Association between Helicobacter pylori VacA antigens and gastric cancer depends on the detection method used: immunoblot versus neutralization of the vacuolating activity of VacA
There are inconsistent findings on the association between Helicobacter pylori anti-VacA antibodies and gastric cancer (GC) risk. The lack of optimally sensitive and specific methods to detect anti-VacA antibodies may partly be responsible for this discrepancy. The aim of this study was to compare the association between GC and the presence of anti-VacA antibodies using two different detection methods. A secondary analysis of sera collected in a hospital-based case–control study in three geographical areas of Mexico was performed. Anti-VacA antibodies were determined by a neutralization assay and an immunoblot assay in serum samples of 203 histologically confirmed GC cases and 430 age- and sex-matched controls. H. pylori IgG status was determined by immunoblotting and H. pylori CagA status data was available for this study. Unconditional logistic regression models were used to estimate the association between anti-VacA antibodies and GC by histological type (diffuse and intestinal). Anti-VacA seroprevalence was higher using neutralization compared with immunoblotting: 68.5 vs 44.3 % for cases and 60.5 vs 44.2 % for controls. A significant association between anti-VacA antibodies and diffuse GC was found using neutralization [odds ratio (OR)=1.69, 95 % CI 1.08–2.66], but the association did not remain significant after adjusting for CagA status (OR 1.37, 95 % CI 0.81–2.32). No association between anti-VacA antibodies and GC was found when using immunoblotting. Thus, the association between anti-VacA antibodies and GC partly depends on the detection method used. These results do not support an independent role for VacA in GC risk in the presence of CagA seropositivity and strengthen the importance of CagA as a potential risk factor for GC.
BoonjakuakulJ. K.,
SyvanenM.,
SuryaprasadA.,
BowlusC. L.,
SolnickJ. V.2004; Transcription profile of Helicobacter pylori in the human stomach reflects its physiology in vivo
. J Infect Dis 190:946–956[CrossRef]
CoverT. L.,
DooleyC. P.,
BlaserM. J.1990; Characterization of and human serologic response to proteins in Helicobacter pylori broth culture supernatants with vacuolizing cytotoxin activity. Infect Immun 58:603–610
CoverT. L.,
KrishnaU. S.,
IsraelD. A.,
PeekR. M.Jr2003; Induction of gastric epithelial cell apoptosis by Helicobacter pylori vacuolating cytotoxin. Cancer Res 63:951–957
de BernardM.,
MoschioniM.,
PapiniE.,
TelfordJ.,
RappuoliR.,
MontecuccoC.1998; Cell vacuolization induced by Helicobacter pylori VacA toxin: cell line sensitivity and quantitative estimation. Toxicol Lett 99:109–115[CrossRef]
de Figueiredo SoaresT.,
de Magalhães QueirozD. M.,
MendesE. N.,
RochaG. A.,
Rocha OliveiraA. M.,
Alvares CabralM. M.,
de OliveiraC. A.1998; The interrelationship between Helicobacter pylori vacuolating cytotoxin and gastric carcinoma. Am J Gastroenterol 93:1841–1847[CrossRef]
FigueroaG.,
TroncosoM.,
ToledoM. S.,
FaundezG.,
AcunaR.2002; Prevalence of serum antibodies to Helicobacter pylori VacA and CagA and gastric diseases in Chile. J Med Microbiol 51:300–304
Garza-GonzalezE.,
Bosques-PadillaF. J.,
Perez-PerezG. I.,
Flores-GutierrezJ. P.,
Tijerina-MenchacaR.2004; Association of gastric cancer, HLA-DQA1, and infection with Helicobacter pylori CagA+ and VacA+ in a Mexican population. J Gastroenterol 39:1138–1142[CrossRef]
HatakeyamaM.2003; Helicobacter pylori CagA – a potential bacterial oncoprotein that functionally mimics the mammalian Gab family of adaptor proteins. Microbes Infect 5:143–150[CrossRef]
HiraiM.,
AzumaT.,
ItoS.,
KatoT.,
KohliY.,
FulikiN.1994; High prevalence of neutralizing activity to Helicobacter pylori cytotoxin in serum of gastric-carcinoma patients. Int J Cancer 56:56–60
KaritaM.,
TeramukaiS.,
MatsumotoS.,
ShibutaH.2005; Intracellular VacA is a valuable marker to predict whether Helicobacter pylori induces progressive atrophic gastritis that is associated with the development of gastric cancer. Dig Dis Sci 50:56–64[CrossRef]
KuckD.,
KolmererB.,
Iking-KonertC.,
KrammerP. H.,
StremmelW.,
RudiJ.2001; Vacuolating cytotoxin of Helicobacter pylori induces apoptosis in the human gastric epithelial cell line AGS. Infect Immun 69:5080–5087[CrossRef]
LaurenP.1965; The two histological main types of gastric carcinoma: diffuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classification. Acta Pathol Microbiol Scand 64:31–49
LepperP. M.,
MorickeA.,
VogtK.,
BodeG.,
TrautmannM.2004; Comparison of different criteria for interpretation of immunoglobulin G immunoblotting results for diagnosis of Helicobacter pylori infection. Clin Diagn Lab Immunol 11:569–576
López-CarrilloL.,
Lopez-CervantesM.,
Robles-DiazG.,
Ramirez-EspitiaA.,
Mohar-BetancourtA.,
Meneses-GarciaA.,
Lopez-VidalY.,
BlairA.2003; Capsaicin consumption, Helicobacter pylori positivity and gastric cancer in Mexico. Int J Cancer 106:277–282[CrossRef]
López-CarrilloL.,
Torres-LopezJ.,
Galvan-PortilloM.,
MunozL.,
Lopez-CervantesM.2004; Helicobacter pylori -CagA seropositivity and nitrite and ascorbic acid food intake as predictors for gastric cancer. Eur J Cancer 40:1752–1759[CrossRef]
ParkinD. M.,
WhelanS. L.,
FerlayJ.,
RaymondL.,
YoungJ.1997Cancer Incidence in Five Continents vol VII IARC Scientific Publication; No 143 Lyon: IARC Press;
RudiJ.,
KolbC.,
MaiwaldM.,
ZunaI.,
von HerbayA.,
GalleP. R.,
StremmelW.1997; Serum antibodies against Helicobacter pylori proteins VacA and CagA are associated with increased risk for gastric adenocarcinoma. Dig Dis Sci 42:1652–1659[CrossRef]
SalamaN. R.,
OttoG.,
TompkinsL.,
FalkowS.2001; Vacuolating cytotoxin of Helicobacter pylori plays a role during colonization in a mouse model of infection. Infect Immun 69:730–736[CrossRef]
Secretaría de Salud1993Compendio de Estadísticas de Morbilidad por Neoplasias Malignas 1982–1989 Mexico City: Registro Histopatológico de Neoplasias Malignas (in Spanish;
ShimoyamaT.,
NeelamB.,
FukudaS.,
TanakaM.,
MunakataA.,
CrabtreeJ. E.1999; VacA seropositivity is not associated with the development of gastric cancer in a Japanese population. Eur J Gastroenterol Hepatol 11:887–890
YamaokaY.,
KodamaT.,
KashimaK.,
GrahamD. Y.1999; Antibody against Helicobacter pylori CagA and VacA and the risk for gastric cancer. J Clin Pathol 52:215–218[CrossRef]
YuJ.,
LeungW. K.,
GoM. Y.,
ChanM. C.,
ToK. F.,
NgE. K.,
ChanF. K.,
LingT. K.,
ChungS. C.,
SungJ. J.2002; Relationship between Helicobacter pylori babA2 status with gastric epithelial cell turnover and premalignant gastric lesions. Gut 51:480–484[CrossRef]
Association between Helicobacter pylori VacA antigens and gastric cancer depends on the detection method used: immunoblot versus neutralization of the vacuolating activity of VacA