REVIEW 10.1111/j.1469-0691.2009.03031.

Helicobacter pylori and gastric adenocarcinoma

V. Herrera1 and J. Parsonnet1,2

1) Division of Infectious Diseases, Department of Medicine, Stanford University School of Medicine and 2) Division of Epidemiology, Department of Health
Research and Policy, Stanford University School of Medicine, Stanford, CA, USA

Abstract

Gastric cancer is the second most common cause of cancer death worldwide. A large body of evidence supports a causal role of Helico-
bacter pylori in the majority of gastric malignancies. Great strides have been made in understanding the pathogenesis of this relationship,
but much remains to be learned. Moreover, because of the high prevalence of infection, the lack of definitive trials, and the challenges
of H. pylori treatment, there remains no consensus on the role of routine screening and treatment of this infection to prevent cancer.
This article reviews the current knowledge on H. pylori and gastric cancer and presents some of the clinical and public health challenges
associated with this pathogen.

Keywords: Epidemiology, gastric adenocarcinoma, gastritis, Helicobacter pylori, pathophysiology, review

Clin Microbiol Infect 2009; 15: 971–976

Corresponding author and reprint requests: V. Herrera,

Division of Infectious Diseases, Department of Medicine, Stanford
University School of Medicine, Grant Building, Room S125, 300
Pasteur Drive, Stanford, CA 94305, USA
E-mail: herrerav@stanford.edu

H. pylori with the incidence of gastric cancer [3]. Sub-

Introduction
Gastric cancer is the second leading cause of death due to
cancer worldwide. In 2002, 934 000 cases were recorded
(9% of new cancers) with 700 000 deaths [1]. Yet, despite
these daunting numbers, which, in part, are consequent to
increased human longevity, the rate of gastric cancer has
actually been declining from the early 20th Century onward.
The precipitous drop in incidence, particularly in industrial-
ized nations, has been the topic of extensive investigation.
Finally, the reason for this declining rate has now become
clear; it is a result of the diminishing prevalence of Helicobact-
er pylori infection, an organism that, until very recently, was
part of the normal flora of humans.
Interest in H. pylori as a cause of cancer began after the
pioneering discoveries of Marshall and Warren in the 1980s
[2]. Prior to the discovery of the organism, it was known
that gastric adenocarcinomas typically arose in areas of gas-
tritis. When the relationship between H. pylori and chronic
gastritis was established, investigators began to take interest
in the causal role of H. pylori in gastric cancer. The first stud-
ies to examine the association between H. pylori and gastric
cancer were ecological, comparing the regional prevalence of
sequently, numerous observational studies of diverse design
confirmed these findings. In 1994, the International Agency
for Research on Cancer declared H. pylori to be a type I car-
cinogen, or a definite cause of cancer in humans [4].
We discuss the epidemiological and pathophysiological
data that led to the consensus that H. pylori is one of the
world’s most important causes of cancer.
Helicobacter pylori
H. pylori is a Gram-negative, spiral-shaped bacterium that is
characterized by its many unipolar flagella, which give it
corkscrew-like motility, and its prodigious production of
urease. Unique among bacteria, it finds a niche in both the
antral and fundic mucosa of the stomach under the mucus
gel. The presence of infection is universally associated with
chronic and acute inflammation and, more variably, with
other gastric lesions, including lymphoid follicles, atrophic
gastritis and intestinal metaplasia. Treatment with antimi-
crobial agents causes inflammation to regress over time
[5]. With relapse of infection, the gastritis is again
observed [6].

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Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases
972 Clinical Microbiology and Infection, Volume 15 Number 11, November 2009
H. pylori is typically acquired during childhood and causes
lifelong infection thereafter [7]. Although previously almost
universal in humans, currently ‘only’ half of the world’s popu-
lation is infected with H. pylori. Transmission is largely from
person to person via the faecal–oral or the gastric–oral
route within families, particularly in settings of poor sanita-
tion and hygiene [8]. The prevalence of infection varies
worldwide, with continued hyper-endemicity in developing
countries but a markedly lower prevalence in developed
countries [9]. H. pylori is now rare in native-born and
middle- or upper-class children of Western Europe [10],
North America [11], Oceania [12] and Japan [13].
Epidemiological Links between Gastric
Cancer and H. pylori
Subsequent to its discovery in the early 1980s, over 1000
studies have been conducted on H. pylori and its association
with cancer, including observational studies (ecological, case–
control and cohort), clinical trials of H. pylori eradication,
pathological studies and animal models. The results have
been overwhelmingly in favour of a link between infection
and malignancy. Among the many observational studies in
humans, case–control studies indicate the lowest risk for
cancer (1.8-fold increase) [14]. It is now understood that
these studies underestimate the true risk due to loss of
H. pylori as the mucosa undergoes malignant transformation.
Nested case–control studies indicate higher relative risks in
meta-analyses [15]. However, the most compelling observa-
tional evidence of an association between H. pylori infection
and gastric cancer comes from longitudinal cohort studies. In
a large prospective trial conducted in Japan, 36 out of 1246
infected individuals developed gastric cancer compared to
none of 280 uninfected participants (infinite OR) [16]. A pro-
spective study of 1225 Taiwanese patients confirmed this
‘infinite’ OR (p 0.015) [17].
Not all H. pylori are alike, however, and the epidemiologi-
cal story is complex. Individuals with antibodies to H. pylori’s
CagA protein (a marker for the more inflammatory and viru-
lent strain bearing a pathogenicity island of genes) have a
particularly high risk of cancer. A meta-analysis of studies
shows that CagA-positive strains increase the risk of noncar-
dia gastric cancer two-fold compared to CagA-negative
strains [18]. Moreover, gastric cancer, similar to H. pylori, is
heterogeneous, with two histological types predominating:
the intestinal-type and the diffuse type. Although H. pylori has
been linked to both histological types, CagA appears to
enhance the risk of the intestinal type that arises in the set-
ting of inflammation, atrophic gastritis and intestinal metapla-
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CMI
sia, but not the risk of the diffuse type that appears to stem
from e-cadherin mutations [19].
Definitive experimental proof that H. pylori causes cancer
in humans lags behind the observational science, largely
because the studies are so difficult to undertake. Random-
ized clinical trials of secondary cancer prevention through
H. pylori eradication require both a large number of subjects
and many years of follow-up [20]. To obviate these prob-
lems, a number of investigators have used gastric cancer pre-
cursors (i.e. multifocal atrophic gastritis and intestinal
metaplasia) as surrogates for measuring the effects of
H. pylori eradication on the malignant process. Overall, these
studies suggest improvement of pre-neoplastic lesions,
although the change is slow and not universally observed
[21]. Indeed, in some studies, continued progression of pre-
neoplastic conditions has been substantial despite H. pylori
eradication. Complicating matters further, the one random-
ized clinical trial concerning cancer prevention completed to
date did not show a significant association between H. pylori
eradication and disease prevention, although there was a
trend towards benefit, particularly in young patients without
pre-neoplastic conditions [22]. By contrast, a randomized,
open-label trial in 544 Japanese patients treated with endo-
scopic resection of early gastric cancer showed significantly
lower rates of secondary, metachronous cancers in those
who received ‘adjuvant’ H. pylori eradication therapy com-
pared to those who did not (OR 0.35, 95% CI 0.16–0.78)
[23]. Again, not all treated patients benefited. Thus, although
the experimental data in humans are thin, they do support
the notion that H. pylori causes cancer and that its treatment
provides some benefit.
Based on the amalgam of observational and experiment
studies, the attributable risk of gastric cancer in the popula-
tion (i.e. the proportion of gastric cancer in the population
that would not occur were the H. pylori not to exist) has
been estimated to be 75% [24]. If this is accurate, H. pylori
would be responsible for as many as 5.5% of all
cancers, making it the leading infectious cause of cancer
worldwide and second only to smoking as a defined cause of
malignancy.
Mechanisms of Carcinogenesis
Although mechanisms of H. pylori-induced carcinogenesis are
only beginning to be understood, inflammation is the most
commonly cited factor in the carcinogenic process. Inflamma-
tion is thought to induce cancer by increasing production of
free radicals [25], increasing apoptotic and necrotic epithelial
cell death [26] and augmenting cell proliferation [27]. To
CMI Herrera and Parsonnet
compound these pro-carcinogenic processes, H. pylori has
been noted to reduce DNA repair in vivo and in vitro [28].
The importance of inflammation as a risk factor is bolstered
by three complementary observations: first, that the bacterial
strains that induce the most inflammation are most closely
linked to malignancy [29]; second, that pro-inflammatory
host cytokine polymorphisms increase cancer risk [30], and
third, that nonsteroidal anti-inflammatory agents appear to
decrease the risk of cancer [31].
Mechanisms other than inflammation have been posited
for H. pylori-related carcinogenesis. H. pylori directly inter-
acts with epithelial cells, resulting in protein modulation
and gene activation [32]. Strains that contain the pathoge-
nicity island of genes have a particularly intimate relation-
ship with the host. These strains produce a type IV
secretion system through which the CagA protein is
injected into gastric epithelial cells. There, the protein
becomes phosphorylated by members of the Sac family of
kinases, implicated in other malignancies. The phosphory-
lated CagA then activates the eukaryotic phosphokinase,
SHP2, as well as extracellular signal-regulated kinase (a
member of the mitogen-activated protein kinase family).
The pathogenicity island also results in a ‘hummingbird’ epi-
thelial phenotype, epithelial motility, loss of gap junctions,
and eventual epithelial cell death [33].
Most recently, much attention has been given to the rela-
tionship between H. pylori, stem cells and cancer. Some have
proposed that H. pylori preferentially damages parietal cells,
thereby altering the maturation process of epithelial stem
cells [34]. Others report that inflammation related to
H. pylori recruits peripheral- or bone-marrow derived stem
cells to the gastric mucosa, which then transform into the
malignant clone. The strongest evidence of this comes from
experiments performed by Houghton et al. [35], who identi-
fied bone-marrow derived stem cells as the cells of malignant
origin in C57BL/6 mice. By contrast, Giannakis et al. [36]
report identifying H. pylori inside gastric stem cells. They fur-
ther observed that an isolate from a cancer patient had clo-
ser affinity to gastric stem cells, causing more profound
regulation of cell function, than did an isolate from the same
patient 4 years before the cancer diagnosis, suggesting that
the organism evolved through crosstalk with the host epithe-
lium. This ‘endosymbiosis’ may be, in the end, a critical factor
in disease development.
Co-factors in Carcinogenesis
Although half of the world’s population is infected with
H. pylori, only a minority of individuals (estimated 1–2%) pro-
Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 15, 971–976
H. pylori and gastric adenocarcinoma 973
gress to gastric cancer over a lifetime. This percentage is
deceptively low, however, because children and young adults
are included in the lifetime risk assessment. When only mid-
dle-aged adults are considered, the risk of cancer appears
more substantial. For example, in prospective studies con-
ducted in Asia, between 3% and 6% of H. pylori-infected sub-
jects developed gastric cancer within a decade [16,37]. Yet,
worldwide, the great majority of adults infected with H. pylori
survive without ever suffering from malignancy. Unfortu-
nately, the reason some develop cancer and others do not is
incompletely understood.
As mentioned above, bacterial factors appear to play a
role in disease outcome. In addition to the pathogenicity
island previously mentioned, a vacuolating cytotoxin (VacA)
has been linked to malignancy. This protein has genotypes of
varying epithelial toxicity. The s1/mL vacA allele has been
particularly linked to epithelial damage and to carcinogenesis
[38]. The vacA alleles have varying global prevalence that can
explain, in part, the marked differences in the incidence of
gastric cancer noted worldwide [29]. Other microbial factors
that vary among strains and may affect the pathogenicity of
H. pylori include apurinic/apyrimidinic endonuclease-1, which
activates transcription factors and is involved in the DNA
repair of oxidative damage [39]; OipA, an outer membrane
protein linked to inflammation; and BabA which binds
H. pylori to Lewis blood group antigens [40].
After bacterial genetics, probably the single most impor-
tant factor influencing carcinogenesis is host genetics. Poly-
morphisms in the interleukin (IL)-1b and IL-1 receptor
antagonist are particularly well studied [41]. IL-1b acts as
both an inhibitor of gastric acid secretion and a pro-inflam-
matory cytokine, both of which would tend to enhance
carcinogenesis. Polymorphisms in tumour necrosis factor
and IL-10 have also been linked to intestinal-type cancer
[30], whereas IL-8 promoter polymorphisms have been
linked to diffuse-type cancer [42]. Human leukocyte antigen
polymorphisms have been variably linked to gastric cancer
[43]. In one of the largest study series to date, 520 H. pylor-
positive patients (330 with noncardia gastric cancer and
190 non-ulcer control patients) were evaluated for the
influence of genetic factors on gastric cancer susceptibility.
The results suggested that the combination of human leu-
kocyte antigen class II and IL-10-592A/C polymorphisms
affected the susceptibility to gastric cancer in a synergistic
manner [44].
There is limited evidence of associations between environ-
mental exposures and gastric cancer in the context of
H. pylori infection. A prospective study from Colombia
demonstrated that H. pylori eradication and increased
dietary vitamin C and b-carotene prevented progression of
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974 Clinical Microbiology and Infection, Volume 15 Number 11, November 2009
pre-neoplastic lesions to cancer [45]. Long-term follow-up of
this trial, however, showed that the dietary benefits disap-
pear when participants are followed for a longer period of
time [46]. Increased consumption of salt may also increase
the risk of gastric cancer. In a study of 2476 participants,
followed prospectively for 14 years, there was a significant
relationship between increased salt consumption and the
development of gastric cancer in subjects infected with
H. pylori [47]. Several studies have also demonstrated that
cigarette smoking amplifies the H. pylori-associated risk of
cancer [48].
An intriguing area of interest is the impact of infection
with helminths on the outcome of H. pylori in humans. It has
been postulated that, by decreasing the Th1 inflammatory
response, helminthes could theoretically reduce gastric
inflammation and cancer incidence. This phenomenon has
been seen in some animal models of co-infection [49] and
has also been suggested in small human studies [50].
Cancer Prevention
Although there is strong agreement that H. pylori causes
cancer, there is little consensus on whether and when this
carcinogenic process can be reversed. The clinical trial of
pre-neoplastic lesions by Fukase et al. [23] suggests that
benefits can come very late in the malignant process, even
after cancer has already begun. This conflicts with other
human data that demonstrate continued disease progres-
sion in many individuals after H. pylori eradication. More-
over, it conflicts with the randomized clinical trial of Wong
et al. [22] that revealed no benefits of H. pylori treatment
in those with pre-neoplastic conditions. Thus, screening for
and treatment of H. pylori infection as a strategy for sec-
ondary prevention of gastric cancer remains controversial.
The controversy is amplified by data indicating benefits by
preventing esophageal adenocarcinoma [51], asthma [52],
diarrhoea [53] and even tuberculosis [54]. These data addi-
tionally call into some question the advisability of creating
a vaccine.
Yet, despite the ongoing academic debate, several impor-
tant consensus groups have recommended screening and
treatment of those at highest risk of malignancy (i.e. those
with a family history of cancer, with prior gastric surgery, or
with documented atrophic gastritis) [55]. These same guide-
lines do not discourage broader screening based on individ-
ual choice. This last point conforms with the view of a
number of H. pylori experts who have strongly advocated
screening and treatment of wide swaths of the population.
Although this is an appealing strategy and numerous studies
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CMI
have indicated it could be cost effective [56], there are
currently no screening and treatment programmes ongoing
outside of the research sphere.
A promising field is the use of molecular testing to predict
clinical outcomes. Currently there is no reliable way to
identify, among individuals infected with H. pylori, those with
the highest risk of developing gastric cancer. Using
high-throughput proteomics, Khoder et al. [57] evaluated
129 H. pylori strains from individuals with gastric cancer or
duodenal ulcers. After identifying 18 statistically significant
biomarkers, there were three proteins that predicted pro-
gression to cancer; these included a neutrophil-activating
protein NapA, a RNA-binding protein, and a DNA-binding
histone-like protein. These novel biomarkers could poten-
tially be used as diagnostic assays to predict the evolution to
gastric cancer. The usefulness of this approach in patients
without pre-cancerous lesions is not clear [58], but it is an
interesting avenue for future research.
Conclusions
H. pylori causes the majority of the world’s gastric cancers.
With this knowledge comes the power to potentially control
and eliminate this highly lethal disease. To date, however, we
have not yet reached a consensus on whether or not to
exterminate this microbe from the human host. It is possible
that the answer may vary for different populations at differ-
ent levels of risk of disease. In the absence of human inter-
vention, we are fortunate that H. pylori appears to be
disappearing from many human populations spontaneously.
With this natural experiment, we will undoubtedly glean fur-
ther data to inform us of our best approach worldwide to
infection and disease.
Transparency Declaration
Both authors declare no conflict of interest.
References
1. Parkin DM, Bray F, Ferlay J, Pisani P. Global cancer statistics, 2002.
CA Cancer J Clin 2005; 55: 74–108.
2. Marshall BJ, Warren JR. Unidentified curved bacilli in the stomach of
patients with gastritis and peptic ulceration. Lancet 1984; 16: 1311–
1315.
3. The Eurogast Study Group. Epidemiology of, and risk factors for, He-
licobacter pylori infection among 3194 asymptomatic subjects in 17
populations. The EUROGAST Study Group. Gut 1993; 34: 1672–
1676.
CMI Herrera and Parsonnet
4. IARC Working Group. IARC working group on the evaluation of car-
cinogenic risks to humans: some industrial chemicals Lyon, 15–22
February 1994. IARC Monogr Eval Carcinog Risks Hum 1994; 60: 1–560.
5. Ohkusa T, Fujiki K, Takashimizu I et al. Improvement in atrophic
gastritis and intestinal metaplasia in patients in whom Helicobacter
pylori was eradicated. Ann Intern Med 2001; 134: 380–386.
6. Patchett S, Beattie S, Leen E, Keane C, O’Morain C. Helicobacter pylori
and duodenal ulcer recurrence. Am J Gastroenterol 1992; 87: 24–27.
7. Rowland M, Daly L, Vaughan M, Higgins A, Bourke B, Drumm B.
Age-specific incidence of Helicobacter pylori. Gastroenterology 2006;
130: 65–72; quiz 211.
8. Perry S, De La Luz Sanchez M, Shufang Y et al. Gastroenteritis and
transmission of Helicobacter pylori infection in households. Emerg Infect
Dis 2006; 12: 1701–1708.
9. Brown LM. Helicobacter pylori: epidemiology and routes of transmis-
sion. Epidemiol Rev 2000; 22: 283–297.
10. Mourad-Baars PE, Verspaget HW, Mertens BJ, Mearin ML. Low prev-
alence of Helicobacter pylori infection in young children in the Nether-
lands. Eur J Gastroenterol Hepatol 2007; 19: 213–216.
11. Segal I, Otley A, Issenman R et al. Low prevalence of Helicobacter
pylori infection in Canadian children: a cross-sectional analysis. Can J
Gastroenterol 2008; 22: 485–489.
12. Hardikar W, Grimwood K. Prevalence of Helicobacter pylori infection
in asymptomatic children. J Paediatr Child Health 1995; 31: 537–541.
13. Okuda M, Miyashiro E, Booka M, Tsuji T, Nakazawa T. Helicobacter
pylori colonization in the first 3 years of life in Japanese children. Heli-
cobacter 2007; 12: 324–327.
14. Huang J-Q, Sridhar S, Chen Y, Hunt RH. Meta-analysis of the rela-
tionship between Helicobacter pylori seropositivity and gastric cancer.
Gastroenterology 1998; 114: 1169–1179.
15. Helicobacter, Cancer Collaborative Group. Gastric cancer and Heli-
cobacter pylori: a combined analysis of 12 case control studies nested
within prospective cohorts. Gut 2001; 49: 347–353.
16. Uemura N, Okamoto S, Yamamoto S et al. Helicobacter pylori infec-
tion and the development of gastric cancer. N Engl J Med 2001; 345:
784–789.
17. Hsu PI, Lai KH, Hsu PN et al. Helicobacter pylori infection and the risk
of gastric malignancy. Am J Gastroenterol 2007; 102: 725–730.
18. Huang JQ, Zheng GF, Sumanac K, Irvine EJ, Hunt RH. Meta-analysis
of the relationship between cagA seropositivity and gastric cancer.
Gastroenterology 2003; 125: 1636–1644.
19. Shibata A, Parsonnet J, Longacre TA et al. CagA status of Helicobacter
pylori infection and p53 gene mutations in gastric adenocarcinoma.
Carcinogenesis 2002; 23: 419–424.
20. Parsonnet J, Forman D. Helicobacter pylori infection and gastric cancer
– for want of more outcomes. JAMA 2004; 291: 244–245.
21. Fuccio L, Zagari RM, Minardi ME, Bazzoli F. Systematic review: Helico-
bacter pylori eradication for the prevention of gastric cancer. Aliment
Pharmacol Ther 2007; 25: 133–141.
22. Wong BC, Lam SK, Wong WM et al. Helicobacter pylori eradication to
prevent gastric cancer in a high-risk region of china: a randomized
controlled trial. JAMA 2004; 291: 187–194.
23. Fukase K, Kato M, Kikuchi S et al. Effect of eradication of Helicobacter
pylori on incidence of metachronous gastric carcinoma after endo-
scopic resection of early gastric cancer: an open-label, randomised
controlled trial. Lancet 2008; 372: 392–397.
24. Parkin DM. The global health burden of infection-associated cancers
in the year 2002. Int J Cancer 2006; 118: 3030–3044.
25. Hocker M, Rosenberg I, Xavier R et al. Oxidative stress activates the
human histidine decarboxylase promoter in ags gastric cancer cells.
J Biol Chem 1998; 273: 23046–23054.
26. Wang TC, Goldenring JR, Dangler C et al. Mice lacking secretory
phospholipase A2 show altered apoptosis and differentiation with
Helicobacter felis infection. Gastroenterology 1998; 114: 675–689.
Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 15, 971–976
H. pylori and gastric adenocarcinoma 975
27. Brenes F, Ruiz B, Correa P et al. Helicobacter pylori causes hyperprolif-
eration of the gastric epithelium: pre- and post-eradication indices of
proliferating cell nuclear antigen. Am J Gastroenterol 1993; 88: 1870–
1875.
28. Witherell H, Hiatt R, Replogle M, Parsonnet J. Helicobacter pylori
infection and urinary excretion of 8-hydroxy-2-deoxyguanosine, an
oxidative DNA adduct. Cancer Epidemiol Biomarkers Prev 1998; 7: 91–
96.
29. Yamaoka Y, Kato M, Asaka M. Geographic differences in gastric can-
cer incidence can be explained by differences between Helicobacter
pylori strains. Intern Med 2008; 47: 1077–1083.
30. El-Omar EM, Rabkin CS, Gammon MD et al. Increased risk of non-
cardia gastric cancer associated with proinflammatory cytokine gene
polymorphisms. Gastroenterology 2003; 124: 1193–1201.
31. Cuzick J, Otto F, Baron JA et al. Aspirin and non-steroidal anti-inflam-
matory drugs for cancer prevention: an international consensus state-
ment. Lancet Oncol 2009; 10: 501–507.
32. Chiba T, Marusawa H, Seno H, Watanabe N. Mechanism for gastric
cancer development by Helicobacter pylori infection. J Gastroenterol
Hepatol 2008; 23 (8 Pt 1): 1175–1181.
33. Bagnoli F, Buti L, Tompkins L, Covacci A, Amieva MR. Helicobacter
pylori CagA induces a transition from polarized to invasive pheno-
types in MDCK cells. Proc Natl Acad Sci USA 2005; 102: 16339–
16344.
34. Correa P, Houghton J. Carcinogenesis of Helicobacter pylori. Gastroen-
terology 2007; 133: 659–672.
35. Houghton J, Stoicov C, Nomura S et al. Gastric cancer originating
from bone marrow-derived cells. Science 2004; 306: 1568–1571.
36. Giannakis M, Chen SL, Karam SM, Engstrand L, Gordon JI. Helicobact-
er pylori evolution during progression from chronic atrophic gastritis
to gastric cancer and its impact on gastric stem cells. Proc Natl Acad
Sci USA 2008; 105: 4358–4363.
37. Yamagata H, Kiyohara Y, Aoyagi K et al. Impact of helicobacter pylori
infection on gastric cancer incidence in a general Japanese population:
the Hisayama study. Arch Intern Med 2000; 160: 1962–1968.
38. Atherton JC, Cao P, Peek RM Jr, Tummuru MKR, Blaser MJ, Cover
TL. Mosaicism in vacuolating cytotoxin alleles of Helicobacter pylori.
J Biol Chem 1995; 270: 17771–17777.
39. Ziel KA, Campbell CC, Wilson GL, Gillespie MN. Ref-1/Ape is criti-
cal for formation of the hypoxia-inducible transcriptional complex on
the hypoxic response element of the rat pulmonary artery endothe-
lial cell VEGF gene. FASEB J 2004; 18: 986–988.
40. Clyne M, Dolan B, Reeves EP. Bacterial factors that mediate coloniza-
tion of the stomach and virulence of Helicobacter pylori. FEMS Micro-
biol Lett 2007; 268: 135–143.
41. El-Omar EM, Carrington M. Interleukin-1 polymorphisms associated
with increased risk of gastric cancer. Nature 2000; 404: 398.
42. Lee WP, Tai DI, Lan KH et al. The -251T allele of the interleukin-8
promoter is associated with increased risk of gastric carcinoma fea-
turing diffuse-type histopathology in Chinese population. Clin Cancer
Res 2005; 11: 6431–6441.
43. Perri F, Piepoli A, Quitadamo M, Quarticelli M, Merla A, Bisceglia M.
HLA-DQA1 and -DQB1 genes and Helicobacter pylori infection in Ital-
ian patients with gastric adenocarcinoma. Tissue Antigens 2002; 59:
55–57.
44. Ando T, Ishikawa T, Kato H, Yoshida N, Naito Y, Kokura S et al.
Synergistic effect of HLA class II loci and cytokine gene polymor-
phisms on the risk of gastric cancer in Japanese patients with Helico-
bacter pylori infection. Int J Cancer2009; Epub ahead of print..
45. Correa P, Fontham ET, Bravo JC et al. Chemoprevention of gastric
dysplasia: randomized trial of antioxidant supplements and anti-Heli-
cobacter pylori therapy. J Natl Cancer Inst 2000; 92: 1881–1888.
46. Mera R, Fontham ET, Bravo LE et al. Long term follow up of patients
treated for Helicobacter pylori infection. Gut 2005; 54: 1536–1540.
ª2009 The Authors
976 Clinical Microbiology and Infection, Volume 15 Number 11, November 2009
47. Shikata K, Kiyohara Y, Kubo M et al. A prospective study of dietary
salt intake and gastric cancer incidence in a defined Japanese popula-
tion: the Hisayama study. Int J Cancer 2006; 119: 196–201.
48. Shikata K, Doi Y, Yonemoto K et al. Population-based prospective
study of the combined influence of cigarette smoking and Helicobacter
pylori infection on gastric cancer incidence: the Hisayama Study. Am J
Epidemiol 2008; 168: 1409–1415.
49. Fox JG, Beck P, Dangler CA et al. Concurrent enteric helminth infec-
tion modulates inflammation and gastric immune responses and
reduces helicobacter-induced gastric atrophy. Nat Med 2000; 6: 536–
542.
50. Whary MT, Sundina N, Bravo LE et al. Intestinal helminthiasis in
Colombian children promotes a Th2 response to Helicobacter pylori:
possible implications for gastric carcinogenesis. Cancer Epidemiol Bio-
markers Prev 2005; 14: 1464–1469.
51. Islami F, Kamangar F. Helicobacter pylori and esophageal cancer risk: a
meta-analysis. Cancer Prev Res 2008; 1: 329–338.
52. Chen Y, Blaser MJ. Inverse associations of Helicobacter pylori with
asthma and allergy. Arch Intern Med 2007; 167: 821–827.
ª2009 The Authors
Journal Compilation ª2009 European Society of Clinical Microbiology and Infectious Diseases, CMI, 15, 971–976
CMI
53. Perry S, Sanchez L, Yang S, Haggerty TD, Hurst P, Parsonnet J. Helicob-
acter pylori and risk of Gastroenteritis. J Infect Dis 2004; 190: 303–310.
54. Perry S, De Jong BC, Hill P, Adegbola R, Parsonnet J. Helicobacter
pylori and the outcome of M. tuberculosis infection. San Diego, CA: Infec-
tious Disease Society of America, annual meeting, 2007.
55. Talley NJ, Fock KM, Moayyedi P. Gastric Cancer Consensus confer-
ence recommends Helicobacter pylori screening and treatment in
asymptomatic persons from high-risk populations to prevent gastric
cancer. Am J Gastroenterol 2008; 103: 510–514.
56. Parsonnet J, Harris RA, Hack HM, Owens DK. Modelling cost-effec-
tiveness of Helicobacter pylori screening to prevent gastric cancer: a
mandate for clinical trials. Lancet 1996; 348: 150–154.
57. Khoder G, Yamaoka Y, Fauchere JL, Burucoa C, Atanassov C. Prote-
omic Helicobacter pylori biomarkers discriminating between duodenal
ulcer and gastric cancer. J Chromatogr B Analyt Technol Biomed Life Sci
2009; 877: 1193–1199.
58. Ito M, Takata S, Tatsugami M et al. Clinical prevention of gastric
cancer by Helicobacter pylori eradication therapy: a systematic review.
J Gastroenterol 2009; 44: 365–371.