document: our understanding of h pylori  induced inflammation leading to cancer is built on the work of 3 pioneering pathologists ( figure  1 ) . 
   rudolf virchow , a 19th century prussian physician - scientist , is widely regarded as the father of modern pathology . among his many contributions to outlining the scientific basis of disease was the idea , based on many of his own observations , that cancer arose from initially normal cells in response to chronic irritation , or inflammation . 
   numerous examples of inflammation - induced cancers are now appreciated , including many of the common gastrointestinal tract and hepatobiliary malignancies , such as acid reflux  induced esophageal adenocarcinoma , inflammatory bowel disease 
   associated colon cancer , and hepatocellular neoplasms associated with chronic viral hepatitis . throughout the 20th century , evidence accrued that gastric cancers tended to arise in stomachs already affected by chronic inflammation , especially atrophic gastritis with its accompanying hypochlorhydria , and that gastric cancer was a consequence and not a mere accompaniment of the gastritis . 
   these ideas set the stage for pelayo correa , a pathologist from colombia , a country with a particularly high gastric cancer prevalence . 
   after training in pathology in colombia and in the united states ( emory university ) , correa devoted his professional career at home and subsequently in the united states ( at the national cancer institute , louisiana state university , and now vanderbilt university ) to understanding the etiology of gastric cancer . in 1975 , correa et  al , from the national cancer institute , massachusetts institute of technology , and from his home country , published a  model for gastric cancer development .  in this landmark report , it was hypothesized that the development of the more common intestinal subtype of gastric cancer resulted from a stepwise process , beginning with chronic atrophic gastritis and progressing to intestinal metaplasia and cancer over the next 3050 years . 
   the initial changes were postulated to occur in the first decade of life , which we now know to be when h pylori colonization occurs . 
   a more detailed model , published in 1988 , included what was known of the phenotypic markers accompanying these sequential changes . 
   correa initially thought that the agent(s ) responsible for promoting this slow progression from gastritis to cancer were environmental , based on studies of migrants from high gastric cancer risk areas . 
   for example , japanese immigrants to hawaii and european immigrants to the united states had been shown to have lower gastric cancer rates than their parents and grandparents , more similar to those of the native population where they settled.7 , 8 the prime environmental culprit originally was thought to be a diet high in salt and n - nitroso - compounds and low in micronutrients from fresh fruits and vegetables . 
   it was postulated that this led to the promotion of gastric mutagenesis and , together with hypochlorhydria , bacterial overgrowth , thereby contributing to further nitrosamine formation . 
   interestingly , in his 1988 publication , correa briefly discussed a possible role for campylobacter pylori , a newly discovered gastric bacterium , in the initiation of the disease . 
   correa s subsequent work has focused primarily on the role of h pylori in gastric cancer , and this model has stood the test of time ( figure  2 ) . for his outstanding contributions to the field of gastric carcinogenesis , 
   the third pathologist of note is robin warren from australia who , together with barry marshall , was awarded the nobel prize in physiology or medicine in 2005 for the discovery of h pylori and its role in gastritis and peptic ulcer disease . in the 1970s , the widespread use of gastrointestinal endoscopy allowed pathologists 
   the opportunity to view gastric tissue that had been removed during a biopsy and fixed rapidly , without the artifacts inherent to the ischemia and autolysis of surgical specimens . 
   he then recruited marshall , a medical resident looking for a research project , to correlate the pathologic findings with the endoscopic features . 
   together , they discovered that these bacteria ( initially termed campylobacter pyloridis , then c pylori , and , subsequently , h pylori ) were very common in peptic ulcer patients . eventually , they successfully cultured these formerly elusive bacteria and showed that they caused gastritis and ulcer disease.11 , 12 , 13 , 14 in retrospect , other investigators also had observed such bacteria over the preceding century , but their clinical significance had not been appreciated and they had even been proven to be a post mortem artifact before their rediscovery in australia . although warren and marshall did not investigate the role of h pylori in gastric cancer directly , they were aware of the relationship between gastritis and cancer . 
   indeed , marshall speculated with amazing prescience in their very first publications ( in unusual side - by - side , single - author letters in 1983 ) that  if these bacteria are truly associated with antral gastritis , as described by warren , they may have a part to play in other poorly understood , gastritis associated diseases ( ie , peptic ulcer and gastric cancer ) . 
   initial investigations into a possible association of h  pylori with gastric cancer that were conducted in the 1980s and early 1990s provided only weak evidence for a link between h pylori and gastric cancer . a positive correlation between h pylori seroprevalence and gastric cancer in cross - sectional sampling 
   was reported in a study conducted among 13 european nations . however , although some other publications reported similar trends,17 , 18 several others did not find a positive correlation between the presence of h pylori antibodies and either gastric cancer or precancerous gastric lesions.19 , 20 , 21 , 22 around this time , clinicopathologic studies performed to look for evidence of h pylori infection ( by serum antibodies ) or in gastric tissue directly in cases of gastric cancer also yielded inconsistent results . 
   some studies showed h pylori infection rates no higher than those observed in noncancer controls . 
   this is most likely because by the time gastric cancer has developed , extensive intestinal metaplasia and hypochlorhydria had rendered the stomach less hospitable to persistent h pylori colonization , thus also explaining some of the negative findings in the cross - sectional studies discussed earlier . 
   much more convincing evidence for the role of h pylori in gastric cancer came from 3 large cohorts with nested case - controls , in which serum had been banked from cancer - free subjects and the cohort had been followed up for approximately a decade.24 , 25 , 26 in each cohort , evidence of prior h pylori infection ( evaluated by enzyme - linked immunosorbent assay [ elisa ] in the banked serum ) was found to be significantly more common in those subjects who subsequently developed gastric cancer compared with a sample of those who had not ( table  1 ) . in a meta - analysis , these 3 studies provided an overall odds ratio for gastric cancer development in h pylori  infected vs -uninfected persons of 3.8 ( 95% confidence interval [ ci ] , 2.36.2 ) . based on the compelling results of these cohort studies , the world health organization s international agency for research on cancer declared in 1994 that there was sufficient evidence to classify h pylori as a definite ( group 1 ) carcinogen . 
   this was despite the fact that at that time there was no significant supporting evidence from either animal models or mechanistic basic science research . 
   subsequent research worldwide has confirmed and expanded upon the early epidemiologic studies , with the key additional clinical findings as follows:1.cardia cancers are not associated strongly with h  pylori infection , supporting the idea that cardia cancers arise via alternative mechanisms , with risk factors more similar to cancers of the gastroesophageal junction and lower esophagus.2.in pooled meta - analysis , the odds ratio for h pylori in gastric cancer was no different when considering intestinal vs diffuse histologic cancer subtypes . 
   thus , in addition to promoting the well - established correa cascade of intestinal - type cancers , h pylori is just as great a risk factor for the much less well - defined pathway leading to diffuse - type gastric cancer.3.measuring h pylori exposure by elisa underestimates prior exposure and , therefore , the attributable h pylori risk in noncardia cancer , because of false - negative results . 
   for example , in a retrospective swedish case - control study , measuring prior exposure through a western blot against h pylori cytotoxin - associated gene a ( caga ) , rather than a conventional igg elisa , increased the odds ratio from 2.2 ( 95% ci , 1.43.6 ) to 21.0 ( 95% ci , 8.353.4).4.in noncardia gastric cancers , caga - positive h pylori strains ( which are the more common strains worldwide ) increase the risk of gastric cancer to a greater extent than do infections by the more rare caga - negative strains . 
   this is consistent with the oncogenic effects of the caga protein that have been evaluated mainly in  vitro.5.h pylori eradication can reduce the risk of developing gastric cancer ( see later ) . 
   cardia cancers are not associated strongly with h  pylori infection , supporting the idea that cardia cancers arise via alternative mechanisms , with risk factors more similar to cancers of the gastroesophageal junction and lower esophagus . in pooled meta - analysis , 
   the odds ratio for h pylori in gastric cancer was no different when considering intestinal vs diffuse histologic cancer subtypes . 
   thus , in addition to promoting the well - established correa cascade of intestinal - type cancers , h pylori is just as great a risk factor for the much less well - defined pathway leading to diffuse - type gastric cancer . 
   measuring h pylori exposure by elisa underestimates prior exposure and , therefore , the attributable h pylori risk in noncardia cancer , because of false - negative results . 
   for example , in a retrospective swedish case - control study , measuring prior exposure through a western blot against h pylori cytotoxin - associated gene a ( caga ) , rather than a conventional igg elisa , increased the odds ratio from 2.2 ( 95% ci , 1.43.6 ) to 21.0 ( 95% ci , 8.353.4 ) . in noncardia gastric cancers , caga - positive h pylori strains ( which are the more common strains worldwide ) increase the risk of gastric cancer to a greater extent than do infections by the more rare caga - negative strains . 
   this is consistent with the oncogenic effects of the caga protein that have been evaluated mainly in  vitro . 
   h pylori eradication can reduce the risk of developing gastric cancer ( see later ) . 
   in a prolonged observational study following patients who had attended a japanese endoscopy unit , uemura et  al showed that those who were h pylori  infected ( and  in whom the infection was not treated ) had a much higher rate of progression to gastric cancer over the  subsequent 12 years than the patients who had no  initial evidence of h pylori . 
   however , to prove conclusively that h  pylori is responsible for the increased gastric cancer risk , prospective interventional studies were necessary . 
   recruitment into such studies was hampered by the 1994 declaration of h pylori as a definite carcinogen , after which it became ethically problematic to enter patients into the control arms of eradication studies designed to determine the gastric cancer risk reduction . 
   consequently , an appropriately powered , definitive study of a large number of subjects followed up for many years to the end point of gastric cancer was never completed . nevertheless , recent meta - analyses of the many underpowered studies that were conducted are conclusive , indicating that h pylori eradication decreases the risk of gastric cancer development by approximately 40% in studies of primary prevention ( asymptomatic individuals ) , and by 54% as a tertiary prevention strategy ( preventing the occurrence of a second gastric malignancy after endoscopic resection of an early gastric cancer).36 , 37 it is not known whether or not there is a point of no return along the correa pathway , beyond which h pylori eradication will not prevent progression to gastric cancer . in the analysis by lee et  al , which included 24 publications of more than 48,000 individuals followed up for more than 340,000 person - years ( 14 studies of primary prevention , 10 studies of tertiary prevention ) , the benefit of h pylori eradication was , not surprisingly , most evident in subjects living in areas with the highest gastric cancer prevalence . 
   because all investigations were conducted in parts of the world where gastric cancer is most prevalent ( mostly in south - east asia ) , it is uncertain if similar reductions can be extrapolated to regions where noncardia gastric cancer is less common , such as the united states . 
   however , it may be reasonable to suppose that high - risk populations in low - risk countries , including immigrants from central and south america and  south - east asia to the united states who remain h  pylori  infected from childhood , should benefit greatly from h pylori eradication too . 
   however , with the exception of endoscopic screening in south korea , and radiologic and endoscopic programs in japan , there had been little effort made previously to control this burden with public health programs . 
   the results of the recent intervention studies reported earlier have now prompted renewed interest in screening for h pylori and eradicating the organism when found as a potentially cost - effective strategy , especially in parts of the world that have a high prevalence of h pylori and gastric cancer.39 , 40 , 41 a pilot study of mass population screening and eradication started in the matsu islands of taiwan in 2004 , and the initial results are very promising . gastric cancer incidence has decreased by approximately 25% , peptic ulcers by two thirds , and gastric atrophy by 77% compared with historical data . 
   several other population - based trials are underway , including one with almost 100,000 chinese subjects from linqu county , a region of high gastric cancer prevalence . 
   the eradication of h pylori from a community should help prevent much gastric cancer , as well as greatly diminish the morbidity of peptic ulcers too . 
   it has been calculated that the number needed to treat to prevent a case of gastric cancer may be as low as 15 in chinese men , to as high as 245 in women in the united states . although there is a concern regarding the ecologic consequences of using multiple antibiotics in a large proportion of the population to prevent h pylori  related disease , the recent exciting results of vaccination against h pylori with an oral urease b  construct suggest that a nonantibiotic strategy may be possible in the future , with potentially less impact on the general human microbiome . 
   further investigation of this vaccine should be a priority , particularly because promising preclinical models with a variety of vaccine candidates since the 1990s had never resulted previously in impressive results in clinical trials . 
   if preventive or therapeutic vaccination emerges as a viable alternative for h pylori eradication , it will help avert widespread antibiotic administration and the consequent problems of microbiome perturbation and the generation of microbial antibiotic resistance among h pylori and other innocent bystander bacteria . 
   in the midst of growing optimism for implementing h  pylori eradication strategies in high gastric cancer risk regions , it is important to recognize that there is considerable hesitation to adopt similar approaches in the developed world , mainly out of concern for a beneficial effect of h  pylori on esophageal diseases . 
   the results of multiple studies have indicated that h  pylori is significantly less common in patients with esophageal adenocarcinoma than in matched controls , although h pylori infection has no association , positive or negative , with esophageal squamous cancer47 , 48 ( figure  3 ) . 
   this places h pylori in a unique position among the world health organization s list of biological agents that cause cancer , in that its presence is associated positively with certain cancers ( gastric noncardia adenocarcinoma , gastric marginal zone b - cell lymphoma ) although related inversely to another cancer type ( esophageal adenocarcinoma ) . 
   the absence of h pylori may promote more severe esophageal mucosal damage , barrett s metaplasia , and the consequent development of esophageal adenocarcinoma . 
   a postulated mechanism is through a greater gastric acid secretory capacity from a pristine , uninflamed , parietal cell mass in the absence of h pylori gastritis , although there is little evidence that this actually leads to enhanced esophageal acid exposure . 
   an inverse relationship between h pylori and esophageal adenocarcinoma does not necessarily imply that h pylori is protective any more than a positive association can be taken to be evidence of causation . 
   h pylori has been an almost universal inhabitant of the human stomach from the dawn of mankind until the 1980s . 
   its recent disappearance from the 21st human microbiome , one of the  missing microbes ,  has been linked to extragastric immune dysregulation ( for which there is good evidence from animal models ) and a multitude of other contemporary maladies ( eg , asthma , obesity , and inflammatory bowel disease ) , for which the evidence is questionable and the biological plausibility equally uncertain.55 , 56 , 57 the decrease in noncardia gastric cancer in north america and western europe over the past 100 years that coincided with ( or maybe even preceded ) decreasing h  pylori prevalence , was famously described as the  epidemiology of an unplanned triumph .  the rapid increase in esophageal adenocarcinoma in the same population more recently ( such that it is now approaching the prevalence of noncardia gastric cancer ) perhaps may be considered the unplanned downside of the disappearance of h pylori from western stomachs . 
   it is this unexpected accompaniment of h pylori eradication that largely has tempered enthusiasm for population - based h pylori eradication efforts in the developed world . whether to pursue population - based h  pylori screening and treatment strategies 
   therefore will need to be individualized according to the current and projected future medical needs of each community , and these differ quite markedly around the globe . 
   the declaration of h pylori as a definite gastric carcinogen in 1994 and the subsequent realization that the vast majority of noncardia cancers are attributable to h pylori infection has led to a fundamental change in the way that we view gastric cancer pathogenesis in the funderburg era . considering gastric cancer as the consequence of an infection has led to enthusiasm for screening for and eradicating h pylori in areas of high gastric cancer prevalence , but the fact that gastric cancer remains a rare consequence of h  pylori infection provides plenty of opportunity for investigating the co - factors that promote gastric neoplastic development after h pylori colonization . 
   recent research in this field has focused on genetic susceptibility ( such as polymorphisms in genes governing gastric inflammatory responses ) , h pylori heterogeneity , and on other environmental influences , such as dietary salt or the presence of non - helicobacter species within the gastrointestinal microbiome that may explain why only a small proportion of individuals who are colonized by h  pylori go on to develop gastric cancer . 
   this knowledge ultimately may have clinical utility in stratifying individuals with h pylori infection into high vs low gastric cancer risk , and to the creation of personalized surveillance , chemoprevention , and dietary intervention programs focused on patients at highest risk . 
   as an example , an early study reported enormous differences ( up to 90-fold ) in gastric cancer susceptibility in h pylori  infected cases from portugal , when stratified by polymorphisms in interleukin 1 and the interleukin 1receptor antagonist , together with h pylori vacuolating cytotoxin a ( vaca ) and caga typing . 
   investigating the precise molecular and cellular mechanisms of gastric cancer development associated with h pylori infection is likely to provide additional insights into gastric cancer , as well as stimulate ideas about the pathogenesis of other cancers that are known to be associated with inflammation , although not necessarily with specific constituents of the microbiome . 
   since 1994 , considerable progress has been made on dissecting the role of h pylori role in the molecular pathogenesis of inflammation - associated gastric cancer ( as outlined in the review by crowe in this issue ) . 
   the multiplicity of animal models to study h pylori  associated gastric carcinogenesis ( reviewed in tsukamoto et  al and krueger et  al , as well as by wang in this issue ) also has provided many important mechanistic insights that were not conceivable back in 1994 , when rodent infection studies were in their infancy and the evidence for h pylori as a carcinogen was based on a limited number of clinical studies . 
   support from the funderburg family has been instrumental in promoting new ideas about gastric cancer and its origins , as well as opening new therapeutic possibilities . 
   the work that started in our laboratory in 2002 as a result of this funding has allowed us to investigate how h pylori misregulates the expression of p27 , a cyclin - dependent kinase inhibitor that is an important constitutive endogenous cell - cycle regulator.67 , 68 we also subsequently explored the p27-deficient mouse as a model with which to study the mechanisms of h pylori  induced gastric carcinogenesis,69 , 70 and to examine its reversibility after h  pylori eradication . 
   our understanding of gastric carcinogenesis continues to grow rapidly . for many years , pathologists were at the cutting edge of this knowledge , based on their meticulous observations of the unfortunate patients who died of this largely untreatable disease . 
   the realization that a single bacterial species was the inciting cause of the majority of gastric cancers went against the prevailing clinical and scientific dogma . as a result of this initially uncomfortable discovery , gastric cancer , which was a disease that formerly was principally the focus of pathologists and surgeons , 
   has become widely embraced by the scientific and clinical community as a model of bacterial carcinogenesis and a window to inflammation - associated cancers in general .
summary: gastric cancer has long been recognized to be accompanied and preceded by chronic gastritis , lasting decades . 
   arguably , the most important development in our understanding of gastric cancer pathogenesis over the past 50 years has been the realization that , for most cases of gastric cancer , helicobacter pylori is the cause of the underlying gastritis . 
   gastritis can promote gastric carcinogenesis , typically via the correa cascade of atrophic gastritis , intestinal metaplasia , and dysplasia . 
   nested case - control studies have shown that h pylori infection increases the risk of gastric cancer significantly , both of the intestinal and diffuse subtypes , and that h pylori is responsible for approximately 90% of the world s burden of noncardia gastric cancer . based largely on randomized studies in high gastric cancer prevalence regions in east asia 
   , it appears that primary and tertiary intervention to eradicate h pylori can halve the risk of gastric cancer . 
   some public health authorities now are starting screening and treatment programs to reduce the burden of gastric cancer in these high - risk areas . 
   however , there is currently much less enthusiasm for initiating similar attempts in the united states . 
   this is partially because gastric cancer is a relatively less frequent cause of cancer in the united states , and in addition there are concerns about theoretical downsides of h pylori eradication , principally because of the consistent inverse relationship noted between h pylori and esophageal adenocarcinoma . nevertheless , 
   establishing a link between chronic h pylori infection and gastric cancer has led to novel insights into cancer biology , the gastrointestinal microbiome , and on individual and population - based gastric cancer prevention strategies .