Causal role of Helicobacter pylori infection in gastric cancer

Gastric cancer is the second most frequent cancer in the world, accounting for a large proportion of all cancer cases in Asia, Latin America, and some countries in Europe. Helicobacter pylori(H pylori) is regarded as playing a specific role in the development of atrophic gastritis, which represents the most recognized pathway in multistep intestinal-type gastric carcinogenesis. Recent studies suggest that a combination of host genetic factors, bacterial virulence factors, and environmental and lifestyle factors determine the severity of gastric damage and the eventual clinical outcome of H pylori infection. The seminal discovery of H pylori as the leading cause of gastric cancer should lead to effective eradication strategies. Prevention of gastric cancer requires better screening strategies to identify candidates for eradication.     

Molecular alteration of gastric carcinoma

Gastric cancer is constituted by two histomorphological entities 'intestinal' and 'diffuse' that differ in epidemiology, pathogenesis, clinical outcome and genetic profile. Two distinct molecular pathways of genomic destabilization have been identified in gastric carcinogenesis: the microsatellite mutator phenotype (MMP) and a phenotype associated with chromosomal and intrachromosomal instability (CIN). The microsatellite mutator phenotype is caused by mismatch repair (MMR) deficiency and is associated with mutational inactivation; this condition is identified as microsatellite instability (MIN). CIN is characterized by chromosomal rearrangements and losses or gains of chromosomes, which in turn can induce oncogene activation and/or tumour-suppressor-gene inactivation. Mounting evidence suggests that MMP alterations, DNA aneuploidy and expression of the products of cancer-related genes are early markers of cell transformation, and may serve to identify the genetic pathway of gastric carcinoma. However, the lack of a clear genetic basis lends weight to the notion that gastric cancer may be affected by exposure to environmental factors. Helicobacter pylori is one of the most frequent infections worldwide and is the most important environmental risk factor associated with sporadic gastric cancer. Exposure of gastric epithelial cells to H. pylori results in the generation of reactive oxygen species and an increased level of inducible nitric oxide synthase that in turn may cause genetic alterations leading to cancer in a subset of subjects. In conclusion gastric cancer is the result of an interplay between genetic and environmental factors. The new technologies for the molecular analysis will be a useful tool to understand the individual's risk and settle novel biological therapeutic strategies.     

Role of Helicobacter pylori infection in pathogenesis of gastric carcinoma

Gastric cancer(GC) is one of the most common carcino-ma and the second leading cause of cancer-related deaths worldwide. Helicobacter pylori(H. pylori) infection causes a series of precancerous lesions like gastritis, atrophy, intestinal metaplasia and dysplasia, and is the strongest known risk factor for GC, as supported by epidemiological, preclinical and clinical studies. However, the mechanism of H. pylori developing gastric carcinoma has not been well defined. Among infected individuals, approximately 10% develop severe gastric lesions such as peptic ulcer disease, 1%-3% progresses to GC. The outcomes of H. pylori infection are determined by bacterial virulence, genetic polymorphism of hosts as well as environmental factors. It is important to gain further understanding of the pathogenesis of H. pylori infection for developing more effective treatments for this common but deadly malignancy. The recent findings on the bacterial virulence factors, effects of H. pylori on epithelial cells, genetic polymorphism of both the bacterium and its host, and the environmental factors for GC are discussed with focus on the role of H. pylori in gastric carcinogenesis in this review.     

Simultaneous Occurrence of Gastric Carcinoma in Identical Twins

Gastric carcinoma is a rare entity in twins at any age. A 31-year old black male presented with a nine-month history of epigastric pain and was found to have cancer of the stomach. His asymptomatic twin was therefore evaluated and also found to have gastric carcinoma. Both patients underwent gastric resection. Pathologically the cancers were similar, although the associated changes of the gastric mucosa showed some remarkable differences. The uniqueness of carcinoma in twins has resulted in extensive utilization of twin studies in an attempt to clarify genetic, environmental and immunological factors in the development of cancer. The results of these studies reported in the literature, however, are inconclusive. Gastric cancer is quite uncommon in the younger population but must be promptly excluded when symptoms do not quickly respond to usual therapy.     

Treatment of Helicobacter pylori and prevention of gastric cancer

Gastric cancer is the second commonest fatal malignancy in the world with a high incidence in China. Helicobacter pylori infection is an important factor in the pathogenesis of gastric cancer. Epidemiological studies have shown a strong causal relationship between H. pylori infection and gastric cancer. Animal studies also show that eradication of H. pylori infection, especially at the early stage, is effective in preventing H. pylori-related gastric carcinogenesis. H. pylori eradication leads to regression and prevents the progression of gastric precancerous lesions, but only in a minority of cases. H. pylori eradication appears to be the most promising approach in gastric cancer prevention. The current available data in human studies showed that H. pylori eradication can reduce the risk of developing gastric cancer and this strategy is more useful in patients without atrophic gastritis or intestinal metaplasia. A longer follow-up and additional studies are needed for better understanding this issue.     

Is screening for and surveillance of atrophic gastritis advisable?

Gastric cancer remains a leading cause of cancer-related deaths in many parts of the world. At present, prevention seems to be the most effective means to reduce its the incidence and mortality rate. Gastric atrophy is considered the first relevant step in the histogenesis of gastric adenocarcinoma. However, whether screening for and surveillance of atrophic gastritis is advisable is debated. The prevalence and pattern of chronic atrophic gastritis varies greatly from country to country, being higher and mainly diffuse pangastritis or localized in those countries with a high gastric cancer incidence. The only method available to detect gastric atrophy is histopathological examination of endoscopic specimens, but there is no consensus about diagnosis. Serum gastric secretion may be a marker of gastric atrophy, although it has high specificity but low sensitivity. Gastric atrophy is mainly related to chronic Helicobacter pylori (H. pylori) infection. Thus, the only effective strategy for gastric cancer prevention is eradication of H. pylori infection to arrest atrophy progression in selected populations. In conclusion, there is insufficient evidence to suggest screening for and surveillance of atrophic gastritis in the general population; however, this strategy should be applied in countries with a high incidence of gastric cancer.     

Dietary habits and epidemiology of gastric carcinoma

Gastric carcinoma has been the primary cause of cancer incidence worldwide until the early eighties. However, its incidence and mortality rates have been declining in most areas of the world over the last decades. This pattern of trends may reflect important changes in lifestyle linked to socioeconomic factors (refrigeration of stored foods, water supply, decline of infections and dietary habits). This article reviews the changing epidemiology of gastric carcinoma including time trends, pathological considerations, and international distribution as well as the main methodological difficulties of the studies about the relationships between dietary habits and gastric carcinoma.     

Diet, Hpylori infection and gastric cancer： Evidence and controversies

Despite decreasing incidence and mortality rates, gastric cancer (GC) still remains the fourth most common cancer and the second most common cause of cancer-related deaths worldwide. Due to the limited treatment options, at present, prevention is likely to be the only effective means of controlling this disease. The success of a prevention strategy depends upon the understanding of etiological and pathogenic mechanisms underlying gastric carcinogenesis. The etiology of GC is multi-factorial, however, in the recent years, mounting evidence suggests that environmental factors play a key role. The most important environmental factors implicated in the pathogenesis of GC are diet and H pylori infection. Thus, modifications in lifestyle and dietary habit associated with eradication of H pylori infection could hypothetically represent the most promising potential targets for GC prevention. In this review we will address the evidence and the controversies on the role of these agents in noncardia GC by focusing on retrospective and prospective observational studies and interventional trials.     

Familial 'minor' adenomatous polyposis coli associated with gastric carcinoma - a hiterto undescribed phenotype of polyposis coli?

A clinical study of a family (Sch.) with a high incidence of death from gastric cancer in the second generation is presented. Endoscopic and/or surgical evaluation of the stomach, upper small intestine, and colon in 14 mainly asymptomatic members of the third and fourth generations revealed single or multiple (solitary) papillary adenomas in the colon or jejunum in 2 members each of the two generations. In addition, single or multiple hyperplastic polyps in the stomach or colon were found in 5 members, in 4 of them in association with papillary adenomas. The findings in family Sch. are consistent with 'minor' adenomatous polyposis coli associated with gastric carcinoma. Gastric carcinoma probably represents another phenotype among the vast variety of extra-colonic and extra-alimentary neoplastic changes known to occur in association with familial polyposis coli (FPC). The relationship of hyperplastic polyps to papillary adenoma in the colon and to gastric carcinoma respectively is discussed. Finally, evidence for a genetic relationship between family Sch. and a case with probable FPC is presented.     

Genes and gastric cancer

Gastric cancer remains quite a common malignancy and counts among the most important causes of cancer-related death worldwide. Although the pathogenesis is multifactorial, familial aggregation in a significant proportion of cases suggests the importance of genetic predisposition. The association between the E-cadherin/CDH1 gene germline mutations and the development of diffuse gastric cancer was the first evidence for a molecular basis of gastric cancer in predisposed families and led many authorities in the world to produce guidelines regarding the management of such families members. The recent advances in genetics resulted in the discovery of numerous genetic events occurring during the course of gastric carcinogenesis (activation of oncogenes, silencing of tumor suppressor genes, mutations in DNA-repairing genes) and contributed to a better understanding in pathogenesis. Many genetic changes described have been found to affect tumor's biological behavior. In this article the authors attempt a review of all the molecular alterations in gastric cancer described in the literature and their impact on the management of patients with an inherited predisposition to gastric cancer. The promising role of gene therapy in the treatment of gastric cancer in the near future is also commented on.     

从临床病理学角度看胃癌的预防

胃癌在病理学上是一种具有异质性且恶性程度极高的恶性肿瘤,是危及国人健康的元凶之一。目前关于胃癌的发生机制仍不清楚。通过越来越多的临床、病理、流行病学、基因学研究结果,可以将胃癌分为三大类：近端胃贲门癌、非近端胃癌、弥漫浸润型胃癌,其发病机制和致癌因子各不相同。在中国,大多数胃癌为非近端胃癌,主要发生在远端胃的胃窦、胃角等部位,多为幽门螺杆菌感染所致,其可以通过改变不良生活方式、全民戒烟、改善环境等措施加以预防。对高危人群,应进行年度胃镜检查和活检,按胃黏膜上皮病变程度和性质对患者进行适当的内镜监控和治疗,以期尽早检出早期胃癌并进行根治,防止其进展至晚期胃癌,从而大幅延长患者生存率,提高患者的生活质量。这是一个需要患者与医务人员相互配合、长期坚持的系统工程。     

A candidate gene approach of immune mediators effecting the susceptibility to and severity of upper gastrointestinal tract diseases in relation to Helicobacter pylori and Epstein-Barr virus infections

This review focuses on immunogenetic aspects of diseases of the upper gastrointestinal tract in which infectious agents may play a role in the aetiopathogenesis, such as Helicobacter pylori, Epstein-Barr virus (EBV) and HIV. Gastric adenocarcinoma is a common cancer all around the world, with declining incidences in Europe and high incidences in Asia and central and south America. Together with gastric atrophy and peptic ulcer disease, gastric adenocarcinoma belongs to the commonest upper gastrointestinal tract diseases. These diseases are multifactorial and factors such as smoking and dietary habits contribute to the pathogenesis. More recently, scientists have turned their eyes on the host. Functional polymorphisms in the genes regulating the host immune system may contribute to the susceptibility to and progression of disease. In multifactorial and polygenetic diseases, candidate gene studies of single nucleotide polymorphisms (SNPs) detect small to moderate relative risks. Unfortunately, only a few functional SNPs have been identified. The candidate gene approach can be seen as a useful first step in exploring causal pathways between genetic determinants and complex diseases such as those mentioned above. To date, little is known about the immunogenetics of upper gastrointestinal tract diseases. We review the literature on H. pylori, EBV and gene polymorphisms that affect key immune mediators influencing the pathogenesis of the inflammatory response, such as the genes that code for the IL-1 family, TNF-alpha, lymphotoxin alpha, and IL-10. IL-1, IL-10, lymphotoxin alpha and TNF-alpha polymorphisms increase the risk of upper gastrointestinal pathogenesis in H. pylori-infected patients, whereas IL-1 and TNF-alpha polymorphisms confer risk in EBV-infected patients.     

Helicobacter pylori and gastric cancer

Gastric cancer despite a declining incidence remains a significant cause of morbidity and mortality world wide. There is strong epidemiological and histological evidence to associate Helicobacter pylori infection with the subsequent development of gastric cancer. The exact pathophysiological mechanisms involved remain to be elucidated. There is evidence to relate Helicobacter pylori infection and subsequent inflammation with an increase in gastric epithelial cell proliferation and with the induction of apoptosis. Such alterations in cellular dynamics may promote the development of mitogenic cell lines by inducing DNA damage. Studies have shown that following successful treatment, proliferation rates return to normal. At what histological stage, eradication is of benefit is less clear. It is likely that following the development of atrophy or intestinal metaplasia eradication will only slow progression. It would, therefore, seem logical, that to establish any benefit for a population, treatment should be employed at an earlier stage. As yet, an at risk group has not been identified, and as such population screening cannot be advised, mainly as a result of financial implications and the risk of promoting the development of resistant strains. Recent studies have explored the rules of bacterial factors, CagA and VacA status, host factors, HLA type, and environmental factors as determinants of outcome. Results have been variable. The establishment of an at risk group would enable selective screening and treatment, and thus prevent the development of gastric carcinoma as a result of Helicobacter pylori infection in the long-term.     

Helicobacter pylori and gastric cancer: the causal relationship

Gastric cancer has been recognized as an important cause of morbidity and mortality all over the world. Helicobacter pylori has been shown to have a causal relationship to gastric cancer. The knowledge into the mechanisms related to this has advanced considerably over the last few years thereby unarguably defining the role of this host-pathogen interaction. Epidemiological studies, research in animal models, molecular pathways involving host and bacterial factors, environmental factors and recent work on stem cells have contributed to understanding the origin and progress of this neoplasia. These form part of the myriad of interplaying factors resulting in the causal relationship. Nevertheless, current evidence is insufficient to accurately identify a definitive population where prevention or treatment strategies have to be targeted. Future trials will have to define the people at risk and shed more light in these areas.     

Helicobacter pylori and risk for gastric adenocarcinoma

Gastric cancer is the second most common cause of cancer death in the world. Helicobacter pylori infection is now a well-accepted cause of this malignancy; in some parts of the world, up to eighty percent of all gastric cancers are at least in part caused by H. pylori infection. H. pylori infection typically starts in childhood as an inflammatory process in the stomach. The changes in the gastric microenvironment facilitate gastric cancer over time. Among infected individuals, genotype of H. pylori, coincident environmental exposures, and genetic factors of host seem to play roles in determining who will get gastric cancer and who will not. Unfortunately, it remains unknown whether treatment of H. pylori prevents gastric cancer. Thus, screening for H. pylori to prevent cancer is not yet widely recommended. Some consensus groups, however, have recommended screening for and treating H. pylori infection in individuals with family histories of gastric malignancy. In high-risk countries, screening programs for early gastric cancer itself may improve therapeutic outcome for this highly lethal disease.     

Helicobacter pylori et néoplasies gastriques

Helicobacter pylori is a major carcinogen that causes gastric MALT (mucosa associated lymphoid tissue) lymphoma and gastric adenocarcinoma, both of which may exist simultaneously. Gastric MALT lymphoma may subside after eliminating the gastric infection. The role of H. pylori in the progression from gastritis to gastric cancer has been established by epidemiologic studies, animal models, and the observation of its actions in atrophic gastritis development, hypochlorhydria and mutagenesis. Various factors are involved in the disease processes, including bacterial (cag pathogenicity island), environmental (alimentary) and host genetic factors (inflammatory cytokine polymorphisms). In cancer prevention, H. pylori treatment is indicated when there is a family history of gastric cancer and after partial gastric resection for cancer. Other groups at risk of gastric neoplasia are discussed.     

Mouse models for gastric cancer: Matching models to biological questions

Gastric cancer is the third leading cause of cancer‐related mortality worldwide. This is in part due to the asymptomatic nature of the disease, which often results in late‐stage diagnosis, at which point there are limited treatment options. Even when treated successfully, gastric cancer patients have a high risk of tumor recurrence and acquired drug resistance. It is vital to gain a better understanding of the molecular mechanisms underlying gastric cancer pathogenesis to facilitate the design of new‐targeted therapies that may improve patient survival. A number of chemically and genetically engineered mouse models of gastric cancer have provided significant insight into the contribution of genetic and environmental factors to disease onset and progression. This review outlines the strengths and limitations of current mouse models of gastric cancer and their relevance to the pre‐clinical development of new therapeutics.     

A review of the genomics of gastric cancer.

Gastric cancer is the fourth most common cancer and the second leading cause of cancer-related death in the world. Over the past 2 decades, many exciting discoveries regarding the genomics of gastric cancer have been made. There are 2 distinct histologic types of gastric adenocarcinoma, and these types differ in their epidemiology, pathogenesis, genetic profile, and clinical outcome. The development of new approaches to functional genomics has significantly improved our ability to explore molecular alterations underlying gastric carcinogenesis and progression. The pathogenesis of intestinal-type gastric cancer follows a multistep progression that usually is initiated by H pylori infection. A wide range of genetic and epigenetic abnormalities including point mutation, loss of heterozygosity, microsatellite instability, and hypermethylation are described in intestinal-type gastric cancer and its precursor lesions. In contrast to the intestinal-type, diffuse-type gastric cancer is defined by a lack of precursor lesions; mutation or epigenetic silencing of the E-cadherin gene appears to be the key carcinogenic event. An improved understanding of the genomics of gastric cancer should lead to the rapid development of novel diagnostic techniques and molecular-based treatment strategies.     

New concepts of molecular biology on gastric carcinogenesis

Gastric cancer not located in the cardia still remains the second most common cancer worldwide, whereas adenocarcinoma of the cardia and gastroesophageal junction has been rapidly rising over the past two decades. Gastric cancer can be subdivided into two distinct pathologic entities, diffuse and intestinal, that have different epidemiologic and prognostic features. Various genetic and environmental factors play important roles in gastric carcinogenesis; both lead to either abnormal genes overexpression or inappropriate expression of normal genes, whose products confer the malignant phenotype. Advances have been made in the genetic changes mostly of the intestinal type; its development is probably a multistep process, as has been well described in colon cancer pathogenesis, whereas it remains tentative whether the diffuse type of malignancy follows an analogous progression. The most common genetic abnormalities in gastric cancer tend to be loss of heterozygosity of tumor suppressor genes, particularly of p53 or "Adenomatous Polyposis Coli" gene. The latter leads to gastric oncogenesis through changes related to E-cadherin-catenin complex, which plays a critical role in the maintenance of normal tissue architecture. Mutation of any of its components results in loss of cell-cell adhesion, thereby contributing to neoplasia. E-cadherin/CDH1 gene germline mutations have been recognized in families with an inherited predisposition to gastric cancer of the diffuse type. Amplification and/or overexpression of putative trophic factors have also been observed in gastric cancer. Finally, Helicobacter pylori (H. pylori) infection is also involved in gastric carcinogenesis through various mechanisms, thereby necessitating H. pylori eradication in patients with gastric cancer.     

Role of gene polymorphisms in gastric cancer and its precursor lesions:Current knowledge and perspectives in Latin American countries

Latin America shows one of the highest incidence rates of gastric cancer in the world,with variations in mortality rates among nations or even within countries belonging to this region.Gastric cancer is the result of a multifactorial complex process,for which a multistep model of carcinogenesis is currently accepted.Additionally to the infection with Helicobacter pylori,that plays a major role,environmental factors as well as genetic susceptibility factors are significant players at different stages in the gastric cancer process.The differences in population origin,demographic structure,socio-economic development,and the impact of globalization lifestyles experienced in Latin America in the last decades,all together offer opportunities for studying in this context the influence of genetic polymorphisms in the susceptibility to gastric cancer.The aim of this article is to discuss current trends on gastric cancer in Latin American countries and to review the available published information about studies of association of gene polymorphisms involved in gastric cancer susceptibility from this region of the world.A total of 40 genes or genomic regions and69 genetic variants,58%representing markers involved in inflammatory response,have been used in a number of studies in which predominates a low number of individuals(cases and controls)included.Polymorphisms of IL-1B(-511 C/T,14 studies;-31 T/C,10 studies)and IL-1RN(variable number of tandem repeats,17 studies)are the most represented ones in the reviewed studies.Other genetic variants recently evaluated in large metaanalyses and associated with gastric cancer risk were also analyzed in a few studies[e.g.,prostate stem cell antigen(PSCA),CDH1,Survivin].Further and better analysis centered in gene polymorphisms linked to other covariates,epidemiological studies and the information provided by meta-analyses and genome-wide association studies should help to improve our understanding of gastric cancer etiology in order to develop appropriate health programs in Latin America.