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Piemonte), Turin, Italy; 10Public Health and Participation Directorate, Health and Health Care Services Council, Asturias; 11Andalusian School of Public Health,
article
CIBER Epidemiologa y Salud Publica (CIBERESP), Granada; 12Department of Epidemiology, Murcia Health Council, CIBER Epidemiologa y Salud Publica
(CIBERESP) Murcia, Murcia; 13Navarre Public Health Institute, CIBER Epidemiologa y Salud Publica (CIBERESP), Pamplona; 14Public Health Division of Gipuzkoa
and Ciberesp, Basque Regional Health Department, San Sebastian, Spain; 15Department of Public Health and Primary Care, University of Cambridge, Cambridge;
16
Cancer Epidemiology Unit, Nuffield Department of Clinical Medicine, University of Oxford, Oxford, UK; 17National Institute for Public Health and the Environment
(RIVM), Bilthoven; 18Department of Gastroenterology and Hepatology, University Medical Centre Utrecht (UMCU), Utrecht; 19Julius Center for Health Sciences and
Primary Care, University Medical Center Utrecht, Utrecht, The Netherlands; 20WHO Collaborating Center for Food and Nutrition Policies, Department of Hygiene,
Epidemiology and Medical Statistics, University of Athens Medical School, Athens; 21Hellenic Health Foundation, Athens, Greece; 22Department of Cancer
Epidemiology, German Cancer Research Center, Heidelberg; 23Department of Epidemiology, German Institute of Human Nutrition Potsdam-Rehbrucke, Potsdam,
Germany; 24Department of Surgery, Skane University Hospital Malmo, Lund University, Malmo; 25Department of Internal Medicine, Division of Gastroenterology and
Hepatology, Sahlgrenska University Hospital, Gothenburg; 26Department of Medical Biosciences, Pathology, Umea University, Umea, Sweden; 27Department of
Public Health and Clinical Medicine, Nutritional Research, Umea University, Umea, Sweden; 28Department of Epidemiology, School of Public Health, Aarhus
University, Aarhus; 29Danish Cancer Society, Institute of Cancer Epidemiology, Diet Cancer and Health, Copenhagen, Denmark; 30Department of Community
Medicine, University of Troms, Tromso, Norway; 31International Agency for Research on Cancer (IARC-WHO), Lyon, France; 32Department of Epidemiology and
Biostatistics, School of Public Health, Imperial College London, London, UK; 33Institute of Molecular Pathology and Immunology of the University of Porto
(IPATIMUP) and Medical Faculty/HS Joao, Porto, Portugal; 34Department of Clinical Pathology, Odense University Hospital, Odense, Denmark; 35School of Public
Health, St Marys Campus, Imperial College London, London, UK
The Author 2011. Published by Oxford University Press on behalf of the European Society for Medical Oncology.
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original article Annals of Oncology
comparing immunoglobulin G positive versus negative by ELISA was 6.8 [95% confidence interval (CI) 3.015.1], and
by immunoblot, the OR was 21.4 (95% CI 7.164.4).
Conclusions: Using a western blot assay, nearly all noncardia GC were classified as H. pylori positive and the OR
was more than threefold higher than the OR assessed by ELISA, supporting the hypothesis that H. pylori infection is
a necessary condition for noncardia GC.
Key words: Helicobacter pylori, noncardia gastric cancer, prospective study, western blot
introduction A nested casecontrol study within the EPIC cohort (EurGast) was
conducted to analyse the relationship between GC risk and baseline H.
Helicobacter pylori infection is a well-established cause of pylori seropositivity status as well as other biomarkers. Each incident
sporadic noncardia gastric cancer (GC) [1]. In epidemiological noncardia GC case with an available blood sample was matched by sex, age
studies, H. pylori infection is usually detected by enzyme-linked group (62.5 years), centre and date of blood collection (645 days) to four
immunosorbent assay (ELISA). A combined analysis of 12 control participants who were randomly selected from the cohort at risk at
casecontrol studies nested within cohorts [2] found an overall the time of diagnosis of the index case. Cases were subjects newly diagnosed
odds ratio (OR) of 3.0 [95% confidence interval (CI) 2.33.8] of GC defined by code C16 of the International Classification of Diseases,
for the risk of noncardia cancer, measuring anti-H. pylori 10th Revision (ICD-10). Noncardia GC were defined by the code C16.1 to
2 | Gonzalez et al.
Annals of Oncology original article
statistical analysis was higher than those positive by ELISA (11.1%). Similar
Data are presented as the number and proportion of controls and cases for results were observed by immunoblot. We did not observe
each H. pylori assay used. Conditional logistic regression was used to any differences regarding the proportion of negative cases
estimate the OR for noncardia GC risk, adjusting for potential confounders: between intestinal and diffuse histological subtypes (data not
education (none, primary, technical/professional, secondary or university), shown).
cigarette smoking (never, former and current) and average daily dietary Table 2 shows the ORs of noncardia GC associated with H.
intakes (fruit, vegetables and red and processed meat). pylori seropositivity, according to the assay, adjusting for
potential confounders. The OR was 6.8 (95% CI 3.015.1)
results comparing IgG positive versus negative by ELISA and 21.4
(95% CI 7.164.3) comparing IgG positive versus negative by
During a mean follow-up of 10.65 years (range 0.317.6 years), immunoblot.
in the update of cancer incidence from the EPIC cohort, 195
new histologically confirmed adenocarcinoma cases (51 from
the cardia, 88 from the noncardia, 4 mixed and 52 for which discussion
the site was not identified) were diagnosed. The analysis Our prospective study found that the OR for noncardia GC and
presented here is based on these 88 noncardia GC cases (of H. pylori seroprevalence is almost fourfold higher by
which 31 were intestinal type, 32 diffuse and 25 mixed or immunoblot than by ELISA. It supports the evidence that
undefined) and 338 matched controls. In 16 (18.2%) of these measuring only IgG by ELISA to classify H. pylori infection
cases (Table 1), SCAG was present according to serological
Table 1. Seroprevalence of Helicobacter pylori IgG antibodies (ELISA) and IgG antibodies (Immunoblot) in noncardia gastric adenocarcinoma cases and
matched controls, in the EurGast-EPIC cohort study
doi:10.1093/annonc/mdr384 | 3
original article Annals of Oncology
OR for seropositivity of H. pylori infection was 2.2 as measured a commercial immunoblot test (HELICOBLOT 2.1) that has
by ELISA and 21.0 as measured by immunoblot. In a hospital- been shown to have a sensitivity of 100% for current and of
based casecontrol study from Germany [9] (including 68 92% for previous H. pylori infection [17, 18], meaning that
noncardia GC and 360 controls), the OR increased from 3.7 by some false-negative results can be expected in subjects with
ELISA to 18.3 by immunoblot. Finally, in a nested casecontrol previous infection. We observed that 93.2% of noncardia GC
study from Australia [8] (including 34 noncardia GC and 134 were positive by immunoblot, which is consistent with the
controls), the OR increased from 2.3 by ELISA to 10.6 by sensitivity of the method.
immunoblot. Our study has several clinical implications. The immunoblot
We found that the prevalence of seronegativity in noncardia might be useful for modelling the relationship between the
GC decreased from 18.2% by ELISA to 6.8% by immunoblot, decline in H. pylori infection prevalence and declines in gastric
confirming the underestimation of the prevalence of H. pylori cancer incidence [19]. Our study should not be a basis for
infection using ELISA. In a meta-analysis [3] of casecontrol justification of massive eradication therapy, because there is no
studies, which included 10 studies (western blot was used only evidence yet of the benefit of this approach in the general
in two of these studies), and >1700 noncardia GC cases, which population [20]. Furthermore, this could lead to the activation
assessed the relationship between GC and H. pylori by CagA of antibiotic-resistant strains of other pathogens [1]. However,
seropositivity, 37.7% of the noncardia GC cases were negative it is a good reason to continue efforts for developing vaccines
for CagA antibodies. On the contrary, using immunoblot in the against H. pylori.
population-based casecontrol study from Sweden [4], only 4% Our study design has several strengths. Most of the cases
4 | Gonzalez et al.
Annals of Oncology original article
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doi:10.1093/annonc/mdr384 | 5