www.impactjournals.com/oncotarget/ Oncotarget, Vol. 7, No. 13 Association of helicobacter pylori infection and chronic atrophic gastritis with risk of colonic, pancreatic and gastric cancer: A ten-year follow-up of the ESTHER cohort study Xin-Zu Chen1,2,*, Ben Schöttker2,*, Felipe Andres Castro2, Hongda Chen2, Yan Zhang2, Bernd Holleczek2,3, Hermann Brenner2,4 1Department of Gastrointestinal Surgery, West China Hospital, Sichuan University, Chengdu, China 2Division of Clinical Epidemiology and Aging Research, German Cancer Research Center (DKFZ), Heidelberg, Germany 3Saarland Cancer Registry, Saarbrücken, Germany 4German Cancer Consortium (DKTK), Heidelberg, Germany *These authors contributed equally to this work Correspondence to: Hermann Brenner, e-mail: [email protected] Keywords: helicobacter pylori, chronic atrophic gastritis, colon cancer, pancreatic cancer, gastric cancer Received: November 21, 2015 Accepted: February 09, 2016 Published: March 06, 2016 ABSTRACT Objectives: To assess the association of H. pylori and chronic atrophic gastritis (AG) with colonic, pancreatic and gastric cancer in a population-based prospective cohort. Methods: Serum antibodies against H. pylori in general and specific to cytotoxin- associated gene A (CagA), as well as serum pepsinogen I and II were analyzed in 9,506 men and women, aged 50–75 years in a cohort study from Saarland, Germany. Incident cases of colonic, pancreatic and gastric cancer were ascertained by record linkage with data from the Saarland Cancer Registry. Results: During an average follow-up of 10.6 years, 108 colonic, 46 pancreatic and 27 gastric incident cancers were recorded. There was no association between H. pylori infection and colonic cancer (HR = 1.07; 95% CI 0.73–1.56) or pancreatic cancer (HR = 1.32; 0.73–2.39), regardless of either CagA seropositivity or AG status. In contrast, CagA+ infection was associated with a strongly increased risk of gastric cancer, especially non-cardia gastric cancer, and this association was particularly pronounced in the presence of AG. Compared to people without AG and without CagA+ infection, people with both risk factors had a significantly increased risk of non-cardia gastric cancer (HR = 32.4; 7.6–137.6). Conclusions: This large cohort study did not observe an association of H. pylori infection or AG with colonic or pancreatic cancer, but underlines that the vast majority of non-cardia gastric cancers arise from AG and infection with CagA+ H. pylori strains. INTRODUCTION Furthermore, H. pylori infection shows a strong association with chronic atrophic gastritis (AG), which is Helicobacter pylori (H. pylori) is well-known as a considered as a precancerous lesion of the gastric mucosa carcinogenic pathogen for gastric cancer [1]. Moreover, [7]. H. pylori infection is likely to be primarily involved H. pylori infection has been suggested to be associated in the early stage of development of AG, and less so in with other cancers of the digestive tract including colonic the development of gastric cancer from AG [8]. In fact, and pancreatic cancer [2–4], but results were inconclusive. clearance of the H. pylori infection may often occur in [5, 6] To our knowledge, no previous cohort study has advanced stages of AG [9]. simultaneously assessed the risk of various gastrointestinal The 4th European Helicobacter Study Group’s cancers in the same study population. Maastricht IV/Florence Consensus Report stated that the www.impactjournals.com/oncotarget 17182 Oncotarget combination of H. pylori infection and AG determined by (HR = 3.45, 95% CI 1.38–8.64), and CagA+ H. pylori serological examination is suiTable for the identification infection was associated with a strongly increased risk of of subjects with a high risk of gastric cancer [10]. The gastric cancer regardless of serological evidence of AG. European Helicobacter Study Group recommends that Even stronger associations were observed when the differences in H. pylori virulence factors shall be taken analyses were restricted to non-cardia gastric cancer, and into account to identify subjects with high risk of gastric the risk was particularly high in the presence of both AG cancer because the oncogenic potential of H. pylori and CagA+ H. pylori infection (Table 4). Compared to infections strongly varies according to the presence of people without AG and without CagA positive infection, virulent strains [10]. For example, the cytotoxin-associated people with both risk factors had a 32.4-fold risk of non- gene A (CagA) strain is thought to contribute to cancer cardia gastric cancer (95% CI 7.6–137.6). development by steps from inflammation to atrophy and No association between AG and risk of colonic or then cancer [11–13]. pancreatic cancer was found (Table 5). However, data are scarce on the joint prediction of gastric cancer risk by both H. pylori infection and DISCUSSION presence of AG while taking major virulence factors into account. Such data are crucial to estimate the potential To our knowledge, this is the first study that of serological screen and treat strategies ahead of their simultaneously assessed the associations of H. pylori implementation. In this article, we report such results infection and AG with gastric, colonic and pancreatic from a large population-based cohort study from Germany, cancer in the same study population.We did not find any paying attention not only to gastric cancer but also to association of H. pylori infection or AG with colonic or colonic and pancreatic cancer. pancreatic cancer. In contrast, very strong associations were found with gastric cancer, especially non-cardia RESULTS gastric cancer. Participants with serological evidence of both AG and CagA+ H. pylori infection had a 32-fold risk The prevalences of overall (IgG+/anyCagA), CagA– of non-cardia gastric cancer compared to participants with and CagA+ H. pylori infection at baseline were 49.9%, neither of these conditions. 22.4%, and 27.5%, respectively. Compared with non- Our study confirms the strong association betweenH. infected participants, H. pylori infected participants were pylori infection and gastric cancer development reported in older (p < 0.001), had lower education levels (p < 0.001) previous cohort studies from high incidence countries with and reported to consume less tobacco (p = 0.030) and high prevalence of H. pylori infection, such as Japan, Korea alcohol (p < 0.001) (Table 1). Among H. pylori infected and China [13–16]. AmongWestern populations, previous persons, those with CagA+ strains included slightly higher observational studies also identified H. pylori as a risk proportions of females (p = 0.019) and never smokers factor for gastric cancer, but few had a prospective cohort (p = 0.002) than those with CagA– strains. design [17–19]. In a meta-analysis of epidemiological During a median follow-up of 10.6 years, 27 gastric, studies published until June 2009, it remained unclear 108 colonic and 46 pancreatic incident cancers were whether additional stratification by virulentH. pylori strains recorded, respectively (Table 2). Crude incidence rates has an additional benefit in identification of those with the were 26.97, 108.94 and 45.96 per 100,000 person-years highest risk for gastric cancer [20]. Our study agrees with for gastric, colonic and pancreatic cancer, respectively. another large prospective cohort study published after the Participants with H. pylori infection had much higher review that risk stratification by virulence factors is indeed incidence of gastric cancer than non-infected participants, important [21]. In our study, we found that participants whereas no such pattern was seen for colonic or pancreatic infected with non-virulent strains (CagA–) did not have an cancer (Figure 1). Furthermore, gastric cancer incidence increased risk of developing gastric cancer, whereas those was much higher among participants infected with CagA+ infected with virulent strains (CagA+) did. Among many H. pylori strains than among those infected with CagA– H. pylori specific proteins, it is widely acknowledged that H. pylori strains. Nevertheless, even among those with CagA, generated from virulent strains, induces extensive CagA+ H. pylori infection, gastric cancer incidence was inflammation and progression to more severe disease still lower than colonic cancer incidence. states [22]. Therefore, if H. pylori testing is carried out, the In Cox regression models, very strong associations serological CagA status should also be determined to better of H. pylori infection were found with gastric cancer judge the gastric cancer risk. Furthermore, previous studies (adjusted hazard ratios [95% CIs] for any and CagA+ H. showed that H. pylori infection might be related to gastric pylori infection: 3.91 [1.48–10.38] and 6.27 [2.33–16.86], cancer through its influence on the onset and progression respectively), but not with the other gastrointestinal of AG [13, 23]. A previous longitudinal analysis of the cancers (Table 2, Figure 2). ESTHER study showed that infection with H. pylori As shown in Table 3, serological evidence of AG was a strong predictor for the development of AG [24]. was associated with an increased risk of gastric cancer In particular, study participants with infection of virulent www.impactjournals.com/oncotarget 17183 Oncotarget Table 1: Characteristics of population by H. pylori infectionand CagA seropositivityat baseline Non-infected H. pylori infected IgG+/any P value P value Characteristics Total IgG–/CagA– IgG+/CagA– IgG+/CagA+ CagA † ‡ n (%) n