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1
High-negative anti-Helicobacter pylori IgG antibody titers and
long-term risk of gastric 1
cancer: Results from a large-scale population-based cohort study
in Japan 2
3
Manami Inoue*, Norie Sawada, Atsushi Goto, Taichi Shimazu, Taiki
Yamaji, Motoki Iwasaki, 4
Shoichiro Tsugane, for the JPHC Study Group** 5
Epidemiology and Prevention Group, Center for Public Health
Sciences, National Cancer 6
Center, Japan 7
8
*Corresponding author: 9
Manami Inoue, M.D., Ph.D. 10
Division of Prevention, Center for Public Health Sciences,
National Cancer Center, 5-1-1 11
Tsukiji, Chuo-ku, Tokyo 104-0045 Japan 12
Telephone: +81 3 3542 2511, Fax: +81 3 3547 8578 13
E-mail: [email protected] 14
15
** JPHC Study Group members are listed at the following site:
16
http://epi.ncc.go.jp/en/jphc/781/3838.html 17
18
Running title: High-negative anti-H. pylori titers and gastric
cancer risk 19
20
Key words: Helicobacter pylori, anti-Helicobacter pylori IgG
antibody titer, gastric cancer, 21
prospective cohort study, Japan 22
23
Count: Abstract, 240 words; Main text, 2789 words; 3 tables
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Abbreviations: 1
AG: atrophic gastritis 2
CI: 95% confidence interval 3
Hp: Helicobacter pylori 4
HR: hazard ratio 5
JPHC Study: Japan Public Health Center-based Prospective Study
6
PAF: population attributable fraction 7
PG: pepsinogen 8
9
Funding: 10
This study was supported by the National Cancer Center Research
and Development Fund 11
(23-A-31 [toku], 26-A-2, and 29-A-4 (since 2011)), a
Grant-in-Aid for Cancer Research from 12
the Ministry of Health, Labour and Welfare (from 1989 to 2010),
and a grant for cancer 13
research (Practical Research for Innovative Cancer Control) from
the Japan Agency for 14
Medical Research and Development (AMED). 15
16
Conflict of Interest: 17
All authors declare no potential conflict of interest. 18
19
Author contributions: 20
M. Inoue and ST designed and conducted the research, analyzed
data and wrote the paper; M. 21
Inoue had primary responsibility for final content; and TS, NS,
AG, TY, and M. Iwasaki made 22
substantial contributions to strengthening the Subjects and
Methods and Discussion sections. 23
All authors read and approved the final manuscript. 24
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Data Availability Statement 1
All materials, data, and protocols described in the manuscript
will be made available upon 2
request, if the request is made within six years of publication.
3
We cannot publicly provide individual data due to participant
privacy, in accordance with 4
ethical guidelines in Japan. Additionally, the informed consent
we obtained does not include a 5
provision for publicly sharing data. Qualifying researchers may
apply to access a minimal 6
dataset by contacting Dr. Shoichiro Tsugane, Principal
Investigator, Epidemiology and 7
Prevention Group, Center for Public Health Sciences, National
Cancer Center, Japan, at 8
[email protected] or the office of the JPHC Study Group at
[email protected]. 9
More information about how to access JPHC data and/or
biospecimens can be found here: 10
https://epi.ncc.go.jp/en/jphc/805/index.html. 11
12
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Abstract 1
Background: Serological testing of anti-Helicobacter pylori (Hp)
antibody, together with 2
testing of pepsinogen I and II, is now widely used to stratify
groups at high risk of gastric 3
cancer in Japan. Those with a negative anti-Hp IgG titer,
especially “high-negative” 4
(3-
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5
Introduction 1
Despite Japan having among the highest rates of gastric cancer
for the last several 2
decades, rates over this period have nevertheless shown a
constant and dramatic decline 3
(International Agency for Research on Cancer;
http://ci5.iarc.fr/CI5plus/). Infection with 4
Helicobacter pylori (Hp) is the most important established cause
of gastric cancer(1). The 5
importance of reducing Hp infection to decreasing the incidence
of gastric cancer at the 6
population level in Japan has been unequivocal(2). Hp infection
occurs during infancy, 7
commonly by 5 years old(3), and prevalence has reflected the
general hygiene environment, 8
along with a reduction in salt and salted food intake (4).
Salted food intake has been 9
positively associated with the prevalence of Hp(5), and mucosal
damage induced by salt and 10
salted food may increase persistent infection with Hp(6). The
reduction in the prevalence of 11
Hp is also hypothesized to have resulted from the widespread use
of antibiotics(7). In addition, 12
a very recent meta-analysis suggests the potential of Hp
eradication treatment in prevention of 13
gastric cancer(8). 14
Hp infection in Japan has dramatically declined by a birth
cohort effect, from nearly 15
70% for those born before 1950 to around 5% for those born after
2000 (2,9), mainly due to 16
drastic improvements in the hygiene environment. This change
will have clear generational 17
effects on primary and secondary prevention strategies, likely
requiring a risk-stratified 18
approach to gastric cancer prevention, especially for the
lower-risk younger generation (2,10). 19
To date, however, no comprehensive and valid stratification
approach for this low-risk 20
population has yet been established. 21
Serological testing of Hp antibody, either alone or in
combination with pepsinogen 22
(PG) I and II testing(11), is now commonly used to stratify
high-risk groups for gastric cancer 23
in Japan. In this testing, serum level of IgG antibody to Hp is
commonly measured by enzyme 24
immunoassay, wherein seropositivity for anti-Hp antibodies is
defined as an IgG titer ≥10 25
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U/mL. This high IgG titer group has been the target of
eradication treatment. Several cohort 1
studies have also used this conventional anti-Hp IgG titer
cut-off to assess gastric cancer risk 2
(12-15), and shown a clear increase in risk. In contrast, those
with past and present Hp 3
infection frequently fall into the category “negative (
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7
excluded 1,084 (5.4%) with missing information on the variables
included in the analysis, 1
finally leaving 19,106 subjects for use in the present analyses.
This study was done without 2
participant involvement in the study design or interpretation of
the results. 3
4
Baseline survey 5
A baseline self-administered questionnaire survey on various
lifestyle factors was 6
conducted at the time of baseline (1993-1994). Some subjects
(31%) voluntarily provided 7
10-mL samples of blood during their health check-up. Individual
plasma samples were 8
divided into three tubes holding 1.0 ml each, which were stored
at -80 °C. 9
10
Exposure measurement 11
Plasma levels of IgG antibodies to Hp (anti-Hp IgG titer) were
measured by enzyme 12
immunoassay (E plate “Eiken” H. pylori Antibody II; Eiken
Kagaku, Tokyo, Japan) and 13
grouped into 3 categories by anti-Hp IgG titer of ≤3 U/mL, >3
to 70 ng/mL or PG I/II >3.0) or “positive” (PG I ≤70 ng/mL &
PG 17
I/II ≤3.0), with positive further categorized as “mild” (PG I
≤70 ng/mL & PG I/II ≤3.0), 18
“moderate” (PG I ≤50 ng/mL & PG I/II ≤3.0), or “severe” (PG
I ≤30 ng/mL & PG I/II ≤2.0). 19
We previously reported a validation study result from an ROC
analysis in our present 20
population elsewhere (19). 21
22
Follow-up and identification of gastric cancer 23
Subjects were followed from the baseline survey until December
2013. Residential 24
status, including survival, was confirmed through the
residential registry. Resident and death 25
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registration are required in Japan by law and the registries are
believed to be complete. The 1
occurrence of gastric cancer was determined by notification from
hospitals in the study areas 2
and data linkage with population-based cancer registries. Death
certificates were used as a 3
supplementary information source. The site of origin and
histological type were coded using 4
the International Classification of Diseases for Oncology, 3rd
Edition (ICD-O-3; C16)(20). In 5
our cancer registry system, the proportion of cases having
information from death certificates 6
only was 3.4%, which was considered satisfactory for the present
study. Through this 7
procedure, a total of 595 newly diagnosed cases of gastric
cancer were identified during 8
follow-up. These gastric cancers were classified according to
tumor location into proximal 9
(C16.0–C16.1) and distal subsites (C16.2–C16.7). Histologic type
was grouped into two 10
major categories according to the degree of structural
differentiation into differentiated and 11
non-differentiated types. In Japan, determination of histologic
subtype is based on the 12
Japanese classification of gastric carcinomas (Japanese Research
Society for Gastric 13
Cancer(21)). Accordingly, the differentiated type consists of
papillary adenocarcinoma (pap), 14
tubular adenocarcinoma, well-differentiated type (tub1) and
moderately differentiated type 15
(tub2), and mucinous adenocarcinoma (muc); and the
non-differentiated type consists of 16
poorly differentiated adenocarcinoma, solid type (por1) and
non-solid type (por2), and 17
signet-ring cell carcinoma (sig). In accordance with a
conversion table (22) for the Japanese 18
classification and Lauren’s classification for grouping, the
differentiated type corresponds to 19
the intestinal type by Lauren and the non-differentiated type
corresponds to the diffuse type. 20
For cases falling into both histologic categories, the dominant
type was applied. Other or 21
unspecified histological types were excluded from analysis by
histologic subtype. 22
Consequently, among the 595 cases of gastric cancer, 50 were
classified as proximal and 383 23
as distal; and 240 as differentiated and 133 as
non-differentiated. 24
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Statistical analysis 1
Person-years of follow-up for each individual were calculated
from the starting point 2
to the date of gastric cancer diagnosis, date of emigration from
the study area, date of death or 3
end of follow-up, whichever came first. For those who withdrew
or were lost to follow-up, the 4
date of withdrawal and the last confirmed date of presence,
respectively, were used as the date 5
of censor. 6
The relative risk of occurrence of gastric cancer by category of
anti-Hp IgG titer (≤3 7
U/mL (reference), >3 to
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10
women) were identified with newly diagnosed gastric cancer and
included in the analyses. 1
Baseline characteristics of the study subjects according to
anti-Hp IgG titer are shown in 2
Table 1. The proportion of current smokers increased in those
with anti-Hp IgG titer >3U/ml 3
in both sexes. In contrast, the proportion of current smokers
was higher among those with 4
more severe AG in men, whereas no such tendency was observed in
women. The proportion 5
of those with a family history of gastric cancer, consumption of
highly salted food, and AG 6
increased with both increased anti-Hp IgG titer category and
severity of AG. 7
HR of gastric cancer according to anti-Hp IgG titer in
combination with the presence 8
and severity of AG is shown in Table 2. Compared with those with
a low-negative anti-Hp 9
IgG titer, we observed a significantly elevated risk of gastric
cancer for those with a 10
high-negative anti-Hp IgG titer (>3 and 3 and 3 and
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Discussion 1
In this study, we evaluated the association between
high-negative anti-Hp IgG titer 2
and the long-term risk of gastric cancer based on a large-scale
population-based cohort in 3
Japan – the JPHC Study Cohort II - using anti-Hp IgG titer along
with AG biomarkers. On 4
long-term follow-up of 18 years, the results revealed an
increased risk of gastric cancer for 5
those with high-negative anti-Hp IgG titers. However, we also
found that this increase in risk 6
was generally dependent on the severity of AG, suggesting that
the severity of AG, resulting 7
from persistent Hp infection, is a crucial factor in the
long-term risk of gastric cancer. 8
It is worth mentioning that when AG was moderate or severe, the
risk of gastric 9
cancer was similarly increased regardless of anti-Hp IgG titer
category. A previous study 10
suggested a precancerous course, in which extremely severe
gastric atrophy leads to a 11
spontaneous decrease in Hp, at about which point gastric atrophy
reaches an irreversible stage 12
and then invariably proceeds to gastric cancer (23). 13
Our results raise a number of interesting points. First, they
suggest the existence of 14
certain factors which exacerbate, directly or indirectly, the
severity of AG. One possibility is 15
an effect on virulence factors, such as CagA, which is thought
to play an important role in 16
gastric carcinogenesis, and to have genetic variation which
contributes to the geographical 17
variation in gastric carcinogenesis (24). Our previous report
using a nested case-control study 18
design, however, found that those with a positive anti-Hp IgG
titer were at an approximately 19
10-fold increased risk of gastric cancer, regardless of CagA
status (25). Due to a lack of 20
information, we were unable to consider CagA status in the
present study, which is one of its 21
limitations. 22
Second, it is possible that other factors promote the severity
of AG after Hp infection. 23
Common traditional Japanese food practices, including high
consumption of rice and salted 24
foods, may play a role in the development of atrophic gastritis
after Hp infection (26), as well 25
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as in a decrease in risk by behavioral change, such as decreased
intake of salty food (27,28). 1
Although smoking is an established risk factor for gastric
cancer (29), its association with 2
atrophic gastritis remains controversial (30-33). Some studies
reported that gastric atrophy 3
grade in Hp-positive subjects was higher among those who smoked
(30,32), whereas others 4
saw no clear association (33). In our data, the proportion of
current smokers was higher only 5
in men with severe atrophy. Further studies are needed to
clarify the mechanism by which 6
smoking influences gastric carcinogenesis, either through the
promotion of gastric atrophy or 7
via an independent pathway. 8
Third, a negative anti-Hp IgG titer may result from any of
several possible factors, 9
other than misclassification by chance, such as a reduction in
IgG antibody production by 10
unknown factors, seroreversion by progression of AG and
eradication treatment of Hp. If the 11
severity of AG is an important risk factor in the long-term
progression to gastric cancer, the 12
question of whether Hp eradication prevents progression to
gastric cancer is critical. As of 13
now, Hp eradication does not guarantee the elimination of
gastric cancer risk, as 14
pre-neoplastic lesions may have already developed (34). The
concept “point of no return” has 15
been emphasized, in which the benefit of Hp eradication
treatment diminishes after the 16
appearance of precancerous regions with the molecular alteration
(35). In the present study, 17
we did not consider Hp eradication episodes, due to the lack of
such follow-up information. 18
This could have influenced our results. However, the Japanese
health insurance scheme 19
approved Hp eradication therapy for patients with chronic
gastritis in February 2013, after 20
which the number of prescriptions for Hp eradication therapy
substantially increased (36). 21
Although we cannot deny the possibility that our subjects were
exposed to the same 22
medication before this timing, our study follow-up period
continued until 2013, and any 23
influence of this therapy on the results is therefore likely to
be negligible. Meanwhile, we 24
should be aware of the possibility that results might differ if
a baseline population were 25
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enrolled after the establishment of eradication treatment. 1
The major strength of our study is its prospective design.
First, data for two core 2
biomarkers - plasma anti-Hp IgG titer and pepsinogens - and
information on lifestyle by 3
questionnaire were collected before the subsequent diagnosis of
gastric cancer, thereby 4
avoiding the exposure recall bias inherent to case-control
studies. Second, the population 5
came from a large sample of the general Japanese population.
Third, the high response rate 6
and low loss to follow-up (0.1%) reduced possible selection
bias. Fourth, the 18 years of 7
follow-up provided not only a sufficient number of cases for
analysis but also a sufficient 8
period to reveal the long-term effects of Hp infection,
especially in those with relatively low 9
titers - the main focus of this study. In this regard, note that
effects have not been observed in 10
studies with less than 10 years of follow-up. 11
However, several limitations are also worth mentioning. First,
the study population 12
was mainly derived from non-metropolitan areas, which slightly
limits our representativeness 13
and generalizability. Second, bias could have been introduced by
the fact that all subjects 14
volunteered to have their blood taken. The subjects of this
study were restricted to 31% of the 15
total study subjects who had complete questionnaire responses
and health checkup data, 16
including blood samples. In our previous validation studies,
more women than men tended to 17
participate in health checkup surveys provided by local
governments, and participants often 18
differed from nonparticipants in socioeconomic status, having a
more favorable lifestyle 19
profile (37,38); this may have influenced the association
between anti-Hp IgG titer and risk of 20
gastric cancer. Finally, the association may have been
confounded by additional unmeasured 21
or unknown risk factors. 22
Allowing for these methodological issues, our results, based on
a large-scale 23
population-based cohort study with long-term follow-up, suggest
that people with 24
high-negative anti-Hp IgG titers are at increased long-term risk
of gastric cancer, mostly 25
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among those with moderate and severe AG. Increased risk of
gastric cancer in those with 1
high-negative anti-Hp IgG titers is suggested to be an outcome
of the development of 2
moderate or severe AG. 3
4
5
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Table 1 Baseline characteristics of study subjects according to
anti-Helicobacter pylori (Hp) IgG titer and severity of atrophic
gastritis (JPHC Cohort II) (n=19,106) 1 Anti-H. pylori IgG titer
Severity of atrophic gastritis
Number of subjects
Low-negative ≤3 U/mL
High-negative >3 and 3 and 70 ng/mL or PG I/II >3.0),
Positive (PG I≤70 ng/mL & PG I/II ≤3.0), Mild (PG I≤70 ng/mL
& PG I/II ≤3.0 & not Moderate/Severe), Moderate (PG I≤50
ng/mL 2 & PG I/II ≤3.0 & not Severe), Severe (PG I≤30 ng/mL
& PG I/II ≤2.0) 3
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-
21
Table 2. Anti-Helicobacter pylori IgG titer and risk of gastric
cancer in combination with atrophic gastritis status (19,106
subjects, 6,934 men, 12,172 women, 18 years of follow-up) 1
Category Number of
participants
Person-
years
Number
of cases
HR (95%CI) Number
of cases
HR (95%CI) Number
of cases
HR (95%CI)
19,106 344,441 Both sexes (n=595) Men (n=370) Women (n=225)
Helicobacter pylori (Hp)
Negative 6,028 109,304 53 1.00
28 1.00
25 1.00
Positive 13,078 235,136 542 3.96 (2.98- 5.27) 342 4.35 (2.96-
6.42) 200 3.53 (2.33- 5.36)
Low-Negative 4,244 77,583 21 1.00
7 1.00
14 1.00
High-Negative 1,784 31,721 32 2.81 (1.62- 4.89) 21 4.67 (1.98-
11.01) 11 1.82 (0.83- 4.02)
Positive 13,078 235,136 542 6.51 (4.20- 10.09) 342 10.64 (5.02-
22.53) 200 4.41 (2.56- 7.59)
p for trend (categorical)
-
22
n: Number. Helicobacter pylori (Hp): Negative (IgG titer
-
23
Table 3. Anti-Helicobacter pylori IgG titer and risk of gastric
cancer in combination with atrophic gastritis status by subsite and
histological type (19,106 subjects, 6,934 men, 12,172 1
women, 18 years of follow-up) 2 Category Number of
participants
Person -years
Number
of cases
HR (95%CI) Number
of cases
HR (95%CI) Number
of cases
HR (95%CI) Number
of cases
HR (95%CI)
19,106 344,441 Proximal (n=50) Distal (n=383) Differentiated
type (n=240) Non-differentiated type (n=133)
Helicobacter pylori (Hp)
Negative 6,028 109,304 5 1.00 31 1.00 17 1.00 7 1.00
Positive 13,078 235,136 45 3.39 (1.34- 8.58) 352 4.38 (3.03-
6.33) 223 4.78 (2.91- 7.84) 126 7.55 (3.52- 16.20)
Low-Negative 4,244 77,583 0 - 16 1.00 8 1.00 0 -
High-Negative 1,784 31,721 5 - 15 1.70 (0.84- 3.45) 9 1.97
(0.76- 5.13) 7 -
Positive 13,078 235,136 45 - 352 5.48 (3.31- 9.06) 223 6.48
(3.19- 13.15) 126 -
p for trend (categorical) 0.005
-
24
Hp Low-Negative & AG
Moderate/Severe
213 3,604 0 - 9 20.41 (7.57- 55.04) 4 14.84 (3.69- 59.67) 0
-
Hp High-Negative & AG
Moderate/Severe
322 5,247 3 - 10 11.99 (4.54- 31.65) 7 13.97 (4.06- 48.07) 5
-
Hp Positive & AG
Moderate/Severe
4,770 84,093 25 - 194 16.48 (7.72- 35.15) 137 18.38 (6.77-
49.90) 45 -
p for interaction
-
Published OnlineFirst December 11, 2019.Cancer Epidemiol
Biomarkers Prev Manami Inoue, Norie Sawada, Atsushi Goto, et al.
population-based cohort study in Japanlong-term risk of gastric
cancer: Results from a large-scale High-negative anti-Helicobacter
pylori IgG antibody titers and
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