Seminars in Cancer Biology 23P (2013) 492501

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Seminars in Cancer Biology

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Review

Eradication of gastric cancer is now both possible and practical

Akiko Shiotani a , Putao Cen b , David Y. Graham c,
a
Department of Internal Medicine, Kawasaki Medical School, Okayama, Japan
b
Medical Oncology University of Texas Health Science Center in Houston, Houston, TX, USA
c
Department of Medicine, Michael E. DeBakey VAMC and 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

Keywords: In 1994, Helicobacter pylori was declared a human carcinogen. Evidence has now accumulated to show
Prevention that at least 95% of gastric cancers are etiologically related to H. pylori. An extensive literature regarding
Pepsinogen atrophic gastritis and its effects on acid secretion, gastric microora, and its tight association with gas-
Atrophic gastritis
tric cancer has been rediscovered, conrmed, and expanded. Methods to stratify cancer risk based on
Gastric cancer
endoscopic and histologic ndings or serologic testing of pepsinogen levels and H. pylori testing have
Helicobacter pylori
Risk been developed producing practical primary and secondary gastric cancer prevention strategies. H. pylori
Surveillance eradication halts progressive mucosal damage. Cure of the infection in those with non-atrophic gastritis
Primary prevention will essentially prevent subsequent development of gastric cancer. For all, the age-related progression
Secondary prevention in cancer risk is halted and likely reduced as eradication reduces or eliminates mucosal inammation
Natural history and reverses or reduces H. pylori-associated molecular events such aberrant activation-induced cytidine
Cancer screening deaminase expression, double strand DNA breaks, impaired DNA mismatch repair and aberrant DNA
methylation. Those who have developed atrophic gastritis/gastric atrophy however retain some residual
risk for gastric cancer which is proportional to the extent and severity of atrophic gastritis. Primary and
secondary cancer prevention starts with H. pylori eradication and cancer risk stratication to identify
those at higher risk who should also be considered for secondary cancer prevention programs. Japan
has embarked on population-wide H. pylori eradication coupled with surveillance targeted to those with
signicant remaining risk. We anticipate that countries with high gastric cancer burdens will follow their
lead. We provide specic recommendations on instituting practical primary and secondary gastric can-
cer prevention programs as well identifying research needed to make elimination of gastric cancer both
efcient and cost effective.
2013 Published by Elsevier Ltd.

1. Introduction
Gastric cancer is the fourth most common cancer and second
leading cause of cancer deaths worldwide with more than 700,000
deaths annually [1]. Currently the highest incidence rates are
in Japan, Korea, China, Eastern Europe and parts of Central and
South America [2]. This is a marked change from the early 20th
century when gastric cancer was the most common cancer in many
Abbreviations: AID, activation-induced cytidine deaminase; H. pylori, Helicobac-
ter pylori; IARC, International Agency for Research on Cancer; GI, gastrointestinal;
CI, condence interval; KLF5, Krppel-like factor 5; VCP, valosin-containing pro-
tein; OLGA, Operative Link on Gastritis Assessment; hMLH1, human mutL homolog
1; BRCA1, breast cancer susceptibility gene 1; MGMT, methylated-DNAprotein-
cysteine methyltransferase; CDKN2A, cyclin-dependent kinase inhibitor 2A; CDH1,
cadherin-1; MLH1, mutL homolog 1; RUNX3, runt-related transcription factor 3; CpG,
cytosine-phosphate-guanine are regions of DNA.
Corresponding author at: Michael E. DeBakey Veterans Affairs Medical Center,
RM 3A-318B (111D), 2002 Holcombe Boulevard, Houston, TX 77030, USA.
Tel.: +1 713 795 0232; fax: +1 713 790 1040.
E-mail address: dgraham@bcm.edu (D.Y. Graham).
Western countries including the United States [3]. It is now rec-
ognized that the vast majority of gastric cancers are etiologically
related to infection with the bacterium Helicobacter pylori (H.
pylori) [4]. The different clinical outcomes of H. pylori infections
(e.g., duodenal ulcer, gastric ulcer, gastric cancer) relate to the
different pattern of gastritis that occur (e.g., antral predominant
gastritis is associated with duodenal ulcer disease whereas atrophic
pangastritis is associated with gastric ulcer and gastric cancer).
The predominant pattern of gastritis depends on interactions
between the predominant H. pylori strain (and its virulence), host
factors (especially those related to genes that enhance or reduce
the inammatory response to the infection), and environmental
factors (of which diet appears to be the most important).
The prevalence of H. pylori and pattern of gastritis can change
rapidly within a population [5,6]. The incidence of gastric cancer
can also change rapidly. For example, between 1965 and 1995 the
incidence of gastric cancer in Japan fell approximately 60% in the
age groups between 40 and 69 (Fig. 1) [7]. During this short period
there was no change in host genes, the prevalence of H. pylori within
these age groups, or the predominant H. pylori strain, emphasiz-
ing the key role of environmental factors such as methods of food

1044-579X/$ see front matter 2013 Published by Elsevier Ltd.

http://dx.doi.org/10.1016/j.semcancer.2013.07.004
 A. Shiotani et al. / Seminars in Cancer Biology 23P (2013) 492501
500
450
Gastric Cancer Incidence
400
Ages 65-69
350
300
250
200
Cancer incidence
150
Hp prevalence
100
50
0 0
1950 1955 1960 1965 1970 1975 1980 1985 1990 1995 2000 2004
Year
Fig. 1. Changes in the incidence of gastric cancer and Helicobacter pylori infection
among Japanese men age 6569 during the latter half of the 20th century (Constance
Wang and David Y. Graham, unpublished observations).
From reference [7], with permission.
preservation and diet in dening the risk of different outcomes
[7].
A causal role for H. pylori in gastric cancer was rst accepted
by the International Agency for Research on Cancer (IARC) in 1994
when they labeled H. pylori a class I carcinogen [8]. However, this
did not immediately result in the worldwide H. pylori eradication
programs or even eradication programs in regions where gastric
cancer was especially common. One problem with moving forward
might have been that the actual risk of gastric cancer attributable
to H. pylori was greatly underestimated. This occurred, in part,
because those studying H. pylori seemed unaware of (or chose to
ignore) the tremendous body of prior research linking atrophic
gastritis with gastric cancer [9]. Early H. pylori investigators used
serology to assess its prevalence of H. pylori which systematically
underestimated its prevalence, and thus the role of H. pylori in gas-
tric cancer. The problem with serology was that the results were
frequently falsely negative which occurred because the majority
with cancer also had severe atrophic gastritis/gastric atrophy with
extensive intestinal metaplasia which produced a gastric environ-
ment unsuitable for persistence of H. pylori. Thus, despite the fact
that H. pylori had caused the precancerous changes and the sero-
logy had once been positive, it had become negative [10]. This bias
coupled with a failure to correlate gastric histology to serologic
results or to reconcile these new ndings with the extensive older
literature showing a tight association between atrophic gastritis
and gastric cancer likely set back H. pylori eradication programs by
many decades, a time during which many millions died of their gas-
tric cancers. This bias was only corrected recently by the addition
of CagA serology which generally remains positive despite loss of
the active infection as well as a renewed attention to previously
extensively studied atrophic gastritis-cancer link [9,11,12].
2. Pre-H. pylori studies of gastritis and gastric cancer (late
1800s to 1950 the atrophyachlorhydria period)
In 1879, [i.e., before endoscopy, gastrointestinal (GI) surgery,
or radiology were available], von den Velden reported that gastric
cancer was linked to achlorhydria which for the rst time pro-
vided a diagnostic test for the presence of gastric cancer [9,13].
The era around the beginning of the 20th century saw a virtual
explosion in GI research and was recognized that prior conclusions
based on histological examination of post mortem stomachs often
provided misleading information because the ndings described
largely were due to autolysis [14]. The period between 1880 and
493
100 1920 saw marked advances in histology, chemistry, GI physiology,
90 as well as the development of safe gastric surgery and contrast
radiology. This was a time when many of the heroic gures in gas-
80
troenterology were active including Faber, Pavlov, Einhorn, Ewald,
Hp prevalence
70 Cannon, Moynihan, Sippy, and Mayo. It was also a time when the
60 pattern of gastritis had changed sufciently such that atrophic gas-
tritis was becoming less common and antral predominant gastritis
50
with duodenal ulcer was becoming a common clinical problem.
40 At mid-20th century, Comfort summarized the research relating
acid secretion, gastritis, and gastric cancer from rst half of the 20th
30
century [13]. The data showed that (1) gastric cancer was associated
20
with loss of secretory activity, (2) the reduction in gastric secretion
10
was progressive, (3) that gastric secretory activity was subnormal
before cancer developed, (4) that acid secretion was subnormal in
each decade of life among patients destined to develop gastric can-
cer, and (5) these observations were true no matter how many years
gastric secretion was tested before the cancer developed [13]. Com-
fort concluded that atrophy of the acid secreting cells was the most
likely cause of abnormal gastric acidity in the precancerous stom-
ach and that it (atrophic gastritis) was the soil in which a majority
of gastric cancers appeared [13]. These critical insights seem to
have been largely unknown to most investigators embarking on
the study of H. pylori-related gastritis and its sequalae.
3. Research in the second half of the 20th century
Two Finnish pathologists, Jarvi and Lauren, classied gastric can-
cer as intestinal type, diffuse type, and mixed type and proposed
that gastric cancer might originate from islands of intestinal epithe-
lium within the gastric mucosa [15,16]. They also suggested that
islands of intestinal metaplasia arose in a background of chronic
gastritis and noted that intestinal-type cancer was surrounded
by metaplastic mucosa more frequently than diffuse carcinomas.
Finally, they recommended that prophylaxis should obviously be
directed against gastritis.
Correa in 1975 described a series of sequential steps that culmi-
nated in intestinal-type of adenocarcinoma consisting of chronic
active nonatrophic gastritis, atrophic gastritis, intestinal meta-
plasia and nally intraepithelial neoplasia (then called dysplasia)
[2,1720]. Correa also hypothesized that the initial stages of inam-
mation and atrophy might create a microenvironment favoring
engraftment of cancer stem cells [2]. However, the origin of the
cancer stem cell remains unsettled with data supporting stem cells
being locally derived and other data suggesting they are bone
marrow-derived [21,22]. It is now thought unlikely that cancer
evolves directly from intestinal metaplasia and most agree that
the presence, extent, and possibly the type of intestinal metaplasia
should best be considered an easily recognized biomarker associ-
ated with increasing degrees of risk for gastric cancer [2328].
By the late 1930s it was recognized that if one could nd the
cause of gastritis one should be able to prevent peptic ulcer and
gastric cancer and in the period between 1960 through period of
the discovery of H. pylori there were many experimental and epi-
demiologic studies. Many different associations with gastritis were
reported from different areas of the world [29] and overall they
failed to nd a common denominator. The discovery of H. pylori,
the proof it caused gastritis, and that H. pylori eradication led to
healing of gastritis in the 1980s provided the key to breaking the
chain of events leading to gastric cancer.
4. The natural history of gastritis within the stomach the
advancing atrophic front
H. pylori gastritis is characterized by inltration of the gas-
tric mucosa with both chronic inammatory cells (lymphocytes,
494 A. Shiotani et al. / Seminars in Cancer Biology 23P (2013) 492501
plasma cells, and macrophages) and acute inammatory cells
(polymorphonuclear leukocytes) this is often referred to as acute-
on-chronic inammation. H. pylori infections initially are localized
predominantly to the antrum a site where parietal (acid producing)
cells are absent and thus acid secretion is not directly affected. The
ability to maintain an acid secretory capacity of at least 12 mmol/h
is needed to sustain duodenal ulcer and antral predominant or
the antral restricted or corpus sparing pattern of gastritis is thus
characteristically associated with duodenal ulcer disease.
Over time the zone of inammation, which is also associ-
ated with focal loss of glands (atrophy), progresses from the
antrumcorpus junction and extends proximally into the corpus.
This front advances rapidly along the lesser curvature of the gastric
corpus and more slowly along the greater curvature of the corpus
leaving behind a sheet of atrophic mucosa characterized by loss of
parietal cells (i.e., pseudopyloric atrophy) [14,30,31]. The nding of
atrophy on the greater curvature of the corpus signies the pres-
ence of more extensive atrophy; the more proximal the atrophy
the greater the extent of atrophy. The loss of parietal and chief cells
results in a mucosa that histologically resembles antral mucosa
called pyloric metaplasia or pseudopyloric metaplasia which can be
identied histologically by the presence of pepsinogen-I contain-
ing glands which are normally only found in the corpus. Islands
of intestinal metaplasia may develop within this lawn of pyloric
metaplasia and eventually metaplastic mucosa may encompass the
majority of the gastric mucosal surface [32,33].
5. Effect of H. pylori eradication on gastric structure and
function
H. pylori eradication is associated with rapid resolution of the
acute inammation followed by more gradual reversal of the
chronic inammatory response which may continue over some
years [34] and is thought to halt the gastric oncogenic cascades.
Elimination of the inammatory inltrate results in removal of
inammation-associated inhibitors of acid secretion such as IL-
1 allowing any remaining parietal cells to secrete acid normally
[35,36]. It is thought unlikely that H. pylori eradication will sig-
nicantly reverse the remodeling that has occurred in gastric
mucosa replaced by either pseudopyloric or intestinal metaplasia
[26,37,38].
Despite halting the progression of H. pylori-associated mucosal
damage and prevention of development of new precancerous
lesions, it remains unclear whether H. pylori eradication is able to
reverse or simply delay the progression of existing precancerous
lesions such as intraepithelial neoplastic lesions (gastric adenoma
or dysplasia) to more advanced forms of malignancy.
6. Effect of H. pylori eradication on cancer incidence
The effect of H. pylori eradication on reducing gastric cancer
incidence is related to the risk existing at the time of eradication
therapy. The major benets for treatment of those at little or no
cancer risk at the time of eradication include removal from the
reservoir of infection responsible for spread within society, pre-
vention of development of diseases caused by H. pylori such as
peptic ulcer disease and prevention of progression of gastritis with
its associated risk of gastric cancer. Early studies of H. pylori eradica-
tion in gastric cancer used mixed populations with varying degrees
of cancer risk and were of relatively short duration. The failure to
risk stratify made it difcult or impossible to see a benet even if a
large one was present [26]. An idea trial would have stratied sub-
jects based on established criteria for risk such as the degree and
extent of atrophic changes and then to follow those subjects for a
sufcient period to see if there was a reduction in risk, whether
300 Untreated group
Hp eradicated group
Age-specific Incidence
250
Rate/100,000/yr
200
150
Eradication
100
50
0
35 40 45 50 55 60 65
Age Group
Fig. 2. Model of the natural course of a population in relation to gastric cancer risk.
The reduction in risk of the cohort following H. pylori eradication at approximately
age 50 compared to the untreated population. Any study that does not risk stratify
must plan to have a long duration to take advantage of the increasing separation of
risk over time.
the risk continued to increase with age, remained at the level it
was at the time of H. pylori eradication or decreased (Fig. 2) [26].
No such study was done. However, it became clear that eradica-
tion of H. pylori after the development of atrophic gastritis did not
completely return to zero [37,38].
Subsequently studies were done in subjects at very high risk of
developing gastric cancer and, because cancer risk/year of follow
up was high, only small number of patients was needed and the
follow-up could be relatively short [39]. In 2008, such a multicen-
ter clinical study was begun in Japan to examine the incidence of
new gastric cancers occurring after endoscopic mucosal resection
(EMR) of an early gastric cancer [39]. Subjects were randomized
to eradication of H. pylori or no eradication. The results showed
that the incidence of new gastric cancers was reduced by one-third
among those with H. pylori eradication compared to no eradica-
tion therapy. The study also conrmed that H. pylori eradication did
not completely prevent development of gastric cancer and showed
there was a denite role for secondary prevention (i.e., surveil-
lance programs for patients whose risk remained high despite H.
pylori eradication). It remains unclear whether H. pylori eradication
among those at lower risk (e.g., atrophic changes that are neither
severe nor extensive) is similarly reduced either immediately, or
over time, or whether it remains at the level it was pretreatment.
That question can only be answered by properly powered studies in
which the participants are precisely matched in terms of risk. For
example, one could compare the subsequent cancer risk among
subjects with different extents and severity of atrophic gastritis
over time to identify the time course of change and whether the
trajectory of risk over time was up, down or remained stable [26].
A large-scale cohort study from Taiwan followed 80,000 patients
with peptic ulcer for 10 years after H. pylori eradication therapy
[40]. The patients were assigned to an early eradication group
(patients underwent H. pylori eradication therapy at the time of
diagnosis) or a late eradication group (patients underwent H. pylori
eradication therapy 1 year after diagnosis). The incidence of gas-
tric cancer was markedly lower in the early eradication group than
in the late eradication group suggesting that, while the effect of
H. pylori eradication therapy in reducing the incidence of gastric
cancer is obvious, the earlier the eradication the better. Mass erad-
ication of H. pylori was started in Taiwan in 2004 and initially
included 4121 subjects. Compared to the 5 year period before H.
pylori therapy, the effectiveness of H. pylori eradication therapy in
reducing the incidence of gastric cancer was estimated to be 25%
 A. Shiotani et al. / Seminars in Cancer Biology 23P (2013) 492501
Fig. 3. Molecular mechanisms possibly involved in carcinogenesis directly related to the presence of H. pylori. Aberrant activation-induced cytidine deaminase (AID) expres-
sion, double strand DNA breaks, impaired DNA mismatch repair and aberrant DNA methylation have all been demonstrated to occur in H. pylori infected cells and/or gastric
mucosa and to improve following removal of the organism/H. pylori eradication consistent with the observation that halting of the progression and/or reduction in the risk
of developing gastric cancer.
(rate ratio 0.753, 95% condence interval (CI) 0.3721.525) and the
reduction in peptic ulcer disease 67.4% (95% CI 52.277.8) [41].
Because clinical trials have tended to avoid the elderly and do
not risk stratify, many if not most subjects will have been at low risk.
Any differences in development of cancer will depend on the fact
that the risk among the untreated continues to increase exponen-
tially and thus the two groups (treated and untreated) will continue
to separate over time. Any differences may only become signi-
cant if the follow-up is sufciently long to exaggerate the difference
(Fig. 2) [42]. For example, the Shangdong intervention trial failed to
nd a difference in gastric cancer incidence after 7.3 years but after
14.7 years the incidence of gastric cancer was signicantly reduced
among those who had received H. pylori eradication therapy [43].
7. How eradication reduces subsequent cancer risk?
Even though fundamentally, H. pylori causes the inammation
that ultimately results in gastric cancer, the timing of the eradica-
tion of the infection is important in that irreversible changes occur
that cannot be expected to be completely reversed. Because the
course of mucosal damage varies between individuals, any cohort
of adults from regions where gastric cancer is common will con-
tain individual with a wide variety of H. pylori-associated histologic
ndings varying from nonatrophic gastritis to advanced atrophic
gastritis. Thus, within an age group the risk for development of gas-
tric cancer following successful H. pylori eradication will also vary
in that the despite healing, the gastric has mucosa already suffered
eld defects and precancerous lesions are already present [44,45].
Cancer is a genetic disease and genome-wide analyses of cancer
cells have shown that a single cancer cell often possesses 100
or more mutations in coding regions along with somatic gene
rearrangements and epigenetic changes especially methylation
[4648]. Aberrant DNA methylation also often extends beyond
the actual tumor such that eld cancerization may be extensive
[45,49,50] (Fig. 3). The gastric mucosa in patients with gastric
adenocarcinoma typically shows severe injury with intestinal
metaplasia and areas with dysplasia [32]; intestinal metaplasia,
dysplasia, and adenocarcinoma are thought to often arise coinci-
dentally [51] and detailed examination of stomachs resected for
gastric cancer reveals actual microcarcinomas in up to 10% of cases
[51,52]. Nonetheless, H. pylori eradication following endoscopic
resection of early cancer resulted in a marked reduction in risk for
development of a metachronous cancer [39] suggesting that, irre-
spective the stage of the risk, removal of the infection and reduction
495
in H. pylori-induced inammation can results in a change in the
local intragastric environment affecting cancer promotion and pos-
sibly initiation [44,53]. As described above, in the Japan GAST study,
the reduction in cancer incidence was reduced from one third to
one half [39]. This was a very high risk group and it remains unclear
whether the effects seen represent slower grown thus requiring a
longer time before the second cancer was discovered, prevention
of progression of precancerous lesions to actual cancer, regression
of foci of high grade dysplasia, or some other combination.
A bystander effect is related to the fact that elimination of H.
pylori eliminates or reduces cytokine-induced suppression of the
parietal cells such that if parietal cell remain, recover, or regenerate,
one can expect improvement in gastric acidity [36,54]. An increase
in gastric acidity will have an additional benet of reducing or
eliminating overgrowth of non-H. pylori bacteria that colonize the
hypochlorhydric stomach and are thought to be in part responsible
for production of carcinogens from natural and dietary components
[36,55,56].
H. pylori itself may have direct effects due to exposure of H. pylori
to gastric epithelial cells. For example, in vitro studies using tissue
culture have shown that H. pylori can trigger DNA double-strand
breaks [57] as well as impair DNA mismatch repair [58] (Fig. 3).
Toller et al. suggested that prolonged active infection might itself
lead to saturation of cellular repair capabilities and contributes
to the genetic instability and frequent chromosomal aberrations
found in infected stomachs [57]. Recent studies have shown that
H. pylori infection affects activation-induced cytidine deaminase
(AID), which is one of several human enzymes inducing nucleotide
alterations involved in DNA mutations [59] (Fig. 3). Aberrant AID
expression is widely detectable not only in inammation-induced
cancer tissues but also in a various inammatory epithelial tis-
sues with tumorigenic high risk including H pylori chronic gastritis
[53,60].
H. pylori infection has also been shown to induce aberrant
methylation in a number of gene promoters in the gastric mucosa,
including cell growth-related genes p16(INK4a) and APC; DNA-
repair genes, hMLH1, BRCA1 and MGMT; tumor-suppressor genes
such as CDKN2A, CDH1, MLH1, and RUNX3; the cell adherence gene
E-cadherin; and CpG islands of certain microRNA genes [45,61,62].
There are a large number of factors that are upregulated and
possibly involved in H. pylori-induced gastric carcinogenesis such
as Krppel-like factor 5 (KLF5) and valosin-containing protein
(VCP) [63,64]. The post endoscopic resection of early gastric cancer
provides and excellent model as it allows one to compare changes
in gene expression between individuals with different rates of
496 A. Shiotani et al. / Seminars in Cancer Biology 23P (2013) 492501
recurrent cancer and thus to possibly help pin down the most
important molecular mechanisms.
8. Primary and secondary prevention of gastric cancer
The vast majority of gastric cancer in the world is caused by
H. pylori and eradication of H. pylori will result in gastric cancer
becoming a rare disease with the few remaining cases primar-
ily related to congenital genetic abnormalities and rare non-H.
pylori causes of chronic gastric inammation. Essentially, the state-
ment no H. pylori, no gastric cancer is true and eradication of H.
pylori is the most effective method of primary prevention. Although
approximately one-half of the worlds population has active H.
pylori infections, the incidence of cancer varies widely within and
between populations and the risk typically increases over the life
of any one infected individual. For many individuals H. pylori erad-
ication equates with cancer prevention whereas for others it only
produces a reduction in risk. This difference in outcome depends
on the level of risk when the eradication is performed. For those
at high risk of gastric cancer, H. pylori eradication followed by
surveillance for gastric cancer may often be indicated (i.e., a combi-
nation of primary and secondary prevention), because for many an
increased risk of gastric cancer remains even after H. pylori eradi-
cation [9,65,66].
Until recently, gastric cancer surveillance programs were aimed
entirely at secondary prevention with the primary objective of
identifying cancers at an early stage when curative therapy could
still be employed [9]. The history of these programs has been
one of progressive involvement of new technologies starting with
radiographic screening using contrast barium meals, screening
using gastro-cameras, and more recently with beroptic and video
endoscopy [67]. These programs have resulted in increased iden-
tication of early gastric cancers which currently are often treated
with endoscopically applied mucosal resection or dissection. While,
these programs have been successful in nding many curable can-
cers, the proportion of the population served has remained small
and screening programs are not responsible for the majority of the
decline in gastric cancer deaths in Japan (i.e., the decline has been
a general phenomenon and encompasses both the screened and
unscreened populations) [68].
H. pylori gastritis is progressive such that over time both the
extent and severity of atrophy increase which is reected in the
age-related increase in the incidence of gastric cancer [69]. Sec-
ondary prevention is not designed to alter the natural of the disease,
and although an individual may participate as they age, their cancer
risk continues to increase exponentially (Fig. 4A). On the other hand
primary prevention is designed to change the natural history and
prevent cancer, or at a minimum, to eliminate any further increases
in risk (Fig. 4B). Primary prevention of gastric cancer has only
recently become practical and has recently been begun in Japan as
a combination of primary and targeted secondary prevention [67].
9. Rationale for combined primary and secondary
prevention programs
If H. pylori eradication alone would eliminate the risk of gastric
cancer, secondary prevention programs could be eliminated [65].
However, as noted above, the link between H. pylori and cancer
runs through atrophic gastritis. Eradication of the infection stops
the inammatory process, allows healing of gastritis and resolu-
tion of inammation. Nonetheless, eradication alone cannot undo
the atrophic damage that has already occurred. H. pylori eradication
will thus produce two populations: those with minimal to no risk
and those with some residual risks for cancer. Those with resid-
ual risk can likely be assured that their risk will not increase as
they age and although it will probably decrease somewhat, some
risk remains. Recommendations for the future should therefore be
based on an estimate of that risk [65].
10. Risk stratication
There are many approaches to stratify risk for gastric cancer.
The initial approach was to stratify according to age. The weakness
of that approach is that age provides an average for that subgroup
such that any birth cohort group will include individuals ranging
from those with no risk to those with a very high risk. Generally, the
age to start screening has been chosen based on the age where the
risk increased exponentially. This was reasonable when the goal
was secondary prevention (i.e., to identify early cancers) but is less
attractive when the goal is to prevent cancer. The level of risk can
be more precisely identied using invasive methods such as assess-
ment of gastric secretory ability, endoscopic identication of the
location of the atrophic border, or histologic assessment of degree
and extent of gastric damage. While effective, these methods may
not be cost-effective for screening most populations especially
when a cadre of endoscopists trained in screening for gastric atro-
phy is not already present. Duodenal ulcer has long been known to
protect against gastric cancer although both duodenal ulcer and
gastric cancer are caused by H. pylori infections. This seeming para-
dox is a reection of the fact that active duodenal ulcers require
the presence of a non-atrophic gastric mucosa which can maintain
the high levels of acid secretion needed to stain the ulcer. However,
as the advancing front damages the corpus mucosa, acid secretion
falls causing the ulcer disease to burn out [70]. This is reected in
the fact scars from prior duodenal ulcers may be found in patients
presenting with atrophic gastritis and gastric cancer. These scars
result from duodenal ulcers that occurred decades previously and
have burned out [71].
Age is a surrogate for the age-related increase in risk which is
a manifestation of the size of the proportion of that cohort with
advanced degrees of atrophy (Fig. 5). Because any birth cohort of
infected individuals may contain individuals currently at high risk
for development of gastric cancer, and because the effect of H. pylori
eradication on subsequent risk depends on the risk when erad-
ication is accomplished, most cancer prevention programs must
consist of a combination of primary and secondary prevention. A
comprehensive program would thus include H. pylori eradication
(i.e., primary prevention) along with risk stratication to identify
those still at signicant risk of development of gastric cancer. Those
with signicant risk would then be invited to participate in a sec-
ondary prevention program.
H. pylori is a necessary but not sufcient cause of gastric can-
cer and eradication of H. pylori will ultimately make gastric cancer
a rare disease. The incidence of gastric cancer is related to the fre-
quency and severity of atrophic gastritis (i.e., those with no H. pylori
and no atrophy have essentially no risk and those with non-atrophic
gastritis have very low risk, as long as the gastritis remains non-
atrophic. Risk increases in proportion to the extent and severity of
gastric mucosal damage and is highest among those with gastric
atrophy. As noted above, the age related increase in incidence of
gastric cancer is a reection of the progressive nature of H. pylori
gastritis.
11. Assessment of cancer risk: non-invasive serum
pepsinogen and H. pylori testing
Non-invasive testing for the presence and extent of atrophic
gastritis currently relies primarily on measurement of serum
pepsinogen levels [33]. Pepsinogens are proteolytic enzymes pro-
duced in the stomach. Pepsinogen I is found only in the gastric
 A. Shiotani et al. / Seminars in Cancer Biology 23P (2013) 492501 497

(a) 800 (b) 800

800
700 700

Age-specific Incidence
Age-specific Incidence
600 600

Rate/100,000/yr
Rate/100,000/yr
500 500

400 400

300 300
150
200 200

100 100

0 0
0 10 20 30 40 50 60 70 80 90 0 10 20 30 40 50 60 70 80 90
Age Age
Fig. 4. (A) Illustration of the natural history of subjects entering a secondary prevention program after H. pylori eradication at age 50. At age 50 the average risk of gastric
cancer is 150/100,000 per year and increases to 800/100,000 per year at age 80. Thus, despite annual surveillance the gastric cancer risk would increase 533%. (B) The
postulated effect if H. pylori eradication were done at age 60. After that point their risk stop increasing and would likely remain stable or decrease as healing occurred.
Importantly, the risk does not return to zero.

corpus whereas pepsinogen II is present in both the antrum and
corpus. Atrophic damage of the gastric corpus results in a progres-
sive decline in pepsinogen I levels such that both pepsinogen I levels
and the ratio of pepsinogen I to pepsinogen II (pepsinogen I/II) can
be used as biomarkers for the extent and severity of atrophic gastri-
tis/gastric atrophy. Pepsinogen testing has a long history and was
in use long before the discovery of H. pylori [72]. Pepsinogen test-
ing has been standardized in Japan and in Europe [73,74]. In Japan
a serum pepsinogen I concentration of less than 70 ng/mL and a
pepsinogen I/II of less than 3.0 is indicative of severe atrophic gas-
tritis and it has been successfully used to identify those at high risk
of gastric cancer [73].
The use of biomarkers for the detection of atrophic gastritis
was studied in 22,000 individuals in Finland and the sensitivity
and specicity were high (e.g., 83% and 93% respectively) [75].
Using serum/plasma pepsinogen I of <30 g/L and/or pepsinogen
I/II of <3, the accuracy to diagnose atrophic gastritis (40100%
800
700
Age-specific Incidence
loss of normal oxyntic glands with the appearance of intestinal
metaplasia and chronic inammation) was 87%, the sensitivity
was 40% and the specicity 94% [74]. The results clearly depend
on the cut-off of serum pepsinogen levels as well as the denition
used to identify atrophy.
There are also a number of validated non-invasive methods to
detect H. pylori infection including IgG anti-H. pylori antibody, urea
breath tests, and H. pylori stool antigen tests. Because of the sim-
plicity and cost, most envision preliminary screening will consist of
H. pylori serology and pepsinogen testing. As neither H. pylori IgG
serology nor serum pepsinogen testing are 100% sensitive and spe-
cic, an actual screening program would need to consider the costs
and benets of staged testing as well as the role and nature of con-
rmatory testing [76]. For example, H. pylori antibodies can remain
positive for many years after successful H. pylori eradication and the
question about when, how, and whether to conrm active infection
before recommending antibiotic therapy will need be addressed
when planning for a population wide eradication program.
For those with H. pylori infection and non-atrophic gastritis, H.
pylori eradication alone sufces to eliminate gastric cancer risk. For
those with atrophic damage the risk may vary from low to very high
and it is likely prudent to conrm the actual level of risk to properly

assess the need to commit the individual to long term surveillance.

600 For population wide-screening programs, in general children
Rate/100,000

Degree of gastritis need not be tested as H. pylori infection among children has become
500
increasingly rare in developed countries. However, H. pylori is
None/nonatrophic transmitted within families, making it prudent to consider test-
400
Moderate damage
ing children of couples in which one or both parents is found to be
Atrophic/atrophy
300 infected. Because failure to test all children initially would leave a
small pool of infected individuals, it would be useful to consider
200 testing couples applying for a marriage license in order nd missed
100 infections and to prevent transmission to their children. Similar
programs were common when syphilis was still prevalent.
0
0 10 20 30 40 50 60 70 80 90 12. Experience with combined pepsinogen H. pylori
Age testing

Fig. 5. Illustration of how age is a surrogate for average risk for a birth cohort and
how, because H. pylori gastritis is progressive the proportion with severe damage
(i.e., highest risk) increases over time. Importantly, even at ages less than 50 any
birth cohort of H. pylori infected individuals will likely contain some proportion of
individuals at high risk.
There are a number of examples, for example, Ohata et al.
used pepsinogen testing and H. pylori serology to identify chronic
atrophic gastritis among 4655 candidates for Japanese cancer
screening [77]. Using these tests 967 (21%) were H. pylori negative
498 A. Shiotani et al. / Seminars in Cancer Biology 23P (2013) 492501
Table 1
ABCD gastric cancer risk stratication.
Group A Group B Group C
Atrophic gastritis None Mild Moderate
H. pylori Negative Positive Positive
Pepsinogen Negative Negative Positive
Cancer risk None Low High
without chronic atrophic gastritis, 2341 (52%) had H. pylori infec-
tions and non-atrophic gastritis, 1316 (28%) had H. pylori and
atrophic gastritis; 31 (0.7%) had severe atrophic gastritis. The
rates of development of gastric cancer per 100,000/year with
a mean follow-up of 7.7 years were: none, 107, 238, and 871,
respectively for the 4 groups. The number of endoscopies per year
(as cancers/1000 endoscopies) needed to nd one cancer by annual
surveillance were none, 1/1000, 1/410, and 1/114, respectively
for the 4 groups. All underwent annual surveillance although only
about 0.8% of the total population was in the very high risk group
and if one included those with mild to moderate atrophic gastritis
the proportion who would likely to have beneted by participation
in annual screening only increased to 29%. This study is typical
showing following H. pylori eradication, at least 70% of the popu-
lation undergoing annual surveillance is unlikely to benet from
participation in annual surveillance. Similar data are available from
Watabe et al. who studied 6985 patients (approximately one-third
women) average age approximately 50 [78]. Approximately half,
47.6%, were uninfected and an additional 30.5% had non-atrophic H.
pylori gastritis such that only approximately 22% were at higher risk
and 0nly 6% were in the highest risk group. Even if one restricted
surveillance to those ages 70 or above the proportion potentially
beneting from surveillance would likely remain below 50%.
13. Risk stratication using combined pepsinogen H.
pylori antibody testing
Recent experience with combined H. pylori anti-
body/pepsinogen testing in Japan provides insights into the
feasibility of this approach. The most recent iteration of risk
stratication is called ABC or ABCD stratication (Table 1) [7981].
To date this approach has primarily been used as part of secondary
prevention programs. As noted above, in the Ohata study [77]
no gastric cancer developed in the H. pylori antibody negative
individuals with normal pepsinogens (i.e., group A). There was a
stepwise increase in the risk of developing gastric cancer risk with
increasing atrophy: lowest in those H. pylori antibody positive
with normal pepsinogens (Group B), moderate in the H. pylori
positive with atrophic gastritis pepsinogen values (Group C) and
highest those with the most severe atrophy (i.e., H. pylori antibody
negative/pepsinogen positive for atrophic gastritis. Group D, by
far the smallest group, is enriched in patients with extensive
intestinal metaplasia that resulted in spontaneous loss of the H.
pylori infection.
Both H. pylori eradication and the use of proton pump inhibitors
can substantially alter serum pepsinogen concentrations and com-
promise the predictive value of pepsinogens even among those
at high risk for gastric cancer [82,83]. Because low pepsinogen
I and pepsinogen I/II levels are not limited to only those with
atrophic gastritis, pepsinogen testing is not 100% diagnostic such
that the actual risk category should be conrmed before commit-
ting a patient to a long term endoscopic surveillance program. The
limitations require that patients who are candidates for endoscopic
surveillance programs have conrmatory testing done as part of
their initial surveillance at which time false positive or negative
tests can be identied. Conrmation typically involves endoscopy
as well as a validated method for determining the degree and extent
H. pylori antibody and pepsinogen testing
Adults plus children of infected parents
Group D
Hp neg Hp pos Hp pos Hp pos Hp neg
Severe PG norm PG norm PG inter PG low PG neg
Negative
Positive
Highest Hp eradication with
confirmation of cure
No Follow-up Cured Cured Cured Endoscopy for
PG norm PG inter PG low
Required Atrophic changes
? - Atrophy -
None Mild Moderate/
Severe
? ?
Surveillance?
Surveillance
( adjuvants)
Fig. 6. Possible scenario of population-wide detection and eradication program to
eliminate gastric cancer. The proposal is based on initially identifying those with H.
pylori infections and assessing the health of the gastric mucosa. We outline a plan
using non-invasive testing with a locally or regionally validated IgG H. pylori sero-
logy and serum pepsinogen testing. Those without H. pylori infection or atrophic
gastritis would require no further evaluation or follow-up. All those with H. pylori
infections would undergo eradication therapy with conrmation of cure, prefer-
ably using non-invasive testing with a urea breath or stool antigen testing. After
H. pylori eradication, those with non-atrophic gastritis would require no further
follow-up. Those with suspected atrophic gastritis (based on pepsinogen testing)
would undergo endoscopy for proper risk stratication (e.g., using a validated his-
tologic staging system). Those with cured H. pylori and healed non-atrophic gastritis
would require no further follow-up. Those with conrmed atrophic gastritis (e.g.,
OLGA stage III or IV) would be entered in to a long term endoscopic surveillance pro-
gram. Because the cancer risk if likely to decline over time, they are also candidates
for research regarding surveillance intervals and whether adjuvant therapy such as
anti-inammatory or anti-oxidant therapy would further reduce the risk Current
data does not allow rm recommendations for those after H. pylori eradication with
mild atrophy (e.g., OLGA I and II) and they are considered candidates for research
regarding the best strategy.
of atrophy such as histologic conrmation using a gastric cancer
staging system such as the Operative Link on Gastritis Assessment
(OLGA) or OLGA-IM staging systems [84,85], Despite some limi-
tations, serum pepsinogen testing has a high negative predictive
value allowing conrmatory endoscopic examination to be limited
to only a subset of the population (Fig. 6).
14. What should surveillance programs look like?
There is considerable experience with the one size ts all
approach to gastric cancer surveillance. All the previous attempts
have been labor intensive, only a small proportion of those eligi-
ble could participate, and a high proportion of those screened was
at low or negligible risk. Pepsinogen testing is not perfect as some
will have values below normal but still above the cut-off for severe
atrophic gastritis (currently called intermediate in Fig. 6). Research
is needed to address how to stratify those patients non-invasively
into those who would benet from surveillance from those where
surveillance would not be cost-effective. One approach would be
to resolve the quandary by endoscopic risk stratication.
The natural history of atrophic gastritis after H. pylori eradication
has also not been examined critically. Because risk likely declines
after H. pylori eradication, it may be possible to reduce the screening
interval or possibly stop surveillance altogether over time. While
targeted gastric biopsy using a validated histology staging system is
currently the best approach for more precise risk stratication, it is
important to note that histologic risk stratication is based on data
from untreated H. pylori infected individuals. Whether the same
surveillance intervals are appropriate for different histologic types
and patterns remains to be evaluated (i.e., those with OLGA stage IV
 A. Shiotani et al. / Seminars in Cancer Biology 23P (2013) 492501
might require annual surveillance compared to every two or three
years for OLGA III etc.). The potential to rationally stratify surveil-
lance based on histologic or other parameters emphasizes the need
for further research to rene risk markers as well as surveillance
methods, intervals, and duration. Other areas of study include the
role of adjuvants that in addition to H. pylori eradication further
reduce risk such as co-therapy with anti-inammatory agents, gas-
troprotectives, or antioxidants [65,86,87].
15. Summary
The data regarding gastric cancer are now sufcient to sup-
port the proposal that all with H. pylori infection should receive
H. pylori eradication therapy. In countries, regions, and popula-
tions at increased risk of gastric cancer, evaluation for the presence
and severity of atrophic gastritis is recommended to identify the
subgroup of patients for which continued surveillance (secondary
prevention) should be considered. Japan has already embarked on
an H. pylori eradication program and because of the widespread
availability and expertise in endoscopic surveillance Japan has
chosen endoscopy as the screening method for determining the
extent and severity of atrophic gastritis [67]. Other countries with
fewer resources or lacking the widespread expertise in endoscopic
screening will likely prefer noninvasive screening using pepsino-
gen levels. Because of the limitation in sensitivity and specicity
of pepsinogen screening, endoscopic/histologic conrmation can
then be targeted to the subpopulation likely to benet and better
stratify patients to ensure that those who would obtain little or
no benets from continued surveillance are triaged out of surveil-
lance programs. The ideal frequency and duration of surveillance
following H. pylori eradication remains unknown. For those at very
high risk (e.g., extensive atrophy or intramucosal neoplastic lesions,
or after endoscopic therapy of early gastric cancer) most would
recommend an interval of 1 year although studies are needed to
determine when, if, and for what circumstances this interval could
be lengthened. Studies are also needed to identify the appropriate
frequency and duration of follow-up for those with lesser degrees
of damage with recommendation being subject to the outcome of
surveillance studies based on risk stratication. Because risk strat-
ied targeted surveillance allows surveillance to be restricted to
those who might benet most and it provides much closer match-
ing of surveillance capacity to surveillance needs thus making
surveillance potentially both clinically and cost effective. Japan has
been the rst country to step up to the plate and seriously begin
the process of eradication of gastric cancer by widespread H. pylori
eradication. The approach in other countries will differ based on
the size of the problem and the resources that can be devoted to
it. Nonetheless, making gastric cancer a rare disease is now both
possible and practical.
Conict of interest
Dr. Graham is a unpaid consultant for Novartis in relation to
vaccine development for treatment or prevention of H. pylori infec-
tion. Dr. Graham is a also a paid consultant for RedHill Biopharma
regarding novel H. pylori therapies and for Otsuka Pharmaceut-
icals regarding diagnostic testing. Dr. Graham has received royalties
from Baylor College of Medicine patents covering materials related
to 13 C-urea breath test. Dr. Shiotani and Dr. Cen have no potential
conicts.
Acknowledgements
Dr. Graham is supported in part by the Ofce of Research and
Development Medical Research Service Department of Veterans
499
Affairs, Public Health Service grants DK067366, CA116845 and
DK56338 which funds the Texas Medical Center Digestive Diseases
Center. The contents are solely the responsibility of the authors and
do not necessarily represent the ofcial views of the VA or NIH.
References
[1] Melton SD, Genta RM, Souza RF. Biomarkers and molecular diagnosis of gas-
trointestinal and pancreatic neoplasms. Nature Reviews Gastroenterology &
Hepatology 2010;7:6208.
[2] Correa P, Houghton J. Carcinogenesis of Helicobacter pylori. Gastroenterology
2007;133:65972.
[3] Hoffman FL. The mortality from cancer throughout the world. Newark: Pru-
dential Press; 1915.
[4] IARC. Helicobacter pylori. Biologic agents: a review of human carcinogens. Leon:
International Agency for Research on Cancer; 2012. p. 385435.
[5] Sipponen P, Helske T, Jarvinen P, Hyvarinen H, Seppala K, Siurala M. Fall in the
prevalence of chronic gastritis over 15 years: analysis of outpatient series in
Finland from 1977, 1985, and 1992. Gut 1994;35:116771.
[6] Sipponen P, Kimura K. Intestinal metaplasia, atrophic gastritis and stomach
cancer: trends over time. European Journal of Gastroenterology and Hepatology
1994;6(Suppl. 1):7983.
[7] Graham DY, Lu H, African Yamaoka Y. Asian or Indian enigma, the East
Asian Helicobacter pylori: facts or medical myths. Journal of Digestive Diseases
2009;10:7784.
[8] IARC. IARC monographs on the evaluation of carcinogenic risks to humans (vol.
61): schistosomes, liver ukes and Helicobacter pylori. Lyon, France: Interna-
tional Agency for Research on Cancer; 1994.
[9] Graham DY, Asaka M. Eradication of gastric cancer and more efcient gastric
cancer surveillance in Japan: two peas in a pod. Journal of Gastroenterology
2010;45:18.
[10] Kokkola A, Kosunen TU, Puolakkainen P, Sipponen P, Harkonen M, Laxen F, et al.
Spontaneous disappearance of Helicobacter pylori antibodies in patients with
advanced atrophic corpus gastritis. APMIS 2003;111:61924.
[11] Ekstrom AM, Held M, Hansson LE, Engstrand L, Nyren O. Helicobacter pylori in
gastric cancer established by CagA immunoblot as a marker of past infection.
Gastroenterology 2001;121:78491.
[12] Weck MN, Gao L, Brenner H. Helicobacter pylori infection and chronic
atrophic gastritis: associations according to severity of disease. Epidemiology
2009;20:56974.
[13] Comfort MW. Gastric acidity before and after development of gastric cancer: its
etiologic, diagnostic and prognostic signicance. Annals of Internal Medicine
1951;36:133148.
[14] Faber K. Gastritis and its consequences. Paris: Oxford University Press; 1935.
[15] Lauren P. The two histological main types of gastric carcinoma: diffuse and so-
called intestinal-type carcinoma. An attempt at a histo-clinical classication.
Acta Pathologica et Microbiologica Scandinavica 1965;64:3149.
[16] Jarvi O, Lauren P. On the role of heterotopias of the intestinal epithelium in the
pathogenesis of gastric cancer. Acta Pathologica et Microbiologica Scandinavica
1951;29:2644.
[17] Correa P, Haenszel W, Cuello C, Tannenbaum S, Archer M. A model for gastric
cancer epidemiology. Lancet 1975;2:5860.
[18] Correa P, Cuello C, Duque E, Burbano LC, Garcia FT, Bolanos O, et al. Gastric can-
cer in Colombia. III. Natural history of precursor lesions. Journal of the National
Cancer Institute 1976;57:102735.
[19] Correa P, Cuello C, Duque E. Carcinoma and intestinal metaplasia of the
stomach in Colombian migrants. Journal of the National Cancer Institute
1970;44:297306.
[20] Correa P. Human gastric carcinogenesis: a multistep and multifactorial process
First American Cancer Society Award Lecture on Cancer Epidemiology and
Prevention. Cancer Research 1992;52:673540.
[21] Pritchard DM, Crabtree JE. Helicobacter pylori and gastric cancer. Current Opin-
ion in Gastroenterology 2006;22:6205.
[22] Takaishi S, Okumura T, Wang TC. Gastric cancer stem cells. Journal of Clinical
Oncology 2008;26:287682.
[23] Kakinoki R, Kushima R, Matsubara A, Saito Y, Okabe H, Fujiyama Y, et al.
Re-evaluation of histogenesis of gastric carcinomas: a comparative histopatho-
logical study between Helicobacter pylori-negative and H. pylori-positive cases.
Digestive Diseases and Sciences 2009;54:61420.
[24] Mesquita P, Raquel A, Nuno L, Reis CA, Silva LF, Serpa J, et al. Metaplasia a
transdifferentiation process that facilitates cancer development: the model of
gastric intestinal metaplasia. Critical Reviews in Oncogenesis 2006;12:326.
[25] Meining A, Morgner A, Miehlke S, Bayerdorffer E, Stolte M.
Atrophymetaplasiadysplasiacarcinoma sequence in the stomach: a reality
or merely an hypothesis. Best Practice and Research Clinical Gastroenterology
2001;15:98398.
[26] Shiotani A, Haruma K, Uedo N, Iishi H, Ishihara R, Tatsuta M, et al. Histological
risk markers for non-cardia early gastric cancer: pattern of mucin expression
and gastric cancer. Virchows Archiv 2006.
[27] Shiotani A, Iishi H, Uedo N, Ishiguro S, Tatsuta M, Nakae Y, et al. Evidence that
loss of sonic hedgehog is an indicator of Helicobacter pylori-induced atrophic
gastritis progressing to gastric cancer. American Journal of Gastroenterology
2005;100:5817.
500 A. Shiotani et al. / Seminars in Cancer Biology 23P (2013) 492501
[28] Shiotani A, Iishi H, Uedo N, Kumamoto M, Nakae Y, Ishiguro S, et al. Histologic
and serum risk markers for noncardia early gastric cancer. International Journal
of Cancer 2005;115:4639.
[29] Cheli R, Perasso A, Giacosa A. Gastritis a clinical review. Berlin: Springer-Verlag;
1987.
[30] Kimura K. Chronological transition of the fundic-pyloric border determined by
stepwise biopsy of the lesser and greater curvatures of the stomach. Gastroen-
terology 1972;63:58492.
[31] Satoh K, Kimura K, Taniguchi Y, Yoshida Y, Kihira K, Takimoto T, et al. Distribu-
tion of inammation and atrophy in the stomach of Helicobacter pylori-positive
and -negative patients with chronic gastritis. American Journal of Gastroen-
terology 1996;91:9639.
[32] El-Zimaity HM, Ota H, Graham DY, Akamatsu T, Katsuyama T. Patterns of gastric
atrophy in intestinal type gastric carcinoma. Cancer 2002;94:142836.
[33] Sipponen P, Graham DY. Importance of atrophic gastritis in diagnostics and
prevention of gastric cancer: application of plasma biomarkers. Scandinavian
Journal of Gastroenterology 2007;42:210.
[34] Kokkola A, Sipponen P, Rautelin H, Harkonen M, Kosunen TU, Haapiainen R,
et al. The effect of Helicobacter pylori eradication on the natural course of
atrophic gastritis with dysplasia. Alimentary Pharmacology and Therapeutics
2002;16:51520.
[35] Gutierrez O, Melo M, Segura AM, Angel A, Genta RM, Graham DY. Cure of Heli-
cobacter pylori infection improves gastric acid secretion in patients with corpus
gastritis. Scandinavian Journal of Gastroenterology 1997;32:6648.
[36] Graham DY, Shiotani A, El-Zimaity HM. Chromoendoscopy points the way to
understanding recovery of gastric function after Helicobacter pylori eradication.
Gastrointestinal Endoscopy 2006;64:68690.
[37] Shiotani A, Murao T, Uedo N, Iishi H, Yamanaka Y, Kamada T, et al. Eradica-
tion of H. pylori did not improve abnormal sonic hedgehog expression in the
high risk group for gastric cancer. Digestive Diseases and Sciences 2012;57:
6439.
[38] Shiotani A, Uedo N, Iishi H, Murao T, Kanzaki T, Kimura Y, et al. H.
pylori eradication did not improve dysregulation of specic oncogenic miR-
NAs in intestinal metaplastic glands. Journal of Gastroenterology 2012;47:
98898.
[39] Fukase K, Kato M, Kikuchi S, Inoue K, Uemura N, Okamoto S, et al. Effect of erad-
ication of Helicobacter pylori on incidence of metachronous gastric carcinoma
after endoscopic resection of early gastric cancer: an open-label, randomised
controlled trial. Lancet 2008;372:3927.
[40] Wu CY, Kuo KN, Wu MS, Chen YJ, Wang CB, Lin JT. Early Helicobacter pylori
eradication decreases risk of gastric cancer in patients with peptic ulcer disease.
Gastroenterology 2009;137:16418.
[41] Lee YC, Chen TH, Chiu HM, Shun CT, Chiang H, Liu TY, et al. The benet of mass
eradication of Helicobacter pylori infection: a community-based study of gastric
cancer prevention. Gut 2012.
[42] Graham DY, Uemura N. Natural history of gastric cancer after Helicobacter pylori
eradication in Japan: after endoscopic resection, after treatment of the general
population, and naturally. Helicobacter 2006;11:13943.
[43] Ma JL, Zhang L, Brown LM, Li JY, Shen L, Pan KF, et al. Fifteen-year effects of
Helicobacter pylori, garlic, and vitamin treatments on gastric cancer incidence
and mortality. Journal of the National Cancer Institute 2012;104:48892.
[44] Chiba T, Marusawa H, Ushijima T. Inammation-associated cancer develop-
ment in digestive organs: mechanisms and roles for genetic and epigenetic
modulation. Gastroenterology 2012;143:55063.
[45] Ushijima T, Hattori N. Molecular pathways: involvement of Helicobacter pylori-
triggered inammation in the formation of an epigenetic eld defect, and
its usefulness as cancer risk and exposure markers. Clinical Cancer Research
2012;18:9239.
[46] Sjoblom T, Jones S, Wood LD, Parsons DW, Lin J, Barber TD, et al. The con-
sensus coding sequences of human breast and colorectal cancers. Science
2006;314:26874.
[47] Pleasance ED, Stephens PJ, OMeara S, McBride DJ, Meynert A, Jones D, et al. A
small-cell lung cancer genome with complex signatures of tobacco exposure.
Nature 2010;463:18490.
[48] Stephens PJ, McBride DJ, Lin ML, Varela I, Pleasance ED, Simpson JT, et al. Com-
plex landscapes of somatic rearrangement in human breast cancer genomes.
Nature 2009;462:100510.
[49] Niwa T, Tsukamoto T, Toyoda T, Mori A, Tanaka H, Maekita T, et al.
Inammatory processes triggered by Helicobacter pylori infection cause aber-
rant DNA methylation in gastric epithelial cells. Cancer Research 2010;70:
143040.
[50] Maekita T, Nakazawa K, Mihara M, Nakajima T, Yanaoka K, Iguchi M, et al.
High levels of aberrant DNA methylation in Helicobacter pylori-infected gastric
mucosae and its possible association with gastric cancer risk. Clinical Cancer
Research 2006;12:98995.
[51] Hattori T. Development of adenocarcinomas in the stomach. Cancer
1986;57:152834.
[52] Kodama M, Tur GE, Shiozawa N, Koyama K. Clinicopathological features of mul-
tiple primary gastric carcinoma. Journal of Surgical Oncology 1996;62:5761.
[53] Shimizu T, Marusawa H, Endo Y, Chiba T. Inammation-mediated genomic
instability: roles of activation-induced cytidine deaminase in carcinogenesis.
Cancer Science 2012;103:12016.
[54] Iijima K, Sekine H, Koike T, Imatani A, Ohara S, Shimosegawa T. Long-term
effect of Helicobacter pylori eradication on the reversibility of acid secre-
tion in profound hypochlorhydria. Alimentary Pharmacology and Therapeutics
2004;19:11818.
[55] Houben GM, Stockbrugger RW. Bacteria in the aetio-pathogenesis of gas-
tric cancer: a review. Scandinavian Journal of Gastroenterology Supplement
1995;212:138.
[56] Forsythe SJ, Dolby JM, Webster AD, Cole JA. Nitrate- and nitrite-reducing
bacteria in the achlorhydric stomach. Journal of Medical Microbiology
1988;25:2539.
[57] Toller IM, Neelsen KJ, Steger M, Hartung ML, Hottiger MO, Stucki M, et al. Car-
cinogenic bacterial pathogen Helicobacter pylori triggers DNA double-strand
breaks and a DNA damage response in its host cells. Proceedings of the National
Academy of Sciences of the United States of America 2011;108:149449.
[58] Kim JJ, Tao H, Carloni E, Leung WK, Graham DY, Sepulveda AR. Helicobacter
pylori impairs DNA mismatch repair in gastric epithelial cells. Gastroenterology
2002;123:54253.
[59] Conticello SG. The AID/APOBEC family of nucleic acid mutators. Genome Biol-
ogy 2008;9:229.
[60] Matsumoto Y, Marusawa H, Kinoshita K, Endo Y, Kou T, Morisawa T, et al.
Helicobacter pylori infection triggers aberrant expression of activation-induced
cytidine deaminase in gastric epithelium. Nature Medicine 2007;13:4706.
[61] Shin CM, Kim N, Jung Y, Park JH, Kang GH, Park WY, et al. Genome-wide
DNA methylation proles in noncancerous gastric mucosae with regard to
Helicobacter pylori infection and the presence of gastric cancer. Helicobacter
2011;16:17988.
[62] Zabaleta J. MicroRNA: a bridge from H. pylori infection to gastritis and gastric
cancer development. Frontiers in Genetics 2012;3:294.
[63] Noto JM, Khizanishvili T, Chaturvedi R, Piazuelo MB, Romero-Gallo J, Delgado
AG, et al. Helicobacter pylori promotes the expression of kruppel-like factor 5,
a mediator of carcinogenesis, in vitro and in vivo. PLoS ONE 2013;8:e54344.
[64] Yu CC, Yang JC, Chang YC, Chuang JG, Lin CW, Wu MS, et al. VCP
phosphorylation-dependent interaction partners prevent apoptosis in Heli-
cobacter pylori-infected gastric epithelial cells. PLoS ONE 2013;8:e55724.
[65] Graham DY, Shiotani A. The time to eradicate gastric cancer is now. Gut
2005;54:7358.
[66] Shiotani A, Uedo N, Iishi H, Yoshiyuki Y, Ishii M, Manabe N, et al. Predictive
factors for metachronous gastric cancer in high-risk patients after successful
Helicobacter pylori eradication. Digestion 2008;78:1139.
[67] Asaka M. A new approach for elimination of gastric cancer deaths in Japan.
International Journal of Cancer 2013;132:12726.
[68] Trends in age-specic incidence rate. Cancer statistics in Japan 2011. Tokyo:
Foundation for Promotion of Cancer Research; 2011. p. 2936.
[69] Sipponen P, Kekki M, Haapakoski J, Ihamki T, Siurala M. Gastric cancer risk
in chronic atrophic gastritis: statistical calculations of cross-sectional data.
International Journal of Cancer 1985;35:1737.
[70] Fry J. Peptic ulcer: a prole. British Medical Journal 1964;2:80912.
[71] Ubukata H, Nagata H, Tabuchi T, Konishi S, Kasuga T, Tabuchi T. Why is the
coexistence of gastric cancer and duodenal ulcer rare? Examination of factors
related to both gastric cancer and duodenal ulcer. Gastric Cancer 2011;14:412.
[72] Nomura AM, Stemmermann GN, Samloff IM. Serum pepsinogen I as a predictor
of stomach cancer. Annals of Internal Medicine 1980;93:53740.
[73] Miki K. Gastric cancer screening using the serum pepsinogen test method.
Gastric Cancer 2006;9:24553.
[74] Iijima K, Abe Y, Kikuchi R, Koike T, Ohara S, Sipponen P, et al. Serum biomarker
tests are useful in delineating between patients with gastric atrophy and nor-
mal, healthy stomach. World Journal of Gastroenterology 2009;15:8539.
[75] Vaananen H, Vauhkonen M, Helske T, Kaariainen I, Rasmussen M, Tunturi-
Hihnala H, et al. Non-endoscopic diagnosis of atrophic gastritis with a blood
test. Correlation between gastric histology and serum levels of gastrin-17 and
pepsinogen I: a multicentre study. European Journal of Gastroenterology and
Hepatology 2003;15:88591.
[76] Brenner H, Rothenbacher D, Weck MN. Epidemiologic ndings on serologically
dened chronic atrophic gastritis strongly depend on the choice of the cutoff-
value. International Journal of Cancer 2007;121:27826.
[77] Ohata H, Kitauchi S, Yoshimura N, Mugitani K, Iwane M, Nakamura H, et al.
Progression of chronic atrophic gastritis associated with Helicobacter pylori
infection increases risk of gastric cancer. International Journal of Cancer
2004;109:13843.
[78] Watabe H, Mitsushima T, Yamaji Y, Okamoto M, Wada R, Kokubo T, et al. Pre-
dicting the development of gastric cancer from combining Helicobacter pylori
antibodies and serum pepsinogen status: a prospective endoscopic cohort
study. Gut 2005;54:7648.
[79] Kudo T, Kakizaki S, Sohara N, Onozato Y, Okamura S, Inui Y, et al. Analysis of
ABC (D) stratication for screening patients with gastric cancer. World Journal
of Gastroenterology 2011;17:47938.
[80] Shimoyama T, Aoki M, Sasaki Y, Matsuzaka M, Nakaji S, Fukuda S. ABC screening
for gastric cancer is not applicable in a Japanese population with high preva-
lence of atrophic gastritis. Gastric Cancer 2012;15:3314.
[81] Miki K. Gastric cancer screening by combined assay for serum anti-Helicobacter
pylori IgG antibody and serum pepsinogen levels ABC method. Proceedings
of the Japan Academy Series B: Physical & Biological Sciences 2011;87:
40514.
[82] Kaise M, Miwa J, Fujimoto A, Tashiro J, Tagami D, Sano H, et al. Inuence of
Helicobacter pylori status and eradication on the serum levels of trefoil factors
and pepsinogen test: serum trefoil factor 3 is a stable biomarker. Gastric Cancer
2012.
[83] Kawai T, Miki K, Ichinose M, Kenji Y, Miyazaki I, Kawakami K, et al. Changes in
evaluation of the pepsinogen test result following Helicobacter pylori eradica-
tion therapy in Japan. Inammopharmacology 2007;15:315.
 A. Shiotani et al. / Seminars in Cancer Biology 23P (2013) 492501 501

[84] Capelle LG, de Vries AC, Haringsma J, Ter BF, de Vries RA, Bruno MJ, et al.
The staging of gastritis with the OLGA system by using intestinal metapla-
sia as an accurate alternative for atrophic gastritis. Gastrointestinal Endoscopy
2010;71:11508.
[85] Rugge M, Correa P, Di MF, el-Omar E, Fiocca R, Geboes K, et al. OLGA staging for
gastritis: a tutorial. Digestive and Liver Disease 2008;40:6508.
[86] Wong BC, Zhang L, Ma JL, Pan KF, Li JY, Shen L, et al. Effects of selective COX-2
inhibitor and Helicobacter pylori eradication on precancerous gastric lesions.
Gut 2012;61:8128.
[87] Nardone G, Rocco A. Chemoprevention of gastric cancer: role of COX-2
inhibitors and other agents. Digestive Diseases 2004;22:3206.