IJC

International Journal of Cancer

Helicobacter pylori but not gastrin is associated

with the development of colonic neoplasms
Michael Selgrad1, Jan Bornschein1, Arne Kandulski1, Carla Hille1, Jochen Weigt1, Albert Roessner2,
Thomas Wex1,3 and Peter Malfertheiner1
1
Department of Gastroenterology, Hepatology and Infectious Diseases, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany
2
Department of Pathology, Otto-von-Guericke-University of Magdeburg, Magdeburg, Germany
3
Medical Laboratory for Clinical Chemistry, Microbiology and Infectious Diseases, Department of Molecular Genetics, Magdeburg, Germany

Recent studies have suggested that Helicobacter pylori (H. pylori) constitutes a risk for the development of colonic neoplasia.
Hypergastrinemia can be induced by H. pylori infection, and gastrin can act as putative promoter of colorectal carcinogenesis.
Aim of our study was to assess whether H. pylori infection and/or increased serum gastrin levels are associated with the
occurrence of colonic neoplasms. For this, we reviewed prospectively collected data of 377 patients with a minimum age of
50 years who underwent colonoscopy. H. pylori and CagA status were determined by serology. Serum gastrin levels were
measured in fasting state by commercially available assay. In H. pylori infected patients (n 5 138; 36.6%), the overall preva-
lence of colonic neoplasms was more frequent compared to H. pylori negative patients (n 5 239; 63.4%) (OR 5 2.73, 95% CI:
1.76–4.24). H. pylori infection occurred more frequently in patients with hyperplastic polyps (OR 5 2.66, 95% CI: 1.23–5.74)
and adenomas presenting with low grade intraepithelial neoplasia (IEN) (OR 5 1.85, 95% CI: 1.14–2.99). Attributable risk for
adenomas with high grade IEN and colorectal adenocarcinoma (n 5 14) was not assessed due to the low number of cases. The
expression of CagA was also associated with an increased risk for colonic neoplasms (OR 5 2.25, 95% CI: 1.29–3.94). Hyper-
gastrinemia did not increase the risk for any colonic neoplasms and there was no difference in basal serum gastrin levels

Infectious Causes of Cancer

between H. pylori positive and negative patients. In conclusion, H. pylori infection, including CagA expression is associated
with an increased risk for the development of colonic neoplasm.

Helicobacter pylori (H. pylori) infection affects 20–50% of the
adult population in industrialized nations and remains a sig-
nificant cause of morbidity and mortality in gastro-duodenal
diseases.1,2 H. pylori infection is the main risk factor for the
development of adenocarcinoma of the stomach3,4 and pre-
disposes to several other complications that include peptic
ulcer disease and mucosa-associated lymphoid tissue lym-
phoma. Among bacterial virulence factors of H. pylori that
are responsible for an increase in pathogenicity of the bacte-
ria, CagA plays a prominent role. CagA is not expressed in
all H. pylori strains, but CagA positive H. pylori strains show
Key words: Helicobacter pylori, gastrin, colonic neoplasms
Grant sponsor: BMBF; Grant number: BMBF-0315905D (in the
frame of ERA-NET PathoGenoMics)
DOI: 10.1002/ijc.28758
History: Received 10 July 2013; Accepted 20 Jan 2014; Online 4 Feb
2014
Correspondence to: Michael Selgrad, Department of
Gastroenterology, Hepatology and Infectious Diseases, Otto-von-
Guericke-University of Magdeburg, Leipziger Str. 44, D-39120 Mag-
deburg, Germany, Tel.: 149-391-6713100, Fax: 149-391-6713105,
E-mail: michael.selgrad@med.ovgu.de or Peter Malfertheiner, Depart-
ment of Gastroenterology, Hepatology and Infectious Diseases, Otto-
von-Guericke-University of Magdeburg, Leipziger Str. 44, D-39120
Magdeburg, Germany.
an association with higher grades of inflammation of the gas-
tric mucosa and significantly increase the risk of gastric can-
cer development.5,6 Moreover, H. pylori infection has been
suggested to also play a role in extragastric malignancies.7 In
this context, previous studies have demonstrated that H.
pylori infection is associated with an increased risk for the
development of colonic neoplasms.8–13 Most of the studies
have used positive serology for anti-H. pylori antibodies as a
marker for H. pylori infection. But a recent study has further
strengthened the association by showing that various forms
of H. pylori-induced gastritis display an attributable risk for
the occurrence of colorectal neoplasms.8 The pathophysiolog-
ical mechanism underlying the association between H. pylori
infection and colorectal neoplasms is unclear and certainly
not explained by a direct effect of H. pylori, since H. pylori is
uniquely adapted to colonize the gastric mucosa.7 A hypothe-
sis is that H. pylori may contribute to the colonic carcinogen-
esis indirectly via gastrin: H. pylori-induced atrophic changes
of the gastric body mucosa lead to increased levels of serum
gastrin by negative feedback on the antral G-cells.14 Gastrin
is capable of stimulating growth factor dependent signaling
pathways and therefore hypergastrinemia may act as a puta-
tive promoter of colorectal neoplasia in humans.15 In vitro,
high gastrin levels have been shown to be associated with
growth and proliferation of colon cancer cells.16,17 Further-
more, patients with elevated gastrin levels (i.e., Zollinger-

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 1128 H. pylori is associated with colonic neoplasms

What’s new?
Though the bacteria H. pylori is best known for its effects on the stomach, evidence has been emerging that it may also con-
tribute to cancer of the colon. In this paper, the authors checked for colonic neoplasms in patients with and without H. pylori
infection, paying special attention to strains that express CagA, which are most likely to cause gastric inflammation and can-
cer. They did indeed find neoplasms more often in the colons of patients who harbored the bacteria, especially those that
express CagA. Although the protein gastrin seemed a likely mechanism for spurring these neoplasms, the authors found no
increase in serum gastrin levels among the patients with H. pylori infection.

Ellison Syndrome) show an increased proliferation of the
colonic and rectal mucosa and consecutively an increased
risk for colorectal cancer development.18,19
For this reason, we examined the serological prevalence of
H. pylori and serum levels of gastrin in patients undergoing
colonoscopy to detect a possible association between H. pylori
and colonic neoplasms and the putative mechanisms of
gastrin.
Patients and Methods
We performed a review of a prospectively collected database
that includes 377 patients with a minimum age of 50 years
undergoing colonoscopy in the Department of Gastroenterol-
ogy, Hepatology and Infectious Diseases at the University of
Infectious Causes of Cancer
positive, whereas the lack of both antibodies led to the
assignment of an H. pylori-negative status. The analyses of
serum gastrin (Gastrin EIA Test Kit, Biohit Plc, Finland)
were performed in all subjects at the same aliquot and as
described by the manufacturer.
Statistical analysis
All statistical analyses were performed using SPSS19.0 for
windows (SPSS, Chicago, IL). For groupwise comparison of
parametrical data (age), Student’s t-test and the Mann–Whit-
ney U test for nonparametrical comparisons (serological
parameters) were applied. Categorical data were compared by
Fisher’s exact test also applying Pearson’s v2 for risk assess-
ment and odds ratio calculation. For all tests a two-sided sig-

Magdeburg, Germany, in the period between August 2008
and January 2013. Patients were enrolled in the course of a
different prospectively conducted study that was approved by
the local Ethics Committee. Written informed consent was
obtained from all patients.
Histopathological assessment
Polypectomy samples were processed by routine methods
and sections were stained with hematoxylin and eosin. All
pathological specimens from the colorectal tract were
assessed for the degree of dysplasia and the presence of vil-
lous architecture according to criteria established by the
WHO.20
nificance level of p < 0.05 was considered to be statistically
significant.
Results
General characteristics of the study population
A total of 377 patients, 188 females and 189 males with a
mean age of 66.38 years (69.83 years standard deviation
(SD)) were enrolled in the study. The clinical indications for
performing colonoscopies are listed in Table 1. H. pylori
infection status based on the concentration of anti-H. pylori
IgG antibodies and/or CagA status was positive in 138
patients (36.6%). H. pylori infection was detected more
Table 1. Clinical indications for performing colonoscopy

Assessment of serum parameters H. pylori H. pylori

Indication for positive negative
About 5–7 ml blood sample was taken from patients in fast- colonoscopy (n 5 138) (n 5 239) p value
ing state prior to the endoscopic procedure. Serum was pre-
Abdominal pain 22 (16%) 35 (14.6%) 0.997
pared by centrifugation at 7000g at 4 C for 15 min, aliquoted
in three individual cryotubes (each 1–1.5 ml) within 3 hr Diarrhea 14 (10.1%) 19 (7.9%) 0.735
after sample retrieval. Samples were stored at 280 C until Anemia 13 (9.4%) 25 (10.5%) 0.468
analysis. Anti-H. pylori IgG and anti-CagA antibodies were Hematochezia 9 (6.5%) 19 (7.9%) 0.747
analyzed using an H. pylori IgG enzyme-linked immunosor- Weight loss 10 (7.2%) 14 (5.9%) 0.610
bent assay (Biohit, Rosbach, Germany) and a CagA IgG kit Colon cancer 40 (29%) 68 (28.5%) 0.595
(Genesis Diagnostics, London, United Kingdom), respectively, screening
according to manufacturers’ instructions. The H. pylori IgG Constipation 4 (2.9%) 9 (3.8%) 0.912
enzyme-linked immunosorbent assay provides a sensitivity of
Polyp surveillance 16 (11.6%) 31 (13.0%) 0.657
96.5% (95% CI 5 92.6–98.4) and a specificity of 96.0% (95%
Inflammatory bowel 4 (2.9%) 8 (3.3%) 0.697
CI 5 93.4–97.6).21 Based on the presence of H. pylori-specific
disease
IgG (30 enzyme immunounits) and/or the presence of anti-
Other 6 (4.4%) 11 (4.6%) 0.811
CagA IgG (>6.25 U/ml), patients were classified as H. pylori

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Selgrad et al. 1129

Table 2. Association of H. pylori infection with colonic neoplasm

Total number H. pylori

of patients infection H. pylori negative
Parameter (n 5 377) (n 5 138) (n 5 239) Odds ratio 95% CI
Age 66.38 (69.83 66.72 (69.32 66.18 (6 – –
years SD) years SD) 10.13 years SD)
Female 188 (49.9%) 60 (31.9%) 128 (68.1%) 1 –
Male 189 (50.1%) 78 (41.3%) 111 (58.7%) 1.39 (0.96–2.16)
Colonic neoplasm overall 133 (35.3%) 69 (50.0%) 64 (26.8%) 2.73 (1.76–4.24)
Hyperplastic polyp 29 (7.7%) 17 (12.3%) 12 (5.0%) 2.66 (1.23–5.74)
Low grade IEN polyp 90 (23.9%) 43 (31.2%) 47 (19.7%) 1.85 (1.14–2.99)
High grade IEN polyp 5 (1.3%) 4 (2.9%) 1 (0.4%) n.s. n.a.
Adenocarcinoma 9 (2.4%) 5 (3.6%) 4 (1.7%) n.s. n.a.
High grade 14 (3.7%) 9 (6.5%) 5 (2.1%) 3.26 (1.07–9.95)
IEN 1 adenocarcinoma
No polyps 244 (64.7%) 69 (50.0%) 175 (73.2%) 1 –

frequently in male (41.3%) compared to female patients
(31.9%). There was no significant difference in age between
H. pylori positive (66.72 years; 69.32 years SD) and H. pylori
negative (66.18 years; 610.13 SD) patients (p 5 0.145). A
positive CagA status was detectable in 43.5% of the H. pylori
(OR 5 2.25, 95% CI: 1.29–3.94). After adjustment for con-
founding factors such as sex, age, previous and complete
colonoscopy, H. pylori infection represents the only inde-
pendent risk factor for the development of colonic neoplasms
(OR 5 2.71, 95% CI: 1.74–4.23) (p < 0.001). The overall strat-

Infectious Causes of Cancer

positive patients. A complete colonoscopy, defined as reach-
ing the caecum was performed in 95.7% of the H. pylori posi-
tive patients (n 5 132) compared to 97.1% of the noninfected
patients (n 5 232) (p 5 0.325). Furthermore, there was no sig-
nificant difference in the performance of a previous colono-
scopy between H. pylori positive (n 5 27; 19.6%) and H.
pylori negative (n 5 57; 23.8%) patients (p 5 0.203).
Association of H. pylori infection and colorectal neoplasm
In H. pylori-infected patients (n 5 138), the occurrence of colo-
nic neoplasms was more frequent compared to H. pylori nega-
tive patients (n 5 239) (OR 5 2.73, 95% CI: 1.76–4.24).
Hyperplastic polyps (OR 5 2.66, 95% CI: 1.23–5.74), polyps
with low grade (OR 5 1.85, 95% CI: 1.14–2.99) and high grade
intraepithelial neoplasia (IEN) were all found at a higher per-
centage among patients with H. pylori infection compared to
those without H. pylori infection. Interestingly, H. pylori infec-
tion was most frequently detected in patients with low grade
IEN adenomas of the colon. H. pylori infection was not
detected at a higher rate in patients with colorectal cancer. It
has to be noted, that only 14 patients (3.7%) included in our
study were diagnosed with high grade IEN in the colorectum
or invasive colorectal adenocarcinoma. Due to the low number
of patients in this group, risk stratification was not performed
for these single entities. However, when combing the patients
with high grade IEN and colorectal cancer, H. pylori infection
was associated with an increased risk for developing those enti-
ties (OR 5 3.26, 95% CI: 1.07–9.95).
The presence of the virulence factor CagA was further
associated with an increased risk of colonic neoplasms
ification of the patient population by H. pylori infection sta-
tus and histopathological findings of colonoscopy specimens
are displayed in Table 2.
Association of serum-Gastrin, H. pylori infection and
colorectal neoplasm
Hypergastrinemia was not associated with an increased risk
of occurrence of any colonic neoplasms. In total, 52 patients
(13.8%) had an increased serum gastrin level (defined as >50
pg/ml). There was no difference in the number of patients
with increased gastrin levels with or without H. pylori infec-
tion (p 5 0.125). Interestingly, overall gastrin levels were sim-
ilar between H. pylori positive subjects (mean, 17.17 pg/ml)
and H. pylori negative subjects (mean, 20.77 pg/ml).
Discussion
In our study, we demonstrate that H. pylori infection is more
prevalent among patients with colorectal neoplasia, and the
infection is associated with a risk for the development of
colonic neoplasms. This risk was significant for adenomas
with low grade IEN and hyperplastic polyps. Our results are
consistent with results of previous studies including two
meta-analyses that reported an increased risk of colorectal
neoplasia in patients with H. pylori infection.9,10,22 Even
though some studies did not find an association,11,23,24 the
positive correlation of H. pylori and colonic neoplasia was
strengthened by a recent study including a large number of
patients, in which various forms of gastritis related to H.
pylori consistently increased the risk for colonic neoplasms.8
Recently, another interesting study demonstrated that

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 1130 H. pylori is associated with colonic neoplasms

patients with H. pylori-induced atrophic gastritis are at an
increased risk for the recurrence of colorectal neoplasia after
endoscopic resection.25 The small number of patients with
colorectal cancer or adenomas with high grade neoplasia in
our study did not permit an interpretation of this group of
patients and thus a solid conclusion on the absence of an
association between H. pylori infection and colorectal cancer
or adenomas with high grade neoplasia cannot be given.
A novel aspect of our study is the increased risk for colo-
nic neoplasms in patients infected by a CagA positive H.
pylori strain. CagA positive H. pylori strains are well known
to induce a stronger inflammatory response in the gastric
mucosa and to carry an increased risk for gastric cancer
development. Whether CagA-released proinflammatory mole-
cules might promote the proliferation of colonic cells remains
speculative. Certainly studies addressing this aspect should be
encouraged.
One strength of our study is the fact that we determined
H. pylori infection status based on serology only and thus
not only patients with an active infection were classified as
H. pylori-positive but also possibly patients with prior eradi-
cation therapy or those with a long-standing infection in
which the bacteria have disappeared during the progression
of histological alterations (i.e., atrophic gastritis). However,
Infectious Causes of Cancer
mucosa which has been speculated in two previous stud-
ies.26,27 A plausible explanation was proposed for increased
serum gastrin levels as a consequence of H. pylori infection.
However, in our patient population hypergastrinemia was not
associated with an increased risk for colonic neoplasms. A
possible explanation for this result might represent the fact
that we might have included patients with autoimmune gas-
tritis, prior intake of proton-pump inhibitors, or patients
with an atrophic gastritis in whom a spontaneous eradication
of H. pylori occurred. In those patients, gastrin levels are
lower due to the break of the normal pH-driven feedback on
gastrin regulation. Due to the design of our study some fur-
ther limitations have to be considered. There is a possible
chance of an inadvertent inclusion of subjects with a previous
gastrectomy, previous H. pylori eradication therapy and cur-
rent use of proton-pump inhibitors which are generally
accepted to increase serum-gastrin levels.
Previous studies analyzing the association between serum
gastrin levels and risk of colonic neoplasms have shown
inconsistent results.28–31 Most of the studies have proven that
high serum gastrin level confer an increased risk for colo-
rectal cancer but not for colonic adenomas.11,24,32 One possi-
ble explanation for this is that gastrin might promote
colorectal carcinogenesis at a later stage in the adenoma-

the prevalence of H. pylori infection in our study population
is still lower compared to the general population in our
region.2
Pathophysiological mechanisms underlying the association
between H. pylori infection and the increased risk of colonic
neoplasm development are not understood. One explanation
is that H. pylori antigens may act directly on the colon
carcinoma sequence, and in our study population we mainly
analyzed colonic neoplasms of an early stage.
In conclusion, our study demonstrates that H. pylori infec-
tion and CagA positive strains in particular are associated
with an increased risk for colonic neoplasms. Future studies
are needed to explore the underlying pathophysiological
mechanisms.

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