high nti-helicobacter pylori igg antibody titers and long-term risk of gastric … · 2019. 12....

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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

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Running title: High-negative anti-H. pylori titers and gastric cancer risk 19

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Key words: Helicobacter pylori, anti-Helicobacter pylori IgG antibody titer, gastric cancer, 21

prospective cohort study, Japan 22

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Count: Abstract, 240 words; Main text, 2789 words; 3 tables 24

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on July 6, 2021. © 2019 American Association for Cancer Research. cebp.aacrjournals.org Downloaded from

Author manuscripts have been peer reviewed and accepted for publication but have not yet been edited. Author Manuscript Published OnlineFirst on December 11, 2019; DOI: 10.1158/1055-9965.EPI-19-0993

http://cebp.aacrjournals.org/

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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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mailto:[email protected]:[email protected]://epi.ncc.go.jp/en/jphc/805/index.htmlhttp://cebp.aacrjournals.org/

4

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-

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



http://ci5.iarc.fr/CI5plus/http://cebp.aacrjournals.org/

6

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 (

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




8

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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9

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

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

11

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




12

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




13

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




14

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




15

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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




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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