The relative and attributable risks of cardia and non-cardia gastric cancer associated with Helicobacter pylori infection in China: a case-cohort study

Ling Yang*, Christiana Kartsonaki*, Pang Yao, Catherine de Martel, Martyn Plummer, Daniel Chapman, Yu Guo, Sarah Clark, Robin G Walters, Yiping Chen, Pei Pei, Jun Lv, Canqing Yu, Rima Jeske, Tim Waterboer, Gary M Clifford, Silvia Franceschi, Richard Peto, Michael Hill, Liming Li, Iona Y Millwood†, Zhengming Chen†, for the China Kadoorie Biobank Collaborative Group

Summary

Background Helicobacter pylori infection is a major cause of non-cardia gastric cancer (NCGC), but its causal role in cardia gastric cancer (CGC) is unclear. Moreover, the reported magnitude of association with NCGC varies considerably, leading to uncertainty about population-based H pylori screening and eradication strategies in high-risk settings, particularly in China, where approximately half of all global gastric cancer cases occur. Our aim was to assess the associations of H pylori infection, both overall and for individual infection biomarkers, with the risks of NCGC and CGC in Chinese adults.

Methods A case-cohort study was done in adults from the prospective China Kadoorie Biobank study, aged 30–79 years from ten areas in China (Qingdao, Haikou, Harbin, Suzhou, Liuzhou, Henan, Sichuan, Hunan, Gansu, and Zhejiang), and included 500 incident NCGC cases, 437 incident CGC cases, and 500 subcohort participants who were cancer- free and alive within the first two years since enrolment in 2004–08. H pylori biomarkers were measured in stored baseline plasma samples using a sensitive immunoblot assay (HelicoBlot 2.1), with adapted criteria to define H pylori seropositivity. Cox regression was used to estimate adjusted hazard ratios (HRs) for NCGC and CGC associated with H pylori infection. These values were used to estimate the number of gastric cancer cases attributable to H pylori infection in China.

Findings Of the 512 715 adults enrolled in the China Kadoorie Biobank between June, 2004, and July, 2008, 500 incident NCGC cases, 437 incident CGC cases, and 500 subcohort participants were selected for analysis. The seroprevalence of H pylori was 94·4% (95% CI 92·4–96·4) in NGCG, 92·2% (89·7–94·7) in CGC, and 75·6% (71·8–79·4) in subcohort participants. H pylori infection was associated with adjusted HRs of 5·94 (95% CI 3·25–10·86) for NCGC and 3·06 (1·54–6·10) for CGC. Among the seven individual infection biomarkers, cytotoxin-associated antigen had the highest HRs for both NCGC (HR 4·41, 95% CI 2·60–7·50) and CGC (2·94, 1·53–5·68). In this population, 78·5% of NCGC and 62·1% of CGC cases could be attributable to H pylori infection. H pylori infection accounted for an estimated 339 955 cases of gastric cancer in China in 2018.

Interpretation Among Chinese adults, H pylori infection is common and is the cause of large numbers of gastric cancer cases. Population-based mass screening and the eradication of H pylori should be considered to reduce the burden of gastric cancer in high-risk settings.

Funding Cancer Research UK, Wellcome Trust, UK Medical Research Council, British Heart Foundation, Kadoorie Charitable Foundation, National Key Research and Development Program of China, and National Natural Science Foundation of China.

Copyright © 2021 The Author(s). Published by Elsevier Ltd. This is an Open Access article under the CC BY 4.0 license.

Introduction

Gastric cancer is the fifth most frequently diagnosed cancer and the second leading cause of cancer death globally, causing more than 1 million new cases and approximately 770 000 deaths in 2020, with China alone accounting for approximately half (478 000) of the number of global new cases.1 One of the most notable and preventable causes of gastric cancer is Helicobacter pylori infection, which caused an estimated 0·8 million new gastric cancer cases globally in 2018, based mainly on relative risk (RR) estimates from studies in populations from Europe, the USA, and Australia.2

The prevalence of H pylori infection varies greatly between and within countries, from 20% to 50% in high- income countries to more than 80% in many low-income countries.3 Although several epidemiological studies have consistently shown the strong association of non- cardia gastric cancer (NCGC) with H pylori infection in diverse populations, the reported RR estimates varied considerably between the studies.4–6 Moreover, there is substantial uncertainty about the role of H pylori infection in the cause of cardia gastric cancer (CGC), which accounts for approximately a third of gastric cancer cases globally. By contrast to a few east Asian studies showing a positive association of CGC with H pylori infection,7,8 albeit more modest than that for NCGC, most studies of populations in Europe, the USA, and Australia have reported either null or reduced risks of CGC associated with H pylori infection.5,9

As a result of chronic H pylori infection, a high proportion of people with gastric cancer might develop severe gastric atrophy several years before cancer development,10 which could reduce antibody concen- trations and substantially underestimate the risk of H pylori infection in case-control studies or prospective studies with a short follow-up, in which H pylori infection is measured after or shortly before cancer diagnosis.5 Moreover, the risk estimates might also be affected by the sensitivity of the assay used to measure H pylori antibodies. In populations in Europe, the USA, and Australia, the immunoblot assay has proven to be more sensitive than conventional ELISA to detect H pylori antibodies, with some studies reporting 2–5 times higher risks for NCGC with an immunoblot than with ELISA in the same study populations.6,11–13 However, these previous studies tended to be small, typically involving fewer than 100 patients with cancer. To our knowledge, no large prospective study using an immunoblot assay has been done in China where H pylori infection is highly prevalent, with different H pylori strain-specific features from populations in Europe, the USA, and Australia.14 Using an immunoblot assay and a case-cohort study design within the prospective China Kadoorie Biobank study of more than 0·5 million adults from ten geo- graphically diverse areas, we aimed to assess the associations of H pylori infection, both overall and for individual infection biomarkers, with risks of NCGC and CGC in Chinese adults. We also estimated the number of gastric cancer cases attributable to H pylori infection in China.

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