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REVIEW

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Steven F. Moss
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Gastroenterology Division, Rhode Island Hospital, Brown University, Providence, Rhode Island
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Funderburg
family
started
funding
gastric
cancer
research
SUMMARY
in 1992. As the rst recipient of the award to investigate 71
--H pylori (my project, funded in 2002, was entitled 72
Regulation of Gastric Epithelial p27kip1 by H pylori), this 73
review focuses on the clinicopathologic and epidemiologic 74
Gastric cancer has long been recognized to be accompanied data that have emerged over the past 30 years establishing 75
and preceded by chronic gastritis, lasting decades. Argu- H pylori as the most important etiologic agent in gastric 76
ably, the most important development in our understand- adenocarcinoma, and discusses the implications of this as- 77
78
ing of gastric cancer pathogenesis over the past 50 years sociation for gastric cancer prevention.
79
has been the realization that, for most cases of gastric
80
cancer, Helicobacter pylori is the cause of the underlying
The Inammatory Origins of Gastric
81
gastritis. Gastritis can promote gastric carcinogenesis,
82
typically via the Correa cascade of atrophic gastritis, in- Cancer
testinal metaplasia, and dysplasia. Nested case-control
Our understanding of H pyloriinduced inammation 83
studies have shown that H pylori infection increases the leading to cancer is built on the work of 3 pioneering 84
risk of gastric cancer signicantly, both of the intestinal pathologists (Figure 1).
85
and diffuse subtypes, and that H pylori is responsible for
Rudolf Virchow, a 19th century Prussian physician- 86
approximately 90% of the worlds burden of noncardia scientist, is widely regarded as the father of modern pa- 87
gastric cancer. Based largely on randomized studies in high thology. Among his many contributions to outlining the 88
gastric cancer prevalence regions in East Asia, it appears scientic basis of disease was the idea, based on many of his 89
that primary and tertiary intervention to eradicate H pylori own observations, that cancer arose from initially normal 90
can halve the risk of gastric cancer. Some public health cells in response to chronic irritation, or inammation.2 Q8 91
authorities now are starting screening and treatment Numerous examples of inammation-induced cancers are
92
programs to reduce the burden of gastric cancer in these
now appreciated, including many of the common gastroin- 93
high-risk areas. However, there is currently much less
testinal tract and hepatobiliary malignancies, such as acid 94
enthusiasm for initiating similar attempts in the United
reuxinduced esophageal adenocarcinoma, inammatory 95
States. This is partially because gastric cancer is a relabowel
diseaseassociated colon cancer, and hepatocellular 96
tively less frequent cause of cancer in the United States,
2
97
and in addition there are concerns about theoretical neoplasms associated with chronic viral hepatitis.
Throughout the 20th century, evidence accrued that 98
downsides of H pylori eradication, principally because of
the consistent inverse relationship noted between H pylori gastric cancers tended to arise in stomachs already affected 99
and esophageal adenocarcinoma. Nevertheless, establish- by chronic inammation, especially atrophic gastritis with 100
ing a link between chronic H pylori infection and gastric its accompanying hypochlorhydria, and that gastric cancer 101
cancer has led to novel insights into cancer biology, the was a consequence and not a mere accompaniment of the 102
3
gastrointestinal microbiome, and on individual and gastritis. These ideas set the stage for Pelayo Correa, a 103
population-based gastric cancer prevention strategies. pathologist from Colombia, a country with a particularly 104
(Cell Mol Gastroenterol Hepatol 2017;-:--; http:// high gastric cancer prevalence. After training in pathology in 105
dx.doi.org/10.1016/j.jcmgh.2016.12.001)
Colombia and in the United States (Emory University), 106
Correa devoted his professional career at home and subse- 107
quently in the United States (at the National Cancer Insti- 108
Keywords: ---.
tute, Louisiana State University, and now Vanderbilt 109
University) to understanding the etiology of gastric cancer. 110
111
t is now appreciated that infection with Helicobacter
112
Abbreviations
used
in
this
paper:
CI,
condence
interval;
ELISA,
pylori is the most important risk factor for the devel113
enzyme-linked immunosorbent assay.
opment of noncardia gastric cancer, responsible for almost
114

2017
The
Author.
Published
by
Elsevier
Inc.
on
behalf
of
the
AGA
90% of such cases worldwide and approximately 5% of the
Institute. This is an open access article under the CC BY-NC-ND
115
1
total burden from all cancers globally.
license (http://creativecommons.org/licenses/by-nc-nd/4.0/).
116
2352-345X
It is remarkable that the critical contribution of H pylori

The Clinical Evidence Linking Helicobacter pylori to

Gastric Cancer

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to gastric carcinogenesis was almost unknown when the

http://dx.doi.org/10.1016/j.jcmgh.2016.12.001

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Steven F. Moss

Cellular and Molecular Gastroenterology and Hepatology Vol.

Figure 1. Three pathologists who shaped our understanding of H pyloriinduced gastric carcinogenesis. Left
to right: Rudolf Virchow, Pelayo Correa, and Robin Warren.

In 1975, Correa et al,4 from the National Cancer Institute,

Massachusetts Institute of Technology, and from his home
country, published a Model for Gastric Cancer Development. In this landmark report, it was hypothesized that the
development of the more common intestinal subtype of
gastric cancer resulted from a stepwise process, beginning
with chronic atrophic gastritis and progressing to intestinal
metaplasia and cancer over the next 3050 years. The initial
changes were postulated to occur in the rst decade of life,
which we now know to be when H pylori colonization
occurs.5 A more detailed model, published in 1988,6
included what was known of the phenotypic markers
accompanying these sequential changes. Correa initially
thought that the agent(s) responsible for promoting this
slow progression from gastritis to cancer were environmental, based on studies of migrants from high gastric
cancer risk areas. For example, Japanese immigrants to
Hawaii and European immigrants to the United States had
been shown to have lower gastric cancer rates than their
parents and grandparents, more similar to those of the
native population where they settled.7,8 The prime environmental culprit originally was thought to be a diet high in
salt and N-nitroso-compounds and low in micronutrients
from fresh fruits and vegetables. It was postulated that this
led to the promotion of gastric mutagenesis and, together
with hypochlorhydria, bacterial overgrowth, thereby
contributing to further nitrosamine formation. Interestingly,
in his 1988 publication, Correa briey discussed a possible
role for Campylobacter pylori, a newly discovered gastric
bacterium, in the initiation of the disease. Correas subsequent work has focused primarily on the role of H pylori in
gastric cancer, and this model has stood the test of time
(Figure 2). For his outstanding contributions to the eld of
gastric carcinogenesis, Correa received the American
Gastroenterological Associations Distinguished Achievement Award in 2013.
The third pathologist of note is Robin Warren from
Australia who, together with Barry Marshall, was awarded
the Nobel Prize in Physiology or Medicine in 2005 for the
discovery of H pylori and its role in gastritis and peptic ulcer
disease.9 In the 1970s, the widespread use of gastrointestinal endoscopy allowed pathologists the opportunity to
view gastric tissue that had been removed during a biopsy
and xed rapidly, without the artifacts inherent to the

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Evidence of the H pyloriCancer
202
Connection
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Initial investigations into a possible association of 204
H pylori with gastric cancer that were conducted in the 205
1980s and early 1990s provided only weak evidence for a 206
link between H pylori and gastric cancer. A positive corre- 207
lation between H pylori seroprevalence and gastric cancer in 208
cross-sectional sampling was reported in some studies, such 209
as the EUROGAST study, which was conducted among 13 Q12 210
European nations by Forman et al.16 However, although Q13 211
some other publications found similar trends,17,18 several 212
others did not nd a positive correlation between the 213
presence of H pylori antibodies and either gastric cancer or 214
precancerous gastric lesions.1922
215
Around this time, clinicopathologic studies performed to 216
look for evidence of H pylori infection (by serum antibodies) 217
or in gastric tissue directly in cases of gastric cancer also 218
yielded inconsistent results. Some studies showed H pylori 219
infection rates no higher than those observed in noncancer 220
controls. This is most likely because by the time gastric 221
cancer has developed, extensive intestinal metaplasia and 222
hypochlorhydria had rendered the stomach less hospitable 223
to persistent H pylori colonization,23 thus also explaining 224
some of the negative ndings in the cross-sectional studies 225
discussed earlier.
226
Much more convincing evidence for the role of H pylori 227
in gastric cancer came from 3 large cohorts with nested 228
case-controls, in which serum had been banked from 229
cancer-free subjects and the cohort had been followed up 230
for approximately a decade.2426 In each cohort, evidence of 231
prior H pylori infection (evaluated by enzyme-linked 232
immunosorbent assay [ELISA] in the banked serum) was 233
found to be signicantly more common in those subjects 234
ischemia and autolysis of surgical specimens. Warren
recognized that spiral gastric bacteria were common in
fresh gastritis specimens. He then recruited Marshall, a
medical resident looking for a research project, to correlate
the pathologic ndings with the endoscopic features.10
Together, they discovered that these bacteria (initially
termed Campylobacter pyloridis, then C pylori, and, subsequently, H pylori) were very common in peptic ulcer patients. Eventually, they successfully cultured these formerly
elusive bacteria and showed that they caused gastritis and
ulcer disease.1114 In retrospect, other investigators also had
observed such bacteria over the preceding century, but their
clinical signicance had not been appreciated and they had
even been proven to be a post mortem artifact15 before their
rediscovery in Australia. Although Warren and Marshall did
not investigate the role of H pylori in gastric cancer directly,
they were aware of the relationship between gastritis and
cancer. Indeed, Marshall speculated with amazing prescience in their very rst publications (in unusual side-byside, single-author letters in 1983) that if these bacteria
are truly associated with antral gastritis, as described by
Warren, they may have a part to play in other poorly understood, gastritis associated diseases (ie, peptic ulcer and
gastric cancer).12

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Helicobacter pylori and Gastric Cancer

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Figure 2. Current model
307
of the decades-long
308
sequence of intestinal309
type gastric carcinogen310
esis, based on the
311
classical histopathologic
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Correa cascade in grey
box (left), with (center)
313
postulated stimuli (green
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boxes) and mechanisms
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(red boxes), and some of
316
the key accompanying
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molecular genetic events
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(right).
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who subsequently developed gastric cancer compared with
1. Cardia cancers are not associated strongly with
324
a sample of those who had not (Table 1). In a meta-analysis,
H pylori infection,29 supporting the idea that cardia
325
cancers arise via alternative mechanisms, with risk
these 3 studies provided an overall odds ratio for gastric
326
factors more similar to cancers of the gastroesophacancer development in H pyloriinfected vs -uninfected
327
27
30
geal junction and lower esophagus.
persons of 3.8 (95% condence interval [CI], 2.36.2).
328
Based on the compelling results of these cohort studies,
2. In pooled meta-analysis,31 the odds ratio for H pylori 329
the World Health Organizations International Agency for
in gastric cancer was no different when considering 330
Research on Cancer declared in 1994 that there was sufintestinal vs diffuse histologic cancer subtypes. Thus, 331
cient evidence to classify H pylori as a denite (group 1)
in addition to promoting the well-established Correa Q14 332
carcinogen.28 This was despite the fact that at that time
cascade of intestinal-type cancers, H pylori is just as 333
there was no signicant supporting evidence from either
great a risk factor for the much less well-dened 334
animal models or mechanistic basic science research.
335
pathway leading to diffuse-type gastric cancer.
Subsequent research worldwide has conrmed and
336
expanded upon the early epidemiologic studies, with the key
3. Measuring H pylori exposure by ELISA underestimates
337
additional clinical ndings as follows:
prior exposure and, therefore, the attributable H pylori
338
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Table 1.The Three Cohort Studies That Led to the Classication of H pylori as a Class 1 Carcinogen in 1994
343
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Time from cohort
Cases of H pylori
Controls with H
inception to cancer,
seroprevalence,
pylori seroprevalence, Odds ratio 345
Study
Cohort description
mean
n (%)
n (%)
(95% CI)
346
24
Forman et al, 1991
British men
6y
29 (69)
116 (47)
2.8 (1.08.0) 347
348
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14 y
109 (84)
109 (61)
3.6 (1.87.3)
Parsonnet et al, 1991 Californian men
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and women
350
26
JapaneseAmerican
13 y
109 (94)
109 (76)
6.0 (2.117)
Nomura et al, 1991
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men in Hawaii
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Cellular and Molecular Gastroenterology and Hepatology Vol.

risk in noncardia cancer, because of false-negative

results. For example, in a retrospective Swedish
case-control study, measuring prior exposure through
a Western blot against H pylori CagA, rather than a
conventional IgG ELISA, increased the odds ratio from
2.2 (95% CI, 1.43.6) to 21.0 (95% CI, 8.353.4).32
4. In noncardia gastric cancers, CagA-positive H pylori
strains (which are the more common strains worldwide) increase the risk of gastric cancer to a greater
extent than do infections by the more rare CagAnegative strains.33 This is consistent with the oncogenic effects of the CagA protein that have been
evaluated mainly in vitro.34
5. H pylori eradication can reduce the risk of developing
gastric cancer (see later).

Conclusions From Gastric Cancer

Prevention Studies

Q16

Q17

In a prolonged observational study following up patients

who had attended a Japanese endoscopy unit, Uemura
et al35 showed that those who were H pyloriinfected
(and in whom the infection was not treated) had a much
higher rate of progression to gastric cancer over
the subsequent 12 years than the patients who had
no initial evidence of H pylori. However, to prove conclusively that H pylori is responsible for the increased gastric
cancer risk, prospective interventional studies were
necessary.
Recruitment into such studies was hampered by the
1994 declaration of H pylori as a denite carcinogen,28 after
which it became ethically problematic to enter patients into
the control arms of eradication studies designed to determine the gastric cancer risk reduction. Consequently, an
appropriately powered, denitive study of a large number of
subjects followed up for many years to the end point of
gastric cancer was never completed. Nevertheless, recent
meta-analyses of the many underpowered studies that were
conducted are conclusive, indicating that H pylori eradication decreases the risk of gastric cancer development by
approximately 40% in studies of primary prevention
(asymptomatic individuals), and by 54% as a tertiary prevention strategy (preventing the occurrence of a second
gastric malignancy after endoscopic resection of an early
gastric cancer).36,37 It is not known whether or not there is
a point of no return along the Correa pathway, beyond
which H pylori eradication will not prevent progression to
gastric cancer. In the analysis by Lee et al,37 which included
24 publications of more than 48,000 individuals followed up
for more than 340,000 person-years (14 studies of primary
prevention, 10 studies of tertiary prevention), the benet of
H pylori eradication, not surprisingly, was most evident in
subjects living in areas with the highest gastric cancer
prevalence. However, the risk reduction was evident in
almost every individual study evaluated. Because all investigations were conducted in parts of the world where

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gastric cancer is most prevalent (mostly in South-East Asia),

it is uncertain if similar reductions can be extrapolated to
regions where noncardia gastric cancer is less common,
such as the United States. However, it may be reasonable to
suppose that high-risk populations in low-risk countries,
including immigrants from Central and South America
and South-East Asia to the United States who remain
H pyloriinfected from childhood, should benet greatly
from H pylori eradication too.

Should Widespread Screening and

Eradication Programs Be Adopted
to Prevent Gastric Cancer?
Gastric cancer is the third most common cause of cancer
death worldwide.38 However, with the exception of endoscopic screening in South Korea, and radiologic and endoscopic programs in Japan, there had been little effort made
previously to control this burden with public health programs. The results of the recent intervention studies reported earlier have now prompted renewed interest in
screening for H pylori and eradicating the organism when
found as a potentially cost-effective strategy, especially in
parts of the world that have a high prevalence of H pylori
and gastric cancer.3941
A pilot study of mass population screening and eradication started in the Matsu Islands of Taiwan in 2004, and
the initial results are very promising. Gastric cancer incidence has decreased by approximately 25%, peptic ulcers
by two thirds, and gastric atrophy by 77% compared with
historical data.42 Several other population-based trials are
underway, including one with almost 100,000 Chinese
subjects from Linqu County, a region of high gastric cancer
prevalence.43
The eradication of H pylori from a community should
help prevent much gastric cancer, as well as greatly
diminish the morbidity of peptic ulcers too. It has been
calculated that the number needed to treat to prevent a case
of gastric cancer may be as low as 15 in Chinese men, to as
high as 245 in women in the United States.44 Although there
is a concern regarding the ecologic consequences of using
multiple antibiotics in a large proportion of the population
to prevent H pylorirelated disease, the recent exciting results of vaccination against H pylori with an oral urease
B construct45 suggest that a nonantibiotic strategy may be
possible in the future, with potentially less impact on the
general human microbiome. Further investigation of this
vaccine should be a priority, particularly because promising
preclinical models with a variety of vaccine candidates since
the 1990s had never resulted previously in impressive results in clinical trials.46 If preventive or therapeutic vaccination emerges as a viable alternative for H pylori
eradication, it will help avert widespread antibiotic administration and the consequent problems of microbiome
perturbation and the generation of microbial antibiotic
resistance among H pylori and other innocent bystander
bacteria.

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Why the Hesitancy to Adopt

Widespread H pylori Eradication
in the United States?
In the midst of growing optimism for implementing
H pylori eradication strategies in high gastric cancer risk
regions, it is important to recognize that there is considerable hesitation to adopt similar approaches in the developed
world, mainly out of concern for a benecial effect of
H pylori on esophageal diseases.
The results of multiple studies have indicated that
H pylori is signicantly less common in patients with
esophageal adenocarcinoma than in matched controls,
although H pylori infection has no association, positive or
negative, with esophageal squamous cancer47,48 (Figure 3).
This places H pylori in a unique position among the World
Health Organizations list of biological agents that cause
cancer, in that its presence is associated positively with
certain cancers (gastric noncardia adenocarcinoma, gastric
marginal zone B-cell lymphoma) although related inversely
to another cancer type (esophageal adenocarcinoma).49
How H pylori infection might prevent esophageal cancer
is not known. The absence of H pylori may promote more
severe esophageal mucosal damage, Barretts metaplasia,50
and the consequent development of esophageal adenocarcinoma. A postulated mechanism is through a greater gastric
acid secretory capacity from a pristine, uninamed, parietal
cell mass in the absence of H pylori gastritis,51 although
there is little evidence that this actually leads to enhanced
esophageal acid exposure. An inverse relationship between
H pylori and esophageal adenocarcinoma does not necessarily imply that H pylori is protective any more than a
positive association can be taken to be evidence of causation. H pylori has been an almost universal inhabitant of the

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Helicobacter pylori and Gastric Cancer

2017

Q24

Figure 3. Complex relationship between H pylori and the

common cancers of the esophagus and stomach. Data are
shown as odds ratios for the development of cancer in H
pyloriinfected vs uninfected persons. Reprinted with
permission from Islami and Kamangar.47

human stomach from the dawn of mankind until the 530

1980s.52 Its recent disappearance from the 21st human 531
microbiome, one of the missing microbes,53 has been Q18 532
linked to extragastric immune dysregulation (for which 533
there is good evidence from animal models)54 and a multi- 534
tude of other contemporary maladies (eg, asthma, obesity, 535
and inammatory bowel disease), for which the evidence is 536
questionable and the biological plausibility equally 537
uncertain.5557
538
The decease in noncardia gastric cancer in North 539
America and Western Europe over the past 100 years that 540
coincided with (or maybe even preceded) decreasing 541
H pylori prevalence, was famously described as the epide- 542
miology of an unplanned triumph.58 The rapid increase in 543
esophageal adenocarcinoma in the same population more 544
recently (such that it is now approaching the prevalence of 545
noncardia gastric cancer59) perhaps may be considered the 546
unplanned downside of the disappearance of H pylori from 547
Western stomachs. It is this unexpected accompaniment of 548
H pylori eradication that largely has tempered enthusiasm 549
for population-based H pylori eradication efforts in the 550
developed world. Whether to pursue population-based 551
H pylori screening and treatment strategies therefore will 552
need to be individualized according to the current and 553
projected future medical needs of each community, and 554
these differ quite markedly around the globe.
555
556
557
Conclusions
558
The declaration of H pylori as a denite gastric carcin- 559
ogen in 199428 and the subsequent realization that the vast 560
majority of noncardia cancers are attributable to H pylori 561
infection1 has led to a fundamental change in the way that 562
we view gastric cancer pathogenesis in the Funderburg era. 563
Considering gastric cancer as the consequence of an infec- 564
tion has led to enthusiasm for screening for and eradicating 565
H pylori in areas of high gastric cancer prevalence, but the 566
fact that gastric cancer remains a rare consequence of 567
H pylori infection provides plenty of opportunity for inves- 568
tigating the co-factors that promote gastric neoplastic 569
development after H pylori colonization.
570
Recent research in this eld has focused on genetic 571
susceptibility (such as polymorphisms in genes governing 572
gastric inammatory responses60), H pylori heterogeneity,61 573
and on other environmental inuences, such as dietary 574
salt62 or the presence of non-Helicobacter species within the 575
gastrointestinal microbiome that may explain why only a 576
small proportion of individuals who are colonized by 577
H pylori go on to develop gastric cancer.63 This knowledge 578
ultimately may have clinical utility in stratifying individuals 579
with H pylori infection into high vs low gastric cancer risk, 580
and to the creation of personalized surveillance, chemo- 581
prevention, and dietary intervention programs focused on 582
patients at highest risk. As an example, an early study re- 583
ported enormous differences (up to 90-fold) in gastric 584
cancer susceptibility in H pyloriinfected cases from 585
Portugal, when stratied by polymorphisms in interleukin 586
1b and the interleukin 1receptor antagonist, together with 587
Q19 588
H pylori VacA and CagA typing.64

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Cellular and Molecular Gastroenterology and Hepatology Vol.

Investigating the precise molecular and cellular mechanisms of gastric cancer development associated with H pylori infection is likely to provide additional insights into
gastric cancer, as well as stimulate ideas about the pathogenesis of other cancers that are known to be associated
with inammation, although not necessarily with specic
constituents of the microbiome. Since 1994, considerable
progress has been made on dissecting the role of H pylori
role in the molecular pathogenesis of inammationassociated gastric cancer (as outlined in the review by
Crowe in this issue). The multiplicity of animal models to
study H pyloriassociated gastric carcinogenesis (reviewed
in Tsukamoto et al65 and Krueger et al,66 as well as by Wang
in this issue) also has provided many important mechanistic
insights that were not conceivable back in 1994, when
rodent infection studies were in their infancy and the evidence for H pylori as a carcinogen was based on a limited
number of clinical studies.
Support from the Funderburg family has been instrumental in promoting new ideas about gastric cancer and its
origins, as well as opening new therapeutic possibilities.
The work that started in our laboratory in 2002 as a result
of this funding has allowed us to investigate how H pylori
misregulates the expression of p27, a cyclin-dependent
kinase inhibitor that is an important constitutive endogenous cell-cycle regulator.67,68 We also subsequently
explored the p27-decient mouse as a model with which to
study the mechanisms of H pyloriinduced gastric carcinogenesis,69,70 and to examine its reversibility after
H pylori eradication.71
Our understanding of gastric carcinogenesis continues to
grow rapidly. For many years, pathologists were at the
cutting edge of this knowledge, based on their meticulous
observations of the unfortunate patients who died of this
largely untreatable disease. The realization that a single
bacterial species was the inciting cause of the majority of
gastric cancers went against the prevailing clinical and scientic dogma. As a result of this initially uncomfortable
discovery, gastric cancer, which was a disease that formerly
was principally the focus of pathologists and surgeons, has
become widely embraced by the scientic and clinical
community as a model of bacterial carcinogenesis and a
window to inammation-associated cancers in general.

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Received November 11, 2016. Accepted December 19, 2016.
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Correspondence
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Address correspondence to: Steven F. Moss, MD, Gastroenterology Division,
Rhode Island Hospital, 593 Eddy Street, APC 414, Providence, Rhode Island
898
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02903. e-mail: Steven_Moss@brown.edu; fax: (401) 444-2939.
899
Acknowledgments
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The author appreciates the help of Songhua Zhang, MD, PhD, and Murray
901
Resnick, MD, PhD, for manuscript review.
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Conicts of interest
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The author discloses no conicts.
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