model for epidemiologic studies of G-17 in relation to gastric cancer
intestinal type of gastric cancer (146). In this model, (141), the value of G-17 for screening gastric cancer is
intestinal type gastric cancer develops after a prolonged unclear.
latency period and is preceded by several precancerous
stages, namely superficial gastritis, atrophic gastritis, Antigastric parietal cell antibodies
small intestinal metaplasia, colonic metaplasia, mild, These antibodies, which target parietal cells of the
moderate, and severe dysplasia. Development of atrophic stomach, have been recently associated with a substan-
gastritis leads to reduced production of several proteins tially higher risk of atrophic gastritis (154). The association
secreted from the normal stomach, including pepsinogen was much stronger in H. pylori-negative (OR ¼ 11.3) than
I, which could be used for screening. There are two in H. pylori-positive (OR ¼ 2.6) individuals. Therefore,
immunologically distinct types of pepsinogens: serum antigastric parietal cell antibody (APCA) may play a role
pepsinogen I (PGI) and serum pepsinogen II (PGII; in gastric carcinogenesis via causing atrophy, and it may
ref. 147). With the development of atrophic gastritis, be used as a complement to other markers, such as H.
serum PGI concentration declines, whereas levels of PGII pylori and pepsinogens. However, this needs to be tested
remain relatively constant. Therefore, serum PGI/II ratio in prospective cohort studies.
may be used as a marker future development of gastric
cancer. Some studies suggest that PGI/II ratio can be used Endoscopy
as a continuous marker, meaning that the lower the PGI/II Upper gastrointestinal endoscopy is the gold standard
ratio, the higher the risk of gastric cancer (148, 149). Lower for the diagnosis of gastric cancer. This technique is
PGI/II ratio predicts higher risk of both noncardia and widely used for gastric cancer screening in Japan, Korea,
cardia gastric cancer. Venezuela, and other high-risk areas because of its high
Combining H. pylori serology and serum pepsinogen detection rate. Although the recent literature suggests that
concentrations may aid in better prediction of gastric endoscopic screening is cost-effective in high-incidence
cancer development. It has been suggested that a combi- areas, further studies are needed to determine the overall
nation of low PGI (or PGI/II ratio) with negative H. pylori effectiveness of this approach (155). In average-risk

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 Karimi et al.

populations, there is no evidence that endoscopic screen- than 5 g/day by the year 2025 (164). Although salt restric-
ing is effective or cost-effective (156). Moreover, endos- tion is a topic that most agree on, there seems to be a
copy is an invasive procedure, with a small risk of hem- delicate balance; too restrictive intake of salt, below indi-
orrhage and perforation, and reported mortality of vidual’s needs, may not be recommended either (165).
0.0008% and a morbidity of 0.43% (157).
Consensus guidelines developed in a recent meeting of Increasing fruit and vegetable intake
several European gastroenterology societies (158) suggest The causal association between higher intake of fruit
that patients with extensive atrophy and/or intestinal and vegetables with gastric cancer remains unclear. How-
metaplasia should be offered surveillance endoscopy ever, it may still be advisable to increase fruit and vege-
every 3 years. In addition, the guidelines recommend table intake, as this is an overall healthy behavior.
surveillance for patients with other high-risk conditions,
including FAP and hereditary nonpolyposis colorectal Other healthy behaviors
cancer. The success of endoscopic evaluation is highly Studies thus far suggest that Mediterranean diet, higher
dependent on the skills of the endoscopist and the ability intake of fibers, and physical activity are associated with
to detect highly subtle mucosal changes (159). Several lower risk of gastric cancer. Similar to what was discussed
recent studies suggest that advanced endoscopic imaging for fruit and vegetable intake, the causality with respect to
modalities have greater accuracy for the diagnosis of gastric cancer is unclear but they can be advised because

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gastric neoplasia than standard, "white light" endoscopy. of their other health benefits.
For example, chromoendoscopy, using mucosal dyes and
stains (typically indigo carmine or methylene blue) is H. Pylori eradication
frequently used in Japan and Korea to highlight subtle A meta-analysis of seven randomized studies has dem-
mucosal irregularities and delineate areas for endoscopic onstrated that treatment of H. pylori can reduce gastric
removal (160). Narrow band imaging, a filter-based cancer risk by 35% (166). American and European guide-
enhancement technology, has been shown to increase the lines recommend H. pylori eradication for all patients with
diagnostic yield and accuracy for the detection of gastric atrophy and/or intestinal metaplasia and for all first-
neoplasia (161). Additional, digital-based enhancement degree relatives of gastric cancer patients in addition to
technologies have been developed; however, none have endoscopic and histologic surveillance (67). The Asian
been evaluated rigorously in randomized trials. The lim- Pacific Gastric Cancer Consensus has recommended pop-
itation of these advanced imaging technologies is lack of ulation-based screening and treatment of H. pylori infec-
widespread availability and issues relating to training in tion in regions with an annual gastric cancer incidence
the interpretation of these "enhanced" images. Further more than 20 of 100,000 (167). Screening and treatment for
studies are needed to determine the optimal modality, or H. pylori are perhaps most effective in younger ages (168),
more likely, combination of modalities needed for the at least 10 to 20 years before the age of rapid increase in
detection of gastric neoplasia. gastric cancer incidence (e.g., between 30–40 years of age),
as treatment is less helpful when dysplasia has occurred
(142, 169). Nevertheless, treatment has some effect even
Prevention after cancer has occurred; treating H. pylori after cancer
Prevention of gastric cancer may be achieved using diagnosis reduces the risk of metachronous cancer to
primary prevention, that is, by reducing gastric cancer almost half (170). Despite these findings and guidelines,
incidence, or using secondary prevention, that is, by some have argued that the presence of H. pylori in the
detecting and treating the disease at its early stages. Any stomach may have some benefits (41), and that a decision
prevention strategy should consider all benefits and to mass eradicate it may be premature (171).
harms (162). Some methods of primary and secondary
prevention of gastric cancer, and their benefits and harms, Other medications
have been discussed below. Observational studies suggest that intake of NSAIDs
and statins may reduce gastric cancer risk. If truly causal, a
Smoking cessation byproduct of the recent recommendations to expand the
Because smoking has been recognized as a cause of use of statins (172, 173) may be a reduction of gastric
gastric cancer, avoiding smoking would likely reduce cancer incidence too.
gastric cancer incidence as well as provide many other
health benefits. Secondary prevention
In high-risk populations, such as Japan, annual screen-
Reducing salt intake ing with a double-contrast barium technique and endos-
Salt intake restriction may not only be useful for reduc- copy is recommended for persons over the age of 40 years
ing the incidence of gastric cancer (142), but also for (174). In other populations, targeting high-risk people
lowering the risk of other major diseases, including stroke for aggressive screening and prevention may decrease
and myocardial infarction (163). World Health Organiza- gastric cancer mortality. However, neither the American
tion has made it a goal to reduce salt intake globally to less Cancer Society (175) nor the National Cancer Institute

708 Cancer Epidemiol Biomarkers Prev; 23(5) May 2014 Cancer Epidemiology, Biomarkers & Prevention
 Gastric Cancer

currently recommends gastric cancer screening in the incidence rates are higher in men than women, further
United States. well-conducted trials on the role of aspirin, other NSAIDs,
and statins in the prevention of gastric cancer, whole-
Summary and Suggestions for Further Research genome sequencing of tumors to identify common muta-
Gastric cancer remains a common cancer and a sub- tions and rearrangements, and to determine whether
stantial focus of clinical, epidemiologic, and translational these alterations are associated with particular etiologic
research. Previous research has identified several envi- risk factors and with particular treatments and improving
ronmental and genetic risk factors and also some predis- early detection of these deadly tumors.
posing conditions. However, there are still many gaps in
our knowledge of causes and early detection of gastric Disclosure of Potential Conflicts of Interest
No potential conflicts of interest were disclosed.
cancer. Some areas of potential interest for future research
include monitoring the incidence trends (18), further Acknowledgments
evaluation of suggested but unconfirmed risk factors such The writing of this review article was supported in part by the Intra-
as opium, further assessment of radiation and chemother- mural Program of the National Cancer Institute, NIH.

apy as risk factors for gastric cancer in cancer survivors,

conducting GWAS in Caucasian and African populations, Grant Support
No financial support was sought for writing this review.
identifying the mechanisms of identified SNPs, assessing

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the role of ghrelin, other gastrointestinal tract hormones, Received October 24, 2013; revised February 6, 2014; accepted February
and APCA in gastric cancer risk, understanding why 6, 2014; published OnlineFirst March 11, 2014.

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