IJC International Journal of Cancer
Global burden of gastric cancer attributable to Helicobacter pylori ro ^me Vignat, David Forman and Catherine de Martel Martyn Plummer, Silvia Franceschi, Je International Agency for Research on Cancer, Lyon, France
Chronic infection with the bacterium Helicobacter pylori (H. pylori) causes non-cardia gastric carcinoma (NCGC) and low grade B-cell MALT lymphoma.1 We previously estimated that worldwide 660,000 cases of cancer in the year 2008 were attributable to H. pylori, corresponding to 32.4% of the 2 million cancer cases attributable to infectious agents and 5.2% of the 12.7 million total cancer cases that occurred worldwide.2 The vast majority of the cancers attributable to H. pylori (650,000) were NCGC. These estimates of the global burden are based on the attributable fraction (AF) for H. pylori, which is the proportion of cancers that would not have occurred if H. pylori was absent from the world population. Quantification of the AF requires accurate estimation of both the relative risk and the prevalence of infection in cases.2 This effort was hampered by the low sensitivity of serological tests for H. pylori in NCGC cases. Gastric atrophy is a precursor lesion of gastric cancer that reduces bacterial load and hence leads to a
declining antibody response, reducing the sensitivity of serological tests.2 Prospective studies in which the blood sample for H. pylori testing was taken well before gastric cancer diagnosis are considered to be the most reliable. We previously used a pooled analysis of 11 such studies in which blood draw took place at least 10 years before the development of cancer.3 In that pooled analysis, the average prevalence of H. pylori infection in cases was 90%, and the corresponding relative risk was 5.9, yielding an AF of 74.7% for H. pylori in NCGC. We now consider our AF estimate for NCGC to be an underestimate. In recent years, evidence has accumulated that immunoblot (western blot) is more sensitive for detection of anti-H. pylori antibodies than ELISA, the detection method used in the above pooled analysis. The purpose of this short report is to update the AF estimate for H. pylori after briefly reviewing the evidence, and to reassess the global burden of cancer attributable to H. pylori.
Key words: Helicobacter pylori, gastric cancer, attributable fraction, immunoblot Abbreviations: AF: attributable fraction; EBV: Epstein-Barr virus; H. pylori: Helicobacter pylori; NCGC: non-cardia gastric cancer Grant sponsor: Fondation de France; Grant number: 00039621 DOI: 10.1002/ijc.28999 History: Received 15 Apr 2014; Accepted 26 May 2014; Online 29 May 2014 Correspondence to: Martyn Plummer, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon cedex 08, France; Tel.: 133-(0)4-7273-8446; Fax: 133-(0)4-7273-8345; E-mail: [email protected]
Methods
C 2014 UICC Int. J. Cancer: 00, 00–00 (2014) V
A review of the literature was undertaken in Pubmed and Web of Science, using the following keywords: “Helicobacter,” “immunoblot*,” “western-blot*,” and “gastric neoplasms.” We included prospective studies and case–control studies in which the risk of developing NCGC in individuals with and without cancer was compared, using both ELISA and multiple antigen immunoblot for detection of H. pylori. Studies that had used immunoblot only for detection of antibodies to the CagA protein, which is expressed by some H. pylori strains, were not included. The results from prospective studies were combined by fixed effects meta-analysis to give pooled estimates of the
Short Report
We previously estimated that 660,000 cases of cancer in the year 2008 were attributable to the bacterium Helicobacter pylori (H. pylori), corresponding to 5.2% of the 12.7 million total cancer cases that occurred worldwide. In recent years, evidence has accumulated that immunoblot (western blot) is more sensitive for detection of anti-H. pylori antibodies than ELISA, the detection method used in our previous analysis. The purpose of this short report is to update the attributable fraction (AF) estimate for H. pylori after briefly reviewing new evidence, and to reassess the global burden of cancer attributable to H. pylori. We therefore reviewed the literature for studies comparing the risk of developing non-cardia gastric cancer (NCGC) in cases and controls, using both ELISA and multiple antigen immunoblot for detection of H. pylori. The results from prospective studies were combined, and the new pooled estimates were applied to the calculation of the AF for H. pylori in NCGC, then to the burden of infection-related cancers worldwide. Using the immunoblot-based data, the worldwide AF for H. pylori in NCGC increased from 74.7% to 89.0%. This implies approximately 120,000 additional cases of NCGC attributable to H. pylori infection for a total of around 780,000 cases (6.2% instead of 5.2% of all cancers). These updated estimates reinforce the role of H. pylori as a major cause of cancer.
2
Helicobacter pylori in gastric cancer
What’s new? Some 5.2 percent of the estimated 12.7 million new cancer cases in 2008, including 75% of non-cardia gastric cancer cases (NCGC), were attributed to the bacterium Helicobacter pylori. However, those percentages may be an underestimate, given the low sensitivity of detection of anti-H. pylori antibodies. Here, using improved estimates from prospective studies based on immunoblot, the fraction of all cancers and NCGC attributable to H. pylori was found to be 6.2 and 89% percent, respectively. Our findings reinforce the significance of the bacterium as a major cause of cancer.
relative risk and the prevalence of H. pylori in cases. These pooled estimates were applied to the calculation of the AF for H. pylori in NCGC, then to the burden of infection-related cancers worldwide as previously described.2,4
Short Report
Results Four published studies of NCGC have directly compared ELISA with immunoblot (Table 1), all using the commercial test Helico Blot 2.1 (Genelabs Diagnostics, Singapore). The three prospective studies showed consistently higher prevalence of H. pylori among cases and consistently higher relative risks when using immunoblot compared with ELISA,5–8 whereas the case–control study found no difference between the results by ELISA and immunoblot.9 Our literature search also found a cross-sectional study of 54 Chinese patients undergoing upper GI endoscopy using the earlier Helico Blot 2.0 test.10 This study is not included in Table 1 as it did not directly compare immunoblot with ELISA, but we estimated the odds ratio for NCGC from this study to be 20.9 (95% CI: 2.58–980) for immunoblot, i.e., consistent with odds ratios in Table 1. When the results from the three prospective studies are pooled, the prevalence in cases is 82.6% by ELISA and 94.6% by immunoblot, and the relative risks are 4.77 (95% CI: 3.56–6.39) and 17.0 (95% CI: 11.6–25.0), respectively. Using the immunoblot-based data, the AF for H. pylori in NCGC is 89.0%. Compared with our previous AF estimate of 74.7% this implies approximately 120,000 additional cases of NCGC attributable to H. pylori infection for a total of around 780,000 cases (6.2 % instead of 5.2% of all cancers). With this revised AF, H. pylori is responsible for 36.3% of the 2.2 million cancers attributable to infection worldwide in the year 2008. This proportion is higher in men (46.7%) than in women (26.2%) and higher in more developed (50.3%) than less developed regions (32.7%). Figure 1 shows the distribution of cancers attributable to infection by infectious agent within more developed and less developed regions. As previously noted,2 H. pylori is one of four infectious agents that dominate the infectious causes of cancer. The others are human papillomavirus (causing cervical cancer, other anogenital cancers, and oropharyngeal cancers); hepatitis B virus (hepatocellular carcinoma) and hepatitis C virus (hepatocellular carcinoma and non-Hodgkin lymphoma). With the revised AF, H. pylori remains the most important infectious
agent causing cancer, especially in more developed countries, where it bears half the burden of infection-related cancers.
Discussion In three prospective studies conducted in Europe and Australia, multiple antigen immunoblot substantially increases the detection of H. pylori compared with ELISA in cases but not in controls. This differential increase translates into higher odds ratios for NCGC. In contrast, the similar results for ELISA and immmunoblot in the case–control study suggest that immunoblot cannot necessarily overcome the known difficulty of detecting H. pylori by ELISA in people with advanced precancerous lesions. Evidence for the higher AF for H. pylori in NCGC comes exclusively from low-risk populations. The age-standardized incidence rate for gastric cancer in men is 4.9 per 100,000 person years in Sweden, 6.7 in Australia and ranges between 4.9 and 11.0 (median 7.5) in the 10 European countries contributing to the European Prospective Investigation into Cancer and Nutrition.11 People with H. pylori infection are therefore a high-risk sub-group even in low-risk populations. Extrapolation of our AF estimate of 89.0% to the world population, including high-risk countries for gastric cancer, is justified by the absence of other strong risk factors for gastric cancer. As noted by Gonzalez et al.,8 the AF for H. pylori may be underestimated by non-differential misclassification of H. pylori status. The Helico Blot 2.1 test has a reported sensitivity of 95.6% (95% CI: 91.5–99.6) and specificity of 92.6% (95% CI: 91.5–96.2).12 We incorporated these estimates into a misclassification model to estimate the AF adjusted for false positive and negative results. This yielded a 95% confidence interval of 89.8 to 100.0% for the AF. Although the confidence interval is consistent with an AF of 100% this statistical evidence is not sufficient to classify H. pylori as a necessary cause of NCGC. Around 10% of gastric carcinomas contain Epstein-Barr virus (EBV).1 The role of EBV and its interaction with H. pylori is not fully understood; it is possible that EBV is an independent cause of a minority of NCGC. The studies6,8,9 in Table 1 also emphasise the role of CagA-positive H. pylori strains, as the Helico Blot 2.1 test includes a 116kDa (CagA) band for the detection of antiCagA antibodies. In one of the prospective studies6 all of the cases that were positive for H. pylori were also CagA-positive (65/65). In another,8 all but one of the H. pylori-positive C 2014 UICC Int. J. Cancer: 00, 00–00 (2014) V
3
Plummer et al.
Table 1. Studies of non-cardia gastric cancer comparing H. pylori assessment by ELISA and by immunoblot ELISA Study
Country
N cases Follow-up (yrs) % Cases positive
Immunoblot
OR
95% CI
% Cases positive
OR
95% CI
Prospective n et al., 19975 Sima
Sweden1 27
5.7
89%
11.1 2.4-71.8
–
–
6
n et al., 2007 Sima
Sweden1 67
9.2
–
–
–
97%
17.8 4.2-74.8
Mitchell et al., 20087
Australia
34
11.6
79%
2.3
0.9-5.8
94%
10.6 2.4-47.4
88
10.7
82%
6.81 3.0-15.1
93%
21.4 7.1-64.4
272
–
84%
0.66 0.37-1.17 76%
lez et al., 20128 Europe2 Gonza
–
Case–control Peleteiro et al., 20109
Portugal
0.73 0.46-1.17
1
The same cohort with different follow-up. Multicentric study, part of the European Prospective Investigation into Cancer and Nutrition (EPIC). Abbreviations: OR 5 odds ratio; CI 5 confidence interval.
Figure 1. Number of new cancer cases in 2008 attributable to infection, by infectious agent and development status (updating Fig. 2 of de Martel et al. 2012).2
cases were CagA-positive (81/82). The third did not report specific findings for CagA.7 The case–control study9 also found a strong association when the 116kDa band was interpreted as CagA-positivity, ignoring the other markers that are required to define H. pylori infection according to the
manufacturer’s instructions. The prevalence of CagA in cases was 96.0% and the relative risk for CagA was 11.3 (95% CI: 5.64–22.7), in contrast to the low prevalence and null relative risk for H. pylori overall (Table 1). This reinforces the findings of previous case–control studies that have supplemented H. pylori detection by ELISA by CagA immunoblot.13,14 These previous studies were based on the hypothesis that CagA antibodies are more persistent than antibodies to H. pylori surface antigens, and are therefore a more sensitive marker to past infection with a CagA-positive strain. It should be noted, however, that this hypothesis is not accepted by all authors.15 Further evidence for the role of cagA-positive H. pylori strains come from studies of precancerous lesions, which allow detection and typing using PCR on gastric biopsies. Such studies have shown strong crosssectional associations between cagA-positive strains and severity of precancerous lesions16 and increased progression among cagA-positive strains that also have the more virulent vacA s1/m2 genotype.17 In conclusion, immunoblot is to be preferred to ELISA in epidemiological studies of NCGC, although it cannot completely overcome the problems of the retrospective assessment of infection status in case–control studies. The increased estimates of the burden of cancer attributable to H. pylori obtained by taking these studies into account reinforce its role as a major cause of cancer.
Acknowledgement Dr. Catherine de Martel was funded by the Fondation de France (grant number 00039621).
References 1.
2.
IARC. Monographs on the evaluation of carcinogenic risks to humans volume 100b: a review of human carcinogens: biological agents. Lyon: International Agency for Research on Cancer, 2012. de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in
C 2014 UICC Int. J. Cancer: 00, 00–00 (2014) V
3.
2008: a review and synthetic analysis. Lancet Oncol 2012;13:607–15. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001;49: 347–53.
4.
5.
Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127: 2893–917. Siman JH, Forsgren A, Berglund G, et al. Association between Helicobacter pylori and gastric carcinoma in the city of Malmo, Sweden. A
Short Report
2
4
6.
7.
8.
prospective study. Scand J Gastroenterol 1997;32: 1215–21. Siman JH, Engstrand L, Berglund G, et al. Helicobacter pylori and CagA seropositivity and its association with gastric and oesophageal carcinoma. Scand J Gastroenterol 2007;42:933–40. Mitchell H, English DR, Elliott F, et al. Immunoblotting using multiple antigens is essential to demonstrate the true risk of Helicobacter pylori infection for gastric cancer. Aliment Pharmacol Ther 2008;28:903–10. Gonzalez CA, Megraud F, Buissonniere A, et al. Helicobacter pylori infection assessed by ELISA and by immunoblot and noncardia gastric cancer risk in a prospective study: the Eurgast-EPIC project. Ann Oncol 2012;23:1320–4. Peleteiro B, Lunet N, Barros R, et al. Factors contributing to the underestimation of Helicobacter pylori-associated gastric cancer risk in a high-
10.
11.
12.
13.
prevalence population. Cancer Causes Control 2010;21:1257–64. Yang KC, Chu A, Liao CS, et al. Evaluation of the role of H pylori infection in pathogenesis of gastric cancer by immunoblot assay. World J Gastroenterol 2006;12:7029–32. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worlwide: IARC cancerbase no. 11. Lyon, France: International Agency for Research on Cancer, 2013. Available from: http://globocan. iarc.fr. Monteiro L, de Mascarel A, Sarrasqueta AM, et al. Diagnosis of Helicobacter pylori infection: noninvasive methods compared to invasive methods and evaluation of two new tests. Am J Gastroenterol 2001;96:353–8. Ekstr€om AM, Held M, Hansson LE, et al. Helicobacter pylori in gastric cancer established by
14.
15.
16.
17.
CagA immunoblot as a marker of past infection. Gastroenterology 2001;121:784–91. Brenner H, Arndt V, Stegmaier C, et al. Is Helicobacter pylori infection a necessary condition for noncardia gastric cancer? Am J Epidemiol 2004; 159:252–8. Siman JH, Engstrand L, Berglund G, et al. Evaluation of western blot CagA seropositivity in Helicobacter pylori-seropositive and -seronegative subjects. Clin Diagn Lab Immunol 2005;12:304–9. Plummer M, van Doorn LJ, Franceschi S, et al. Helicobacter pylori cytotoxin-associated genotype and gastric precancerous lesions. J Natl Cancer Inst 2007;99:1328–34. Gonzalez CA, Figueiredo C, Lic CB, et al. Helicobacter pylori cagA and vacA genotypes as predictors of progression of gastric preneoplastic lesions: a long-term follow-up in a high-risk area in Spain. Am J Gastroenterol 2011;106:867–74.
Short Report
9.
Helicobacter pylori in gastric cancer
C 2014 UICC Int. J. Cancer: 00, 00–00 (2014) V
Global burden of gastric cancer attributable to Helicobacter pylori ro ^me Vignat, David Forman and Catherine de Martel Martyn Plummer, Silvia Franceschi, Je International Agency for Research on Cancer, Lyon, France
Chronic infection with the bacterium Helicobacter pylori (H. pylori) causes non-cardia gastric carcinoma (NCGC) and low grade B-cell MALT lymphoma.1 We previously estimated that worldwide 660,000 cases of cancer in the year 2008 were attributable to H. pylori, corresponding to 32.4% of the 2 million cancer cases attributable to infectious agents and 5.2% of the 12.7 million total cancer cases that occurred worldwide.2 The vast majority of the cancers attributable to H. pylori (650,000) were NCGC. These estimates of the global burden are based on the attributable fraction (AF) for H. pylori, which is the proportion of cancers that would not have occurred if H. pylori was absent from the world population. Quantification of the AF requires accurate estimation of both the relative risk and the prevalence of infection in cases.2 This effort was hampered by the low sensitivity of serological tests for H. pylori in NCGC cases. Gastric atrophy is a precursor lesion of gastric cancer that reduces bacterial load and hence leads to a
declining antibody response, reducing the sensitivity of serological tests.2 Prospective studies in which the blood sample for H. pylori testing was taken well before gastric cancer diagnosis are considered to be the most reliable. We previously used a pooled analysis of 11 such studies in which blood draw took place at least 10 years before the development of cancer.3 In that pooled analysis, the average prevalence of H. pylori infection in cases was 90%, and the corresponding relative risk was 5.9, yielding an AF of 74.7% for H. pylori in NCGC. We now consider our AF estimate for NCGC to be an underestimate. In recent years, evidence has accumulated that immunoblot (western blot) is more sensitive for detection of anti-H. pylori antibodies than ELISA, the detection method used in the above pooled analysis. The purpose of this short report is to update the AF estimate for H. pylori after briefly reviewing the evidence, and to reassess the global burden of cancer attributable to H. pylori.
Key words: Helicobacter pylori, gastric cancer, attributable fraction, immunoblot Abbreviations: AF: attributable fraction; EBV: Epstein-Barr virus; H. pylori: Helicobacter pylori; NCGC: non-cardia gastric cancer Grant sponsor: Fondation de France; Grant number: 00039621 DOI: 10.1002/ijc.28999 History: Received 15 Apr 2014; Accepted 26 May 2014; Online 29 May 2014 Correspondence to: Martyn Plummer, International Agency for Research on Cancer, 150 cours Albert Thomas, 69372 Lyon cedex 08, France; Tel.: 133-(0)4-7273-8446; Fax: 133-(0)4-7273-8345; E-mail: [email protected]
Methods
C 2014 UICC Int. J. Cancer: 00, 00–00 (2014) V
A review of the literature was undertaken in Pubmed and Web of Science, using the following keywords: “Helicobacter,” “immunoblot*,” “western-blot*,” and “gastric neoplasms.” We included prospective studies and case–control studies in which the risk of developing NCGC in individuals with and without cancer was compared, using both ELISA and multiple antigen immunoblot for detection of H. pylori. Studies that had used immunoblot only for detection of antibodies to the CagA protein, which is expressed by some H. pylori strains, were not included. The results from prospective studies were combined by fixed effects meta-analysis to give pooled estimates of the
Short Report
We previously estimated that 660,000 cases of cancer in the year 2008 were attributable to the bacterium Helicobacter pylori (H. pylori), corresponding to 5.2% of the 12.7 million total cancer cases that occurred worldwide. In recent years, evidence has accumulated that immunoblot (western blot) is more sensitive for detection of anti-H. pylori antibodies than ELISA, the detection method used in our previous analysis. The purpose of this short report is to update the attributable fraction (AF) estimate for H. pylori after briefly reviewing new evidence, and to reassess the global burden of cancer attributable to H. pylori. We therefore reviewed the literature for studies comparing the risk of developing non-cardia gastric cancer (NCGC) in cases and controls, using both ELISA and multiple antigen immunoblot for detection of H. pylori. The results from prospective studies were combined, and the new pooled estimates were applied to the calculation of the AF for H. pylori in NCGC, then to the burden of infection-related cancers worldwide. Using the immunoblot-based data, the worldwide AF for H. pylori in NCGC increased from 74.7% to 89.0%. This implies approximately 120,000 additional cases of NCGC attributable to H. pylori infection for a total of around 780,000 cases (6.2% instead of 5.2% of all cancers). These updated estimates reinforce the role of H. pylori as a major cause of cancer.
2
Helicobacter pylori in gastric cancer
What’s new? Some 5.2 percent of the estimated 12.7 million new cancer cases in 2008, including 75% of non-cardia gastric cancer cases (NCGC), were attributed to the bacterium Helicobacter pylori. However, those percentages may be an underestimate, given the low sensitivity of detection of anti-H. pylori antibodies. Here, using improved estimates from prospective studies based on immunoblot, the fraction of all cancers and NCGC attributable to H. pylori was found to be 6.2 and 89% percent, respectively. Our findings reinforce the significance of the bacterium as a major cause of cancer.
relative risk and the prevalence of H. pylori in cases. These pooled estimates were applied to the calculation of the AF for H. pylori in NCGC, then to the burden of infection-related cancers worldwide as previously described.2,4
Short Report
Results Four published studies of NCGC have directly compared ELISA with immunoblot (Table 1), all using the commercial test Helico Blot 2.1 (Genelabs Diagnostics, Singapore). The three prospective studies showed consistently higher prevalence of H. pylori among cases and consistently higher relative risks when using immunoblot compared with ELISA,5–8 whereas the case–control study found no difference between the results by ELISA and immunoblot.9 Our literature search also found a cross-sectional study of 54 Chinese patients undergoing upper GI endoscopy using the earlier Helico Blot 2.0 test.10 This study is not included in Table 1 as it did not directly compare immunoblot with ELISA, but we estimated the odds ratio for NCGC from this study to be 20.9 (95% CI: 2.58–980) for immunoblot, i.e., consistent with odds ratios in Table 1. When the results from the three prospective studies are pooled, the prevalence in cases is 82.6% by ELISA and 94.6% by immunoblot, and the relative risks are 4.77 (95% CI: 3.56–6.39) and 17.0 (95% CI: 11.6–25.0), respectively. Using the immunoblot-based data, the AF for H. pylori in NCGC is 89.0%. Compared with our previous AF estimate of 74.7% this implies approximately 120,000 additional cases of NCGC attributable to H. pylori infection for a total of around 780,000 cases (6.2 % instead of 5.2% of all cancers). With this revised AF, H. pylori is responsible for 36.3% of the 2.2 million cancers attributable to infection worldwide in the year 2008. This proportion is higher in men (46.7%) than in women (26.2%) and higher in more developed (50.3%) than less developed regions (32.7%). Figure 1 shows the distribution of cancers attributable to infection by infectious agent within more developed and less developed regions. As previously noted,2 H. pylori is one of four infectious agents that dominate the infectious causes of cancer. The others are human papillomavirus (causing cervical cancer, other anogenital cancers, and oropharyngeal cancers); hepatitis B virus (hepatocellular carcinoma) and hepatitis C virus (hepatocellular carcinoma and non-Hodgkin lymphoma). With the revised AF, H. pylori remains the most important infectious
agent causing cancer, especially in more developed countries, where it bears half the burden of infection-related cancers.
Discussion In three prospective studies conducted in Europe and Australia, multiple antigen immunoblot substantially increases the detection of H. pylori compared with ELISA in cases but not in controls. This differential increase translates into higher odds ratios for NCGC. In contrast, the similar results for ELISA and immmunoblot in the case–control study suggest that immunoblot cannot necessarily overcome the known difficulty of detecting H. pylori by ELISA in people with advanced precancerous lesions. Evidence for the higher AF for H. pylori in NCGC comes exclusively from low-risk populations. The age-standardized incidence rate for gastric cancer in men is 4.9 per 100,000 person years in Sweden, 6.7 in Australia and ranges between 4.9 and 11.0 (median 7.5) in the 10 European countries contributing to the European Prospective Investigation into Cancer and Nutrition.11 People with H. pylori infection are therefore a high-risk sub-group even in low-risk populations. Extrapolation of our AF estimate of 89.0% to the world population, including high-risk countries for gastric cancer, is justified by the absence of other strong risk factors for gastric cancer. As noted by Gonzalez et al.,8 the AF for H. pylori may be underestimated by non-differential misclassification of H. pylori status. The Helico Blot 2.1 test has a reported sensitivity of 95.6% (95% CI: 91.5–99.6) and specificity of 92.6% (95% CI: 91.5–96.2).12 We incorporated these estimates into a misclassification model to estimate the AF adjusted for false positive and negative results. This yielded a 95% confidence interval of 89.8 to 100.0% for the AF. Although the confidence interval is consistent with an AF of 100% this statistical evidence is not sufficient to classify H. pylori as a necessary cause of NCGC. Around 10% of gastric carcinomas contain Epstein-Barr virus (EBV).1 The role of EBV and its interaction with H. pylori is not fully understood; it is possible that EBV is an independent cause of a minority of NCGC. The studies6,8,9 in Table 1 also emphasise the role of CagA-positive H. pylori strains, as the Helico Blot 2.1 test includes a 116kDa (CagA) band for the detection of antiCagA antibodies. In one of the prospective studies6 all of the cases that were positive for H. pylori were also CagA-positive (65/65). In another,8 all but one of the H. pylori-positive C 2014 UICC Int. J. Cancer: 00, 00–00 (2014) V
3
Plummer et al.
Table 1. Studies of non-cardia gastric cancer comparing H. pylori assessment by ELISA and by immunoblot ELISA Study
Country
N cases Follow-up (yrs) % Cases positive
Immunoblot
OR
95% CI
% Cases positive
OR
95% CI
Prospective n et al., 19975 Sima
Sweden1 27
5.7
89%
11.1 2.4-71.8
–
–
6
n et al., 2007 Sima
Sweden1 67
9.2
–
–
–
97%
17.8 4.2-74.8
Mitchell et al., 20087
Australia
34
11.6
79%
2.3
0.9-5.8
94%
10.6 2.4-47.4
88
10.7
82%
6.81 3.0-15.1
93%
21.4 7.1-64.4
272
–
84%
0.66 0.37-1.17 76%
lez et al., 20128 Europe2 Gonza
–
Case–control Peleteiro et al., 20109
Portugal
0.73 0.46-1.17
1
The same cohort with different follow-up. Multicentric study, part of the European Prospective Investigation into Cancer and Nutrition (EPIC). Abbreviations: OR 5 odds ratio; CI 5 confidence interval.
Figure 1. Number of new cancer cases in 2008 attributable to infection, by infectious agent and development status (updating Fig. 2 of de Martel et al. 2012).2
cases were CagA-positive (81/82). The third did not report specific findings for CagA.7 The case–control study9 also found a strong association when the 116kDa band was interpreted as CagA-positivity, ignoring the other markers that are required to define H. pylori infection according to the
manufacturer’s instructions. The prevalence of CagA in cases was 96.0% and the relative risk for CagA was 11.3 (95% CI: 5.64–22.7), in contrast to the low prevalence and null relative risk for H. pylori overall (Table 1). This reinforces the findings of previous case–control studies that have supplemented H. pylori detection by ELISA by CagA immunoblot.13,14 These previous studies were based on the hypothesis that CagA antibodies are more persistent than antibodies to H. pylori surface antigens, and are therefore a more sensitive marker to past infection with a CagA-positive strain. It should be noted, however, that this hypothesis is not accepted by all authors.15 Further evidence for the role of cagA-positive H. pylori strains come from studies of precancerous lesions, which allow detection and typing using PCR on gastric biopsies. Such studies have shown strong crosssectional associations between cagA-positive strains and severity of precancerous lesions16 and increased progression among cagA-positive strains that also have the more virulent vacA s1/m2 genotype.17 In conclusion, immunoblot is to be preferred to ELISA in epidemiological studies of NCGC, although it cannot completely overcome the problems of the retrospective assessment of infection status in case–control studies. The increased estimates of the burden of cancer attributable to H. pylori obtained by taking these studies into account reinforce its role as a major cause of cancer.
Acknowledgement Dr. Catherine de Martel was funded by the Fondation de France (grant number 00039621).
References 1.
2.
IARC. Monographs on the evaluation of carcinogenic risks to humans volume 100b: a review of human carcinogens: biological agents. Lyon: International Agency for Research on Cancer, 2012. de Martel C, Ferlay J, Franceschi S, et al. Global burden of cancers attributable to infections in
C 2014 UICC Int. J. Cancer: 00, 00–00 (2014) V
3.
2008: a review and synthetic analysis. Lancet Oncol 2012;13:607–15. Helicobacter and Cancer Collaborative Group. Gastric cancer and Helicobacter pylori: a combined analysis of 12 case control studies nested within prospective cohorts. Gut 2001;49: 347–53.
4.
5.
Ferlay J, Shin HR, Bray F, et al. Estimates of worldwide burden of cancer in 2008: GLOBOCAN 2008. Int J Cancer 2010;127: 2893–917. Siman JH, Forsgren A, Berglund G, et al. Association between Helicobacter pylori and gastric carcinoma in the city of Malmo, Sweden. A
Short Report
2
4
6.
7.
8.
prospective study. Scand J Gastroenterol 1997;32: 1215–21. Siman JH, Engstrand L, Berglund G, et al. Helicobacter pylori and CagA seropositivity and its association with gastric and oesophageal carcinoma. Scand J Gastroenterol 2007;42:933–40. Mitchell H, English DR, Elliott F, et al. Immunoblotting using multiple antigens is essential to demonstrate the true risk of Helicobacter pylori infection for gastric cancer. Aliment Pharmacol Ther 2008;28:903–10. Gonzalez CA, Megraud F, Buissonniere A, et al. Helicobacter pylori infection assessed by ELISA and by immunoblot and noncardia gastric cancer risk in a prospective study: the Eurgast-EPIC project. Ann Oncol 2012;23:1320–4. Peleteiro B, Lunet N, Barros R, et al. Factors contributing to the underestimation of Helicobacter pylori-associated gastric cancer risk in a high-
10.
11.
12.
13.
prevalence population. Cancer Causes Control 2010;21:1257–64. Yang KC, Chu A, Liao CS, et al. Evaluation of the role of H pylori infection in pathogenesis of gastric cancer by immunoblot assay. World J Gastroenterol 2006;12:7029–32. Ferlay J, Soerjomataram I, Ervik M, et al. GLOBOCAN 2012 v1.0, cancer incidence and mortality worlwide: IARC cancerbase no. 11. Lyon, France: International Agency for Research on Cancer, 2013. Available from: http://globocan. iarc.fr. Monteiro L, de Mascarel A, Sarrasqueta AM, et al. Diagnosis of Helicobacter pylori infection: noninvasive methods compared to invasive methods and evaluation of two new tests. Am J Gastroenterol 2001;96:353–8. Ekstr€om AM, Held M, Hansson LE, et al. Helicobacter pylori in gastric cancer established by
14.
15.
16.
17.
CagA immunoblot as a marker of past infection. Gastroenterology 2001;121:784–91. Brenner H, Arndt V, Stegmaier C, et al. Is Helicobacter pylori infection a necessary condition for noncardia gastric cancer? Am J Epidemiol 2004; 159:252–8. Siman JH, Engstrand L, Berglund G, et al. Evaluation of western blot CagA seropositivity in Helicobacter pylori-seropositive and -seronegative subjects. Clin Diagn Lab Immunol 2005;12:304–9. Plummer M, van Doorn LJ, Franceschi S, et al. Helicobacter pylori cytotoxin-associated genotype and gastric precancerous lesions. J Natl Cancer Inst 2007;99:1328–34. Gonzalez CA, Figueiredo C, Lic CB, et al. Helicobacter pylori cagA and vacA genotypes as predictors of progression of gastric preneoplastic lesions: a long-term follow-up in a high-risk area in Spain. Am J Gastroenterol 2011;106:867–74.
Short Report
9.
Helicobacter pylori in gastric cancer
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