Nature meets nurture: molecular genetics of gastric cancer

Hum Genet (2009) 126:615–628 DOI 10.1007/s00439-009-0722-x REVIEW PAPER Nature meets nurture: molecular genetics of gastric cancer Anya N. Milne · F. Carneiro · C. O’Morain · G. J. A. OVerhaus Received: 19 June 2009 / Accepted: 16 July 2009 / Published online: 6 August 2009 © The Author(s) 2009. This article is published with open access at Springerlink.com Abstract The immensity of genes and molecules implicated in gastric carcinogenesis is overwhelming and the relevant importance of some of these molecules is too often unclear. This review serves to bring us up-to-date with the latest Wndings as well as to look at the larger picture in terms of how to tackle the problem of solving this multipiece puzzle. In this review, the environmental nurturing of intestinal cancer is discussed, beginning with epidemiology (known causative factors for inducing molecular change), an update of H. pylori research, including the role of inXammation and stem cells in premalignant lesions. The role of E-cadherin in the nature (genotype) of diVuse gastric cancer is highlighted, and Wnally the ever growing discipline of SNP analysis (including IL1B) is discussed. A. N. Milne (&) · G. J. A. OVerhaus Pathology Department H04.2.25, University Medical Centre Utrecht, Postbus 85500, 3508GA Utrecht, The Netherlands e-mail: a.n.a.milne@umcutrecht.nl F. Carneiro Institute of Molecular Pathology and Immunology, University of Porto (IPATIMUP), Porto, Portugal F. Carneiro Medical Faculty, Hospital S. João, Porto, Portugal C. O’Morain Department of Gastroenterology, Adelaide and Meath Hospital, Dublin, Ireland G. J. A. OVerhaus Department of Pathology, Academic Medical Centre, Amsterdam, The Netherlands Introduction Gastric cancer (GC) is a worldwide health burden (Jemal et al. 2007) with little hopeful progress. Even after a curative resection alone or after adjuvant therapy, nearly 60% of those patients aVected succumb to GC (Macdonald et al. 2001; Bonenkamp et al. 1999; de Maat et al. 2007). Despite tremendous advances in the past few decades, there are still no tools to address the inherent molecular heterogeneity of GC that expresses itself in divergent clinical biology. The age-old debate of whether diseases are inherited (“nature”) or occur as a result of environmental inXuences (“nurture”) has been resolved to a certain extent, and we now acknowledge that environment and genetics have a delicate interplay which varies between sexes, individuals and ethnic backgrounds, providing in each individual a unique environment for cancer growth or suppression. The relative importance of nature versus nurture can however vary with tumour type, and it is long known that the impact of environmental triggers can be seen at gene level. With this knowledge and the age of personalized medicine, the importance of the crucial relationship between nature and nurture is ever increasing. Gastric cancer is thought to result from a combination of environmental factors and the accumulation of generalized and speciWc genetic alterations, and consequently aVects mainly older patients often after a long period of atrophic gastritis. The commonest cause of gastritis is infection by H. pylori, which is the single most common cause of gastric cancer (Forman et al. 1991; Parsonnet et al. 1991) and has been classiWed by the WHO as a class I carcinogen since 1994 (IARC monographs 1994; Suerbaum and Michetti 2002) and the causal role has been extensively studied in animal models (Watanabe et al. 1998). The risk of infection varies with age, geographical location and ethnicity, but overall 15–20% of infected patients 123 616 develop gastric or duodenal ulcer disease and less than 1% will develop gastric adenocarcinoma (Suerbaum and Michetti 2002). The pattern of gastritis has also been shown to correlate strongly with the risk of gastric adenocarcinoma. The presence of antral-predominant gastritis, the most common form, confers a higher risk of developing peptic ulcers; whereas, corpus predominant gastritis and multifocal atrophic gastritis leads to a higher risk of developing gastric ulcers and subsequent gastric cancer (Watanabe et al. 1998; Craanen et al. 1992). The response to H. pylori infection and the subsequent pattern of gastritis depends on the genotype of the patients and in particular a polymorphism in interleukin 1 beta, an inXammatory mediator triggered by H. pylori infection, is known to be of importance as will be discussed (El-Omar et al. 2000). The most commonly used classiWcations of GC are the World Health Organization (WHO) (Hamilton and Aaltonen 2000) and the Laurén classiWcations which describes two main histological types, diVuse and intestinal (Lauren 1965), which have diVerent clinicopathological characteristics. DiVuse cancer occurs more commonly in young patients, can be multifocal, is not often accompanied by intestinal metaplasia and can be hereditary, as will be discussed in detail below (Matley et al. 1988; Kokkola and Sipponen 2001; Lim et al. 2003; Furukawa et al. 1989; Carneiro et al. 2004). Intestinal type is more frequently observed in older patients and follows multifocal atrophic gastritis. This is usually accompanied by intestinal metaplasia and leads to cancer via dysplasia, and thus intestinal metaplasia is considered a dependable morphological marker for gastric cancer risk. Unlike intestinal gastric cancer, the diVuse type typically develops following chronic inXammation without passing through the intermediate steps of atrophic gastritis or intestinal metaplasia. Intestinal adenocarcinoma predominates in the high-risk areas whereas the diVuse adenocarcinoma is more common in low-risk areas (Hamilton and Aaltonen 2000). These clinicopathological factors suggest that the “nurture” component of intestinal GC is greater than that of diVuse GC and conversely that the “nature” aspect of diVuse GC may be stronger than that of intestinal-type GC. Previous reviews have given us an overview of the general state of GC research (Milne et al. 2007), and this current review serves to bring us up-to-date with the latest Wndings. Gastric carcinogenesis can be considered a multistep process involving generalized and speciWc genetic alterations that drive the progressive transformation of cells into cancer. In fact some have even tried to quantify the number of steps needed for various cancers, with GC averaging at 4.18 genomic alterations necessary (Nishimura 2008). Hanahan and Weinberg describe how virtually all mammalian cells carry a similar molecular machinery regu- 123 Hum Genet (2009) 126:615–628 lating their proliferation, diVerentiation, and death and suggest that there are six essential alterations in cell physiology that collectively dictate malignant growth (Hanahan and Weinberg 2000) and this framework can be applied to GC, as described previously (Milne et al. 2007). Despite the breadth of molecules, genes and indeed pathways implicated in GC, there are a few that stand out and deserve mention. In this review, the environmental “nurturing” of intestinal cancer is discussed, beginning with epidemiology (known causative factors for inducing molecular change), an update of H. pylori research, including the role of inXammation and stem cells in premalignant lesions. The role of E-cadherin in the “nature” (genotype) of diVuse gastric cancer is highlighted, and Wnally the ever growing discipline of SNP analysis (including IL1B), which can account for individual inherited cancer risk, is discussed. The “Nurture” component Epidemiology Cigarette smoking and H. pylori infection are classically associated with GC(Shikata et al. 2008), and diet is a known etiological factor, especially for intestinal-type adenocarcinoma whereby an adequate intake of fruit and vegetables appears to lower the risk with ascorbic acid, carotenoids, folates and tocopherols acting as antioxidants (Hamilton and Aaltonen 2000; Jenab et al. 2006a). It is possible that cereal Wbre intake may reduce the risk of adenocarcinoma, particularly diVuse type (Mendez et al. 2007), and the interplay of diet on genomic stability has been recognized (Young 2007), by showing that substances such as green tea can aVect methylation status of genes (Yuasa et al. 2009). It is said by some that salt intake strongly associates with the risk of gastric carcinoma and its precursor lesions (Pelucchi et al. 2009; Kato et al. 2006), and this risk is increased in certain genetically predisposed individuals (Chen et al. 2004), yet others refute the importance of salt as a risk factor (Sjodahl et al. 2008). Other foods associated with high risk in some populations include smoked or cured meats and Wsh, pickled vegetables and chilli peppers (Hamilton and Aaltonen 2000). Alcohol and occupational exposure to nitrosamines and inorganic dusts have been studied in several populations, but the results have been inconsistent (Hamilton and Aaltonen 2000) and the possible role of vitamin C remains under scrutiny (Jenab et al. 2006b). The incidence of gastric adenocarcinoma is declining worldwide, mainly due to decline of the intestinal type. There has also been a change in the anatomical distribution of this malignancy, with a fall in the incidence of mid and distal GC and a progressive increase in cardia cancer. This fall in incidence may be explained by the decline in Hum Genet (2009) 126:615–628 H. pylori infection and associated atrophic gastritis. Interestingly, H. pylori infection is a strong risk factor for non-cardia GC, but is inversely associated with the risk of gastric cardia cancer (Kamangar et al. 2006). Relatively high rates of cancer in the central/distal portions of the stomach among North American Indians and Alaska Natives in some geographic regions may indicate a disproportional burden of H. pylori-associated disease (Wiggins et al. 2008). There is a male predominance of GC which may be related to hormonal factors (Chandanos and Lagergren 2008), and this male predominance mainly relates to the intestinal type (Derakhshan et al. 2009). In addition, a further decrease of at least 24% in the incidence of gastric corpus cancer in the coming decade may be anticipated in Western countries without speciWc intervention (de Vries et al. 2007). On the other hand, because the risk of gastric cardia adenocarcinoma increases with higher BMI, growing obesity may explain the rising incidence of oesophageal and gastric cardia adenocarcinoma in the Western world (Merry et al. 2007). Long-term pharmacological gastric acid suppression is yet another marker of increased risk of oesophageal and gastric non-cardia adenocarcinoma (Garcia Rodriguez et al. 2006). These associations may be explained by the underlying treatment indication being a risk factor for the cancer rather than an independent harmful eVect of these agents per se although this is a subject of debate (Langman and Logan 2007; McColl 2006). InXammation and H. pylori One of the triumphs of 19th century biology was the understanding that neoplastic processes were diVerent and distinguishable from infectious or inXammatory processes (Rather 1978). From late in the 20th century, it has become increasingly clear that these processes are not as distinct as the histopathology had suggested. There are a variety of chronic inXammatory conditions (where no causal agents have been identiWed), e.g. Barrett oesophagus, chronic ulcerative colitis, as well as a variety of infectious conditions, such as chronic gastric infection with H. pylori and chronic viral hepatitis, that markedly elevate the risk of cancer. Chronic inXammation induces increased tissue turnover, which is thought to predispose to an excessive rate of proliferation, and in many cases results in more frequent mitotic errors and an increased rate of mutagenesis. Notably, Matsumoto et al. recently reported that H. pylori infection of the gastric epithelium induced the expression of the activation-induced cytidine deaminase (AID) gene (Matsumoto et al. 2007), a gene originally linked to immunoglobulin class switching and B lymphocyte hypermutation, but aberrantly expressed in cancer, where it may predispose to point mutations of the p53 tumour suppressor gene. Recent studies have also highlighted important roles 617 for speciWc immune cell populations (e.g., macrophages, T cells) and proinXammatory cytokines [e.g., interleukin (IL)1B, IL-6, tumour necrosis factor] in the pathogenesis of cancer (Fox and Wang 2007; Lin and Karin 2007). Although infection with H. pylori signiWcantly increases the risk of developing GC, the exact mechanism underlying the malignant transformation needs to be clariWed, but it is believed that the combination of a virulent organism, a permissive environment and a genetically susceptible host is necessary (Figueiredo et al. 2002; Machado et al. 2003; Amieva and El-Omar 2008; Egan et al. 2007). Molecular and cell biology approaches aimed at understanding the interaction between H. pylori and the transforming epithelial cell are the subject of intense research (Ferreira et al. 2008; Chiba et al. 2008), including new insights into the mechanisms by which H. pylori disrupts gastric barrier function via urease-mediated myosin II activation (Wroblewski et al. 2009). In addition, persistent inXammation is known to cause genetic instability through the generation of mutagenic substances such as reactive oxygen species (Baik et al. 1996; Farinati et al. 2008) and reactive nitrogen species (Fu et al. 1999) which may act to directly damage the host cell nuclear and mitochondrial DNA(Machado et al. 2009) and limit the mucosal defence by decreasing the antioxidant properties of the gastric mucosa (Sobala et al. 1993). Such a direct gastric mutagenic eVect through oxidative DNA damage in H. pylori infection has been shown in transgenic mouse models (Touati et al. 2003). Nitric oxide can also directly inXuence mitochondrial pathways of apoptosis (Mannick et al. 1999) and also potentially plays a role in multiple levels of cell signal transduction during H. pylori infection. Furthermore, bacterial factors may also directly induce apoptosis (Galmiche et al. 2000). The ultimate eVectors of apoptosis include an array of intracellular proteases termed caspases. Caspases are important in the life and death of immune cells and therefore inXuence immune surveillance of malignancies. Two “gatekeeper” caspases, caspase-8 and -9, are activated by death receptors such as FAS or by the cytochrome C released from mitochondria, respectively, and the Fas antigen pathway of apoptosis is recognized as the leading cause of tissue destruction during H. pylori infection (Cai et al. 2005). In fact, a six-nucleotide deletion (-652 6N del) variant in the CASP8 promoter has been found to be associated with decreased risk of lung cancer.(Sun et al. 2007) Further case–control analyses in a Chinese population showed that this genetic variant is associated with reduced susceptibility to multiple cancers, including lung, oesophageal, gastric, colorectal, cervical and breast cancers (Sun et al. 2007), supporting the hypothesis that genetic variants inXuencing immune status modify cancer susceptibility, and strengthening the argument that both nature and nurture are needed for carcinogenesis. 123 618 DiVerent strains of H. pylori vary in their carcinogenic potential, with those containing the virulence factor CagA inducing a greater degree of inXammation. CagA is delivered into gastric epithelial cells through a bacterial type IV secretion system, and interacts with several major growthregulating signal transduction pathways including the Ras/ MEK/ERK pathway (Mimuro et al. 2002) and the Src family of protein kinases (Tsutsumi et al. 2003). In addition, forms of cagA encoding multiple type C EPIYA segments (which increase phosphorylation-dependent CagA activity) have been shown and the number of cagA EPIYA-C segments relate to cancer risk amongst Western strains (Basso et al. 2008). Loss of cell polarity and tissue architecture is a hallmark of carcinomas that arise from epithelial cells. Studies on Drosophila tumour suppressors have provided evidence that epithelial polarity and cell proliferation are functionally coupled, suggesting a function for polarity defects in the development of carcinomas. It has been discovered that CagA speciWcally binds and inhibits PAR1/ MARK polarity-regulating kinase, thereby causing junctional and polarity defects in epithelial cells (Hatakeyama 2008). Thus, the bacterial oncoprotein simultaneously targets the polarity-regulating system and growth-regulatory system. H. pylori can also produce the vacuolating cytotoxin VacA responsible for epithelial damage which contributes to gastric carcinogenesis. A new type i1 “intermediate region” polymorphism, in vacA (which confers toxicity) has recently been described (Rhead et al. 2007; Ogiwara et al. 2008), and it appears that this it is the intermediate region type of vacA confers peptic ulcer risk (Basso et al. 2008). Bacterial factors (motility, adhesion, urease, cag pathogenicity), components of the host immune response (toll-like receptors, adaptive immunity, IL1B polymorphisms, MHCII), gastrin hormonal responses and decreased acid secretion are all thought to play a role in malignant transformation of the gastric mucosa (Stoicov et al. 2004). Gastrin, whose main role is acid secretion, is a diverse transcriptional activator, mediating gene expression that is associated with cell division, invasion, angiogenesis and anti-apoptotic activity, which are all pivotal in the gain of malignant potential. However, it is still unclear whether gastrin is a central player or a secondary phenomenon in the development of gastric adenocarcinoma, as has been previously discussed (Watson et al. 2006). There is a long-standing association of gastrin with malignant progression in transgenic mouse models, yet clinical conditions associated with hypergastrinaemia in humans, such as the Zollinger– Ellison syndrome, result in the development of hyperplasia of enterochromaYn-like (ECL) cells and carcinoid tumours, not GC, suggesting that the role of gastrin is not critical in gastric carcinogenesis. Despite this observation, H. pylori infection in the insulin–gastrin transgenic mouse 123 Hum Genet (2009) 126:615–628 produces an early increase in acid secretion and over time progresses to atrophy, achlorhydria, hyperplasia of mucous cell compartment, metaplasia, dysplasia and invasive GC by 8 months of age (Wang et al. 2000). Conversely, gastrin deWciency has also been reported to cause gastric adenocarcinoma (Zavros et al. 2005). Interestingly, expression proWles of gastrin knock-out mice revealed activation of immune defence genes, interferon-regulated response genes, and intestinal metaplasia of the gastric mucosa. Over time, the changes accumulated, became irreversible, and progressed into metaplasia and polyp development (FriisHansen et al. 2006). The intricacy of our defence systems are constantly being reWned, and bacterial interactions with the human immune system play a crucial role in triggering inXammation and ultimately cancer. Chochi et al. have highlighted that H. pylori augments the growth of GC via the lipopolysaccharide toll-like receptor 4 pathway, whereas its lipopolysaccharide attenuates antitumour activities of human mononuclear cells (Chochi et al. 2008). In addition, antitumour T lymphocytes play a pivotal role in immunosurveillance of malignancy, with the CTL antigen 4 (CTLA-4) being a vital negative regulator of T-cell activation and proliferation. This polymorphism is associated with increased susceptibility to multiple cancers, including lung, breast, oesophagus, and gastric cardia cancers, as demonstrated by genotyping in 5,832 individuals with cancer and 5,831 control subjects in northern and southern Chinese populations (Sun et al. 2008). It has also been reported that CCL17 and CCL22 chemokines within the tumour microenvironment are associated with the accumulation of regulatory T cells (Tregs) in GC (Mizukami et al. 2008). Furthermore, the density of tumour inWltrating lymphocytes was found to be independently predictive of regional lymph node metastasis and patient survival (Lee et al. 2008), highlighting the importance of the individual immune defences. Individual genetic variation may also explain the probable dual role of eosinophils in chronic gastritis, whereby elevated eosinophil density in the low-risk area, representing a T helper 2biased response down-regulate the eVects of proinXammatory cytokines preventing cancer development, whereas eosinophils in the high-risk area promote a T helper 1-type response leading to progression of precancerous lesions (Piazuelo et al. 2008). An in-depth understanding of the mechanism by which inXammation can lead to carcinogenesis may also enable the development of drugs targeted at signal transduction systems that are involved in the progression from inXammation to carcinogenesis, providing a powerful tool for preventing cancer development (Maeda and Omata 2008; Levidou et al. 2007). COX-2 has long been known to play a role in GC, although there are numerous debates on the relative value of the COX-2 polymorphism (Sitarz et al. 2008a). In a Hum Genet (2009) 126:615–628 surveillance/screening study of 2,813 subjects in China (Liu et al. 2006), investigators found a greater than twofold higher risk for progressing to GC among those with the 1195AA COX-2 genotype and report that this risk of progression was largely accounted for by those with the ¡1195AA COX-2 genotype that were also infected with H. pylori or were smokers (Liu et al. 2006). COX-2, is frequently upregulated in gastric adenocarcinomas (Ristimaki et al. 1997) and its expression, which can be induced by H. pylori (Fu et al. 1999; Sung et al. 2000) is thought to be a relatively early event in gastric carcinogenesis (van Rees et al. 2002). It is predominantly expressed in intestinal-type gastric carcinomas and its precursor lesions (van Rees et al. 2002; Saukkonen et al. 2001; Milne et al. 2006). Recently, the molecule C/EBP-
, a transcription factor for COX-2 (Caivano et al. 2001) has been shown to play a role in GC (Milne et al. 2006; Sankpal et al. 2006; Regalo et al. 2006). Patients with COX-2 methylated tumours have been shown to have a signiWcantly longer time to recurrence and improved overall survival (de Maat et al. 2007) and COX-2 expression has been suggested as a prognostic indicator (Park et al. 2009; Mrena et al. 2005). Studies have highlighted the reduced risk of GC in non-steroidal anti-inXammatory drug users (Hu et al. 2004; Langman et al. 2000; Akre et al. 2001), in particular non-cardia gastric adenocarcinoma (Abnet et al. 2009) and recent reports have suggested that a COX-2 inhibitor may be useful for prophylaxis of lymph node metastasis by reducing macrophage-mediated tumour lymphangiogenesis (Iwata et al. 2007). Worthy of mention is that growth factors of the epidermal growth factor (EGF) family and their respective receptors including c-erbB2 oncogene are also preferentially overexpressed in intestinal gastric cancers (Park et al. 1989; Yokota et al. 1988) and with the advent of anti-Her-2 antibody based treatment, more may heard on this subject in the future (Marx et al. 2009; Gravalos and Jimeno 2008). Interestingly, despite the importance of H. pylori as an initiating factor in gastric carcinogenesis, the molecular pathology of H. pylori and non-H. pylori cancers cannot be easily separated, and it has been reported that H. pylori related and non-related GCs do not diVer with respect to chromosomal aberrations (van Grieken et al. 2000). Also, although it may seem intuitively obvious that removing the oVending organism would negate the cancer risk, this approach is not straightforward. Most patients are infected in childhood, and present with varying degrees of mucosal damage before any therapy (Correa and Houghton 2007). Prophylactic eradication of H. pylori after endoscopic resection of early GC should be used to prevent the development of metachronous GC say researchers (Fukase et al. 2008). However, the causal association seems somewhat enigmatic in some Asian countries where high prevalence of H. pylori infection does not translate into high GC inci- 619 dence (Sharma 2008). H. pylori infection is more common and contracted earlier in India, Pakistan, Bangladesh, and Thailand, where seroprevalence of H. pylori infection in adults varies from 55 to 92% compared with about 50% in China and Japan. However, the frequency of GC is low in these so-called Asian enigma countries compared with that in Japan and China. The increased understanding of the relationship between inXammation and GC still leaves many questions unanswered regarding recommendations for prevention and treatment (Fox and Wang 2007; Buckley and O’Morain 1995). Premalignant lesions Intestinal-type GC typically arises in the setting of chronic gastritis and develops through intermediate stages of atrophic gastritis, intestinal metaplasia, dysplasia, and Wnally GC. This lengthy process, known commonly as the Correa pathway, is dependent on continued chronic inXammation (Correa and Houghton 2007; Correa 1995; Correa and Piazuelo 2008). Genetic changes can already be detected in intestinal metaplasia, with p16 methylation being signiWcantly associated with H. pylori infection in precancerous lesions (Dong et al. 2009). Studies have also shown decreased E-cadherin expression in the gastric mucosa of H. pylori infected individuals (Terres et al. 1998) and the interaction of CagA with E-cadherin, which causes cytoplasmic and nuclear accumulation of beta-catenin has been documented and implicated in the development of intestinal metaplasia (Murata-Kamiya et al. 2007). Metaplasia is a particularly interesting feature because it is a permanent alteration that suggests a marked change in the genetic and epigenetic program of the gastric stem or progenitor cells. Some argue that biologic detection of genomic instability in intestinal metaplasia may be a surrogate marker for GC risk and for clinical evaluation of malignant potential (Zaky et al. 2008). Intestinal metaplasia occurs in a variety of settings, including induction by bile reXux, where it is also associated with induced COX-2, via the sequential transcriptional induction of SHP and CDX1 in precancerous lesions (Park et al. 2008). It is known that loss of Sonic hedgehog (Shh), an essential regulator of patterning processes throughout development, and CDX2, a regulator for intestinal development and diVerentiation, have a role in early premalignant change (Watson et al. 2006) and they seem to be interdependently linked with cellular diVerentiation through diVerent signal cascades (Shiotani et al. 2008). H. pylori downregulates Shh expression, resulting in the loss of morphogenic diVerentiation, the disruption of glandular structure and the gain of a more intestinal phenotype by upregulation of intestine-related genes, such as CDX2, MUC2 and villin (Zavros et al. 2005). Notably, ectopi- 123 620 cally-expressed Cdx2 was found to induce gastric intestinal metaplasia in two separate mouse models (Mutoh et al. 2002; Silberg et al. 2002). Furthermore, in the insulin–gastrin (InsGas) hypergastrinaemic mouse +/¡ Helicobacter felis (H. felis) infection, Sonic hedgehog gene and protein expression was reduced in pre-metaplastic lesions from non-infected mice compared to normal mucosa, and was reactivated in gastric metaplasia of H. felis-infected mice (El-Zaatari et al. 2007). A study by Wang et al. found that SHH was completely absent in the upper part of normal gastric epithelia (gastric pit cells), and no signiWcant diVerences were observed among the lower parts of normal epithelia, chronic gastritis, and intestinal metaplasia. However, Shh expression was signiWcantly elevated in neoplastic lesions, such as carcinoma and high- and low-grade dysplasia, compared to non-neoplastic lesions. In carcinomas, Shh expression was associated with clinical stage, direct tumour invasion, and diVerentiation of tumour cells (Wang et al. 2006). These results suggest that the increased and constitutive Shh expression is implicated in gastric carcinogenesis. Stem cells in gastric cancer Given the current hypothesis that cancer arises from cancer stem cells (CSCs), the mechanism by which chronic inXammation leads to the emergence of CSCs needs to be addressed. It has been presumed that the gastric stem or progenitor cell is located in the isthmus of the gastric glands in the corpus, and gives rise to diVerentiated daughter cells via bidirectional migration patterns. In the gastric antrum, the stem or progenitor cells are located at the bottom of the glands, and descendents migrate toward the surface unidirectionally (Takaishi et al. 2008). Bjerknes et al. provided the evidence for the existence of multipotent stem cells in the adult mouse gastric epithelium using chemical mutagenesis to label random epithelial cells by loss of transgene function in transgenic mice (Bjerknes and Cheng 2002). This work revealed that many gastric glands showed a loss of transgene function in all major epithelial cell types, consistent with clonal expansion of a single mutation, therefore indicating the existence of multipotent gastric stem cells. For many years, resident tissue stem cells have been viewed as the best candidate for CSCs, because the simplest model is one in which a tumour arises from stem or progenitor cells at the existing site. In the intestine, mutations in long-lived (Lgr5+) stem cells located at the crypt bottoms are believed to be the precursor to intestinal cancer (Barker et al. 2009). Barker et al. reported that the G-protein coupled receptor Lgr5 was expressed in the bottom of gastric glands, and ongoing lineage tracing experiments implied that the entire gastric gland derived 123 Hum Genet (2009) 126:615–628 from Lgr5+ cells.(Barker et al. 2007) Possible gastric progenitor cells are recently shown to give rise to multiple gastric cell lineages in the gland (Qiao et al. 2007). McDonald et al. have investigated the clonality of the gastric unit and have shown how mutations expand in normal mucosa and in intestinal metaplasia, using mitochondrial DNA (mtDNA) mutations as a marker of clonal expansion. They showed that mtDNA mutations establish themselves in stem cells within normal human gastric body units, and are passed on to all their diVerentiated progeny, thereby providing evidence for clonal conversion to a new stem cell-derived unit–monoclonal conversion, encompassing all gastric epithelial lineages. The presence of partially mutated units indicates that more than one stem cell is present in each unit. Mutated units can divide by Wssion to form patches, with each unit sharing an identical, mutant mtDNA genotype. They also showed that intestinal metaplastic crypts are clonal, possess multiple stem cells, and that Wssion is a mechanism by which intestinal metaplasia spreads (McDonald et al. 2008). Interestingly, methylation of promoter CpG islands in intestinal metaplasia, which is known to be deeply involved in the progression to cancers, occurs independently in multiple genes in multiple glands, each of which has its own stem cell (Mihara et al. 2006). Although gastric stem or progenitor cells might seem to be good candidates for gastric CSCs, another possible source is the bone marrow-derived cell (BMDC) identiWed during the course of studies employing mouse models of H. pylori-induced GC (Houghton et al. 2004). Bone marrow-derived stem cells tend to migrate through peripheral organs as a result of inXammation and tissue injury and the diVerentiation pattern and growth regulation of these cells may depend largely on local environmental signals and cues (Krause et al. 2001; Okamoto et al. 2002). Studies have demonstrated that cancer-associated Wbroblasts can be partly derived from BMDCs (Iwano et al. 2002; Direkze et al. 2004) and it has also been reported that bone marrowderived human mesenchymal stem cells, when mixed with otherwise weakly metastatic human breast carcinoma cells, cause the cancer cells to increase their metastatic potency greatly, through stimulation of de novo secretion of the chemokine CCL5 (Karnoub et al. 2007). In view of the remarkable plasticity of BMDC, it has been suggested that BMDCs might contribute directly or indirectly to epithelial cancers, particularly those associated with chronic inXammation (Takaishi et al. 2008). Dysregulation of the stem cell signalling network due to the accumulation of germline mutation, SNP, H. pylori infection, epigenetic change and genetic alteration has been suggested to give rise to GC (Katoh 2007). H. pylori may adapt to and inXuence stem cell biology, thus contributing to gastric tumourigenesis (Giannakis et al. 2008). Hum Genet (2009) 126:615–628 621 The “Nature” component The gastric mucosa in CDH1 germline mutation carriers is normal until the second CDH1 allele is inactivated. It is postulated that this downregulation occurs in multiple cells in the gastric mucosa, accounting for the multifocal tumour lesions which develop and (Carneiro et al. 2004) environmental and physiological factors such as diet, carcinogen exposure, ulceration and gastritis are suggested to promote this downregulation event. The tumour then expands slowly until additional genetic events, probably in combination with an altered microenvironment, lead to clonal expansion and tumour progression. Interestingly, because the second hit only rarely involves somatic, irreversible, mutation of the second CDH1 allele, but rather more frequently occurs via methylation (Grady et al. 2000; Oliveira et al. 2009a; Barber et al. 2008), it is plausible that the early stage lesions may be reversible. IdentiWcation of patients with germline CDH1 mutations paves the way for studies to increase our understanding of the mechanisms by which these mutations ultimately lead to sporadic cancer as well as HDGC. Analysis of all reported genetic abnormalities in CDH1 found in HDGC reveals that the majority are inactivating mutations (splice site, frameshift, and nonsense) rather than missense mutations. Furthermore, CDH1 germline mutations are evenly distributed along the E-cadherin gene, in contrast with the clustering in exons 7–9 observed in sporadic diVuse GC (Berx et al. 1998). Frequent deletions of CDH1 in HDGC families have recently been recognized (Oliveira et al. 2009b). Loss of heterozygosity as the “second hit” does not appear to be frequent in HDGC. Instead, hypermethylation of the CDH1 promoter is likely to be a common cause of down-regulation or inactivation of the second CDH1 allele in HDGC tumours (Grady et al. 2000). A remarkably high percentage (approximately 80%) of CDH1 mutations in HDGC patients and carriers generate premature termination codons (PTCs). It is possible to examine whether CDH1 transcripts harbouring PTCs are downregulated by nonsense-mediated decay (NMD), an RNA surveillance pathway that degrades PTC-bearing transcripts. Analysis of HDGC patients harbouring CDH1 alleles with PTCs at a wide variety of diVerent positions indicates an association of their predicted ability to induce NMD and an earlier age of onset of GC (Karam et al. 2008). Interestingly, regulators of E-cadherin-mediated cell adhesion, such as the Rho GTPases are implicated in the carcinogenic process by deregulated expression of the family members itself or of upstream modulators or downstream eVectors (Walch et al. 2008). As well as E-cadherin dysregulation, overexpression of epidermal growth factor receptor (EGFR) is among the most frequent genetic alterations associated with diVuse-type gastric carcinoma. Accumulating evidence suggests a functional relationship between E-cadherin and EGFR that regulates both proteins (Bremm et al. 2008). The role of CDH1, encoding E-cadherin The existence of a familial form of GC has been known since the 1800s when multiple cases of GC were noted in the Napoleon Bonaparte family (SokoloV 1938). Approximately 1–3% of GCs arise as a result of inherited GC predisposition syndromes, such as hereditary diVuse GC (HDGC), caused by a germline mutation in the CDH1 gene, encoding E-cadherin, a molecule central in the processes of development, cell diVerentiation, and maintenance of epithelial architecture (Grunwald 1993). GC in its hereditary form can also be caused by germline mutations of the TP53 tumour suppressor gene which occurs in the Li–Fraumeni syndrome (Olivier et al. 2003) and new germ line mutations in this gene continue to be discovered (Yamada et al. 2007). BRCA2 gene mutations are associated with familial aggregations of not only breast but also of gastric, ovarian, pancreatic, and prostate cancers (The Breast Cancer Linkage Consortium 1999; Jakubowska et al. 2002). A proportion of hereditary nonpolyposis colorectal cancer (HNPCC) kindreds (the so-called Lynch II families) are associated with a high frequency of extracolonic carcinomas, most commonly aVecting the endometrium and stomach (Lynch et al. 1996) and these are known to harbour microsatellite instability (Aaltonen et al. 1994). Approximately 30–40% of all HDGC families carry CDH1 germline mutations (Oliveira et al. 2006). The remaining 60–70% are genetically unexplained and may be caused by alterations in other genes. Mutations in CDH1 were initially identiWed in 1998 in three Maori families from New Zealand that were predisposed to diVuse GC (Guilford et al. 1998). Since then, similar mutations have been described in more than 151 HDGC families of diverse ethnic backgrounds Carneiro et al. (2008a). Recurrent CDH1 mutations in families with hereditary diVuse GC are due to both independent mutational events and common ancestry and Wndings support the presence of a founder mutation from Newfoundland (Kaurah et al. 2007). Preliminary data from these families suggest that the penetrance of CDH1 gene mutations is high, ranging between 70 and 80% (Pharoah et al. 2001). Management options for unaVected mutation carriers include prophylactic total gastrectomy (Lynch et al. 2008; Cisco and Norton 2008; Rogers et al. 2008). There also appears to be an increased frequency of cancers occurring at other sites such as the breast, colorectum, and prostate in these mutation carriers (Pharoah et al. 2001). However, inclusion of associated cancers into the deWnition of HDGC is not yet recommended (Caldas et al. 1999) although updated recommendations from the International Gastric Cancer Linkage Consortium (IGCLC) are expected to be published later in 2009. 123 622 Hum Genet (2009) 126:615–628 lighting the importance of environmental interaction on genotype (Jenab et al. 2008). There are various models for the development of HDGC on both the histopathological and molecular level (Carneiro et al. 2004, 2008a; Humar and Guilford 2008). The earliest indications of cancer in the stomachs of CDH1 mutation carriers are microscopic foci of in situ carcinoma, pagetoid spread of signet ring cells and intramucosal signet ring cell carcinoma (SRCC; designated “eHDGC”), as seen in Fig. 1. In a study investigating wild-type (wt) and cdh1(+/¡) mice induced with N-methyl-N-nitrosourea (MNU), intramucosal SRCC developed with an 11 times higher incidence compared with wt mice (Humar et al. 2009). The murine SRCC resembled the human eHDGCs in that they were hypoproliferative, lacked nuclear beta-catenin accumulation, and had reduced membrane localization of E-cadherin and its interacting junctional proteins. The down-regulation of E-cadherin in the murine SRCCs conWrmed the importance of the second CDH1 hit to the initiation of diVuse GC, and promoter hypermethylation of the CDH1 gene was found to be the second hit in 50% of foci. These Wndings provide compelling evidence for a deWciency in cell-to-cell adhesion being suYcient to initiate diVuse GC in the absence of hyperproliferation and beta-catenin activation (Humar et al. 2009). A verdict has not yet been reached concerning the possible carcinogenic role of coexistent infection with H. pylori on a CDH1 mutated background, and it remains possible that H. pylori infection as well as dietary and other environmental inXuences may modify the disease risk in these susceptible individuals (McColl and El-Omar 2002). In addition, the role of genetic polymorphisms of the CDH1 gene in increasing the risk of sporadic GC is under investigation (Zhang et al. 2008a; Wang et al. 2008). In one case– control study (cases = 245/controls = 950) nested within the European Prospective Investigation into Cancer and Nutrition (EPIC) none of the eight CDH1 polymorphisms or haplotypes analysed were associated with GC risk and no diVerences of eVect were observed by H. pylori infection status. However, three CDH1 polymorphisms in the same haplotype block, including the CDH1–160C/A, interacted with smoking to increase GC risk in smokers, again high- Genetic instability at the level of microsatellite instability (MSI) occurs in many sporadic human tumours and the relation between microsatellite instability and gastric carcinoma has received considerable attention. This is due to the discovery that MSI may be found in sporadic carcinomas that are characteristic of hereditary nonpolyposis colorectal cancer (HNPCC) (Peltomaki et al. 1993), a syndrome where germline mutations of the mismatch repair genes are present. The levels of MSI found in gastric carcinomas from both Western and Eastern populations is probably in the region of up to 15–20% (Hayden et al. 1998; Carneiro et al. 2008b). Several authors demonstrated that the subset of sporadic GC with high-frequency MSI (MSI-H) showed a distinct clinicopathologic and genetic proWle from those with a low frequency (MSI-L) or microsatellite stable (MSS) genotype (Wu et al. 2000; Falchetti et al. 2008; dos Santos et al. 1996). For example, frameshift mutations in the Wnt pathway genes AXIN2 and TCF7L2 have been found in GCs with high microsatellite instability (Kim et al. 2009) and alternative lengthening of telomeres frequently occurs in mismatch repair system-deWcient gastric carcinoma (Omori et al. 2009). Genome-wide expression proWles of sporadic GCs with and without microsatellite instability reveal that the immune and apoptotic gene networks eYciently discriminated these two cancer types (D’Errico et al. 2009). However, whereas the role of microsatellite instability and DNA mismatch repair gene defects in HNPCC is unquestionable and well established, the relevance of this phenomenon in GC is far from clear and currently has limited clinical value (Hayden et al. 1998). Somatic mutations of mismatch repair (MMR) genes such as hMLH1 or hMSH2 are extremely rare in sporadic GCs, with only one mutation found, in hMSH2 and two cases of a germline frameshift mutation in hMLH1 (Wu et al. 1997; Bacani et al. 2005). More recently, 29 sporadic GCs with Fig. 1 In situ carcinoma, pagetoid spread of signet ring cells and early invasive signet ring carcinoma. a In situ signet ring cell carcinoma: gland with intact basement membrane lined by signet ring cells (arrow heads) (H&E, original magniWcation £400); b pagetoid spread of signet ring cells below the preserved epithelium of one foveolae (arrow heads) (H&E, original magniWcation £400); c early invasive signet ring cell carcinoma (eHDGC) (HE, original magniWcation £400) 123 Microsatellite instability Hum Genet (2009) 126:615–628 high level of MSI were screened for somatic mutations in MLH1, MSH2, MSH6, MLH3, and MBD4, and only Wve truncating mutations (3 in MSH6, 1 in MLH3, and 1 in MBD4) and one missense mutation (MLH1) were identiWed. All truncating mutations were found in the coding poly-A tracts, thus suggesting that they result from the MSI phenotype rather than causing it (Pinto et al. 2008). However, MSI positive tumours can still lack hMLH1 protein expression and many studies suggest that hypermethylation of the hMLH1 promoter region may be the principal mechanism of gene inactivation in sporadic gastric carcinomas with a high frequency of MSI (Fleisher et al. 1999; Leung et al. 1999). Polymorphisms, including IL1B Countless research articles focus on the role of polymorphism as a risk factor or protective factor for gastric carcinogenesis. Continuing advances in genotyping technologies and the inclusion of DNA collection in observational studies have resulted in an increasing number of genetic association studies. Polymorphisms in genes from diverse molecular pathways have been signiWcantly associated with GC, such as MTHFR C677T, involved in folate metabolism Dong et al. (2008a) prostate stem cell antigen (PSCA), the function of which is not well understood (Sakamoto et al. 2008), and the DNA repair genes XPA, XPC, ERCC2 Dong et al. (2008b; Capella et al. 2008) which play an important role in repairing DNA damage related to H. pylori-induced inXammatory process (Li et al. 2009). The role of the activation and detoxiWcation of polycyclic aromatic hydrocarbons, by genes such as GSTT1, SULT1A1, NAT2 and the EPHX1 gene (Boccia et al. 2007) highlight how environmental carcinogens are crucially triggered by a particular genetic proWle (Agudo et al. 2006). Pathways with a largely unknown role in GC, such as oestrogen and androgen metabolizing genes, have also been found to be associated with GC (Freedman et al. 2009). Polymorphisms in some genes have been highlighted more than other, such as the IL1B gene, which appears pivotal in determining a patient’s inXammatory response to a H. pylori infection. Interleukin-1beta (IL-1
) is a key proinXammatory cytokine, which regulates the expression of several genes involved in inXammation. It is an endogenous inhibitor of gastric acid secretion and is important in initiating and enhancing the inXammatory response to H. pylori infection (Noach et al. 1994). Although the production of IL-1
depends on several factors, there is increasing evidence that the genetic background plays a major role. Several single nucleotide polymorphisms in IL1B gene have been studied, and two biallelic polymorphisms at positions -31 and -511 in the promoter region of IL1B, are in positive linkage disequilibrium and associated with GC risk. It has 623 been reported that carriers of the IL1B-31C allele, showed higher plasmatic concentrations of IL-1
than subjects with wild-type IL1B genotype (Hall et al. 2004) and the IL-1B31C/-511T alleles are associated with increased risk of gastric cancer (El-Omar et al. 2000; El-Omar et al. 2003). However, there are also studies which do not support these results (Sitarz et al. 2008b; Murphy et al. 2009), including Wndings from a relatively extensive Swedish and Spanish study, which did not lend support to the hypothesis that human genetic polymorphisms related to the production of IL-1
are associated with the risk of GC (Persson et al. 2009; Garcia-Gonzalez et al. 2007), which may be explained by population-speciWc cancer risks. Further Wndings which support the importance of IL1B includes human IL-1
in transgenic mice, where spontaneous gastric inXammation and cancer was observed, that correlated with early recruitment of myeloid-derived suppressor cells (MDSCs) to the stomach (Tu et al. 2008). Here, IL-1
activated MDSCs in vitro and in vivo through an IL-1RI/NFkappaB pathway and IL1B transgenic mice deWcient in T and B lymphocytes developed gastric dysplasia accompanied by a marked increase in MDSCs in the stomach. These results demonstrated that the pathologic elevation of a single proinXammatory cytokine can be suYcient to induce neoplasia in experimental mice (Tu et al. 2008). Polymorphisms in other crucial inXammatory molecules have also been implicated in GC. The toll-like receptors (TLRs), again important members of the host’s innate immune response have been found to be polymorphic (El-Omar et al. 2008). Genetic variation allows for a more intricate repertoire that enables the host to withstand microbial challenges. While this may be advantageous on a population level, there may be less favourable outcomes for individuals that harbour certain genotypes associated with excessive immune activation and inXammatory drive. There is a role for innate immune responses and TLRs speciWcally in promoting gastrointestinal malignancies (Fukata and Abreu 2008) and a functional polymorphism of toll-like receptor 4 has been found to be associated with non-cardia cancer (Hold et al. 2007). Candidate pathways linking TLRs to gastrointestinal malignancies include activation of cyclooxygenase-2, and of nuclear factor-kappaB (NFB), a crucial inXammatory transcription factor. TNF alpha, a crucial inXammatory mediator upstream of NFB has also been implicated in the development of GC (Zhang et al. 2008b) and interestingly, it has been shown by meta-analysis that this eVect appears to be restricted to western populations (Gorouhi et al. 2008). Chemokines have also been shown to modulate tumour behaviour, and the sex-speciWc eVect of the chemokine polymorphisms on the host susceptibility to several diseases has been reported (Liou et al. 2008). In addition, variant alleles of TGFB1 and TGFBR2, which occupy a central position in the signalling 123 624 networks that control cell growth and diVerentiation, are associated with a decreased risk of GC (Jin et al. 2007). Numerous other polymorphisms have been implicated, only some of which can be mentioned within the scope of this article. Host genetic factors are emerging as key determinants of disease risk for many cancers, and the interaction of numerous polymorphisms on a countless genes products, combined with environmental triggers may provide crucial clues explaining diverse risks in various populations. The study of these using SNP chips or studies where the whole genome are sequenced, may enable us to assess the strength of the “nature” component in many gastric cancers, assuming we have the accurate bioinformatic expertises available to cope with such vast amounts of data. Summary The immensity of genes and molecules implicated in gastric carcinogenesis is overwhelming and the relevant importance of some of these molecules is too often unclear. Multiple genetic and epigenetic alterations in oncogenes, tumour-suppressor genes, cell cycle regulators, cell-adhesion molecules, DNA repair genes and genetic instability as well as telomerase activation are implicated.(Milne et al. 2007) However, particular combinations of these alterations diVer in the two histological types of GC.(Wu et al. 2002; Hou et al. 2008) The diVuse phenotype in GC (hereditary and sporadic) is related to reduced E-cadherin expression(Machado et al. 1999) and loss of E-cadherin is probably the fundamental defect in diVuse-type gastric carcinoma, providing an explanation for the observed morphological phenotype of discohesive cells with loss of polarity and gland architecture. However, despite the diVerences in diVuse and intestinal cancers in terms of the balance of nature and nurture, there remains a correlation between diVuse GC and H. pylori infection (Eslick et al. 1999). Human genetic variation in countless signalling pathway and aspects of human immune function, along with an individual’s speciWc environmental triggers together with genetic variation and temporal variation in gene expression in H. pylori are determinants of GC. Identifying one discriminating biomarker (e.g. COX-2 or p53) has not led to a new clinical algorithm and has as yet not impacted patient care as a single biomarker is likely insuYcient for making such clinical decisions or providing information. Cancer cells employ multiple and diverse survival pathways (Hahn and Weinberg 2002) and it is necessary to deWne a battery of biomarkers (complex signatures that deWne multiple outcomes). Such signatures might more appropriately represent the breadth of molecular diversity inherent in cancers in general, and pave the way to understanding the impact of 123 Hum Genet (2009) 126:615–628 both nature and nurture on the molecular genetics of gastric carcinogenesis. Open Access This article is distributed under the terms of the Creative Commons Attribution Noncommercial License which permits any noncommercial use, distribution, and reproduction in any medium, provided the original author(s) and source are credited. References Aaltonen LA et al (1994) Replication errors in benign and malignant tumors from hereditary nonpolyposis colorectal cancer patients. Cancer Res 54(7):1645–1648 Abnet CC et al (2009) Non-steroidal anti-inXammatory drugs and risk of gastric and oesophageal adenocarcinomas: results from a cohort study and a meta-analysis. Br J Cancer 100(3):551–557 Agudo A et al (2006) Polymorphisms in metabolic genes related to tobacco smoke and the risk of gastric cancer in the European prospective investigation into cancer and nutrition. Cancer Epidemiol Biomark Prev 15(12):2427–2434 Akre K et al (2001) Aspirin and risk for gastric cancer: a populationbased case-control study in Sweden. Br J Cancer 84(7):965–968 Amieva MR, El-Omar EM (2008) Host–bacterial interactions in Helicobacter pylori infection. Gastroenterology 134(1):306–323 Bacani J et al (2005) Tumor microsatellite instability in early onset gastric cancer. J Mol Diagn 7(4):465–477 Baik SC et al (1996) Increased oxidative DNA damage in Helicobacter pylori-infected human gastric mucosa. Cancer Res 56(6):1279–1282 Barber M et al (2008) Mechanisms and sequelae of E-cadherin silencing in hereditary diVuse gastric cancer. J Pathol 216(3):295–306 Barker N et al (2007) IdentiWcation of stem cells in small intestine and colon by marker gene Lgr5. Nature 449(7165):1003–1007 Barker N et al (2009) Crypt stem cells as the cells-of-origin of intestinal cancer. Nature 457(7229):608–611 Basso D et al (2008) Clinical relevance of Helicobacter pylori cagA and vacA gene polymorphisms. Gastroenterology 135(1):91–99 Berx G et al (1998) Mutations of the human E-cadherin (CDH1) gene. Hum Mutat 12(4):226–237 Bjerknes M, Cheng H (2002) Multipotential stem cells in adult mouse gastric epithelium. Am J Physiol Gastrointest Liver Physiol 283(3):G767–G777 Boccia S et al (2007) Polymorphisms in metabolic genes, their combination and interaction with tobacco smoke and alcohol consumption and risk of gastric cancer: a case–control study in an Italian population. BMC Cancer 7:206 Bonenkamp JJ et al (1999) Extended lymph-node dissection for gastric cancer. Dutch Gastric Cancer Group. N Engl J Med 340(12):908– 914 Bremm A et al (2008) Enhanced activation of epidermal growth factor receptor caused by tumor-derived E-cadherin mutations. Cancer Res 68(3):707–714 Buckley M, O’Morain C (1995) Helicobacter pylori infection and gastric cancer: usefulness of screening high risk groups. Acta Gastroenterol Belg 58(5–6):382–387 Cai X et al (2005) Overcoming Fas-mediated apoptosis accelerates Helicobacter-induced gastric cancer in mice. Cancer Res 65(23):10912–10920 Caivano M et al (2001) The induction of cyclooxygenase-2 mRNA in macrophages is biphasic and requires both CCAAT enhancerbinding protein beta (C/EBP beta) and C/EBP delta transcription factors. J Biol Chem 276(52):48693–48701 Caldas C et al (1999) Familial gastric cancer: overview and guidelines for management. J Med Genet 36(12):873–880 Hum Genet (2009) 126:615–628 Cancer risks in BRCA2 mutation carriers (1999) The Breast Cancer Linkage Consortium. J Natl Cancer Inst 91(15):1310–1316 Capella G et al (2008) DNA repair polymorphisms and the risk of stomach adenocarcinoma and severe chronic gastritis in the EPIC-EURGAST study. Int J Epidemiol 37(6):1316–1325 Carneiro F et al (2004) Model of the early development of diVuse gastric cancer in E-cadherin mutation carriers and its implications for patient screening. J Pathol 203(2):681–687 Carneiro F et al (2008a) Molecular pathology of familial gastric cancer, with an emphasis on hereditary diVuse gastric cancer. J Clin Pathol 61(1):25–30 Carneiro F et al (2008b) Molecular targets and biological modiWers in gastric cancer. Semin Diagn Pathol 25(4):274–287 Chandanos E, Lagergren J (2008) Oestrogen and the enigmatic male predominance of gastric cancer. Eur J Cancer 44(16):2397–2403 Chen SY et al (2004) ModiWcation eVects of GSTM1, GSTT1 and CYP2E1 polymorphisms on associations between raw salted food and incomplete intestinal metaplasia in a high-risk area of stomach cancer. Int J Cancer 108(4):606–612 Chiba T et al (2008) Mechanism for gastric cancer development by Helicobacter pylori infection. J Gastroenterol Hepatol 23(8 Pt 1):1175–1181 Chochi K et al (2008) Helicobacter pylori augments growth of gastric cancers via the lipopolysaccharide-toll-like receptor 4 pathway whereas its lipopolysaccharide attenuates antitumor activities of human mononuclear cells. Clin Cancer Res 14(10):2909–2917 Cisco RM, Norton JA (2008) Hereditary diVuse gastric cancer: surgery, surveillance and unanswered questions. Future Oncol 4(4):553–559 Correa P (1995) Helicobacter pylori and gastric carcinogenesis. Am J Surg Pathol 19(Suppl 1):S37–S43 Correa P, Houghton J (2007) Carcinogenesis of Helicobacter pylori. Gastroenterology 133(2):659–672 Correa P, Piazuelo MB (2008) Natural history of Helicobacter pylori infection. Dig Liver Dis 40(7):490–496 Craanen ME et al (1992) Intestinal metaplasia and Helicobacter pylori: an endoscopic bioptic study of the gastric antrum. Gut 33(1):16–20 D’Errico M et al (2009) Genome-wide expression proWle of sporadic gastric cancers with microsatellite instability. Eur J Cancer 45(3):461–469 de Maat MF et al (2007) Epigenetic silencing of cyclooxygenase-2 aVects clinical outcome in gastric cancer. J Clin Oncol 25(31):4887–4894 de Vries AC et al (2007) Epidemiological trends of pre-malignant gastric lesions: a long-term nationwide study in the Netherlands. Gut 56(12):1665–1670 Derakhshan MH et al (2009) Oesophageal and gastric intestinal-type adenocarcinomas show the same male predominance due to a 17 year delayed development in females. Gut 58(1):16–23 Direkze NC et al (2004) Bone marrow contribution to tumor-associated myoWbroblasts and Wbroblasts. Cancer Res 64(23):8492–8495 Dong LM et al (2008a) Genetic susceptibility to cancer: the role of polymorphisms in candidate genes. JAMA 299(20):2423–2436 Dong Z et al (2008b) Polymorphisms of the DNA repair gene XPA and XPC and its correlation with gastric cardiac adenocarcinoma in a high incidence population in North China. J Clin Gastroenterol 42(8):910–915 Dong CX et al (2009) Promoter methylation of p16 associated with Helicobacter pylori infection in precancerous gastric lesions: a population-based study. Int J Cancer 124(2):434–439 dos Santos NR et al (1996) Microsatellite instability at multiple loci in gastric carcinoma: clinicopathologic implications and prognosis. Gastroenterology 110(1):38–44 Egan BJ et al (2007) Helicobacter pylori gastritis, the unifying concept for gastric diseases. Helicobacter 12(Suppl 2):39–44 625 El-Omar EM et al (2000) Interleukin-1 polymorphisms associated with increased risk of gastric cancer. Nature 404(6776):398–402 El-Omar EM et al (2003) Increased risk of noncardia gastric cancer associated with proinXammatory cytokine gene polymorphisms. Gastroenterology 124(5):1193–1201 El-Omar EM, Ng MT, Hold GL (2008) Polymorphisms in Toll-like receptor genes and risk of cancer. Oncogene 27(2):244–252 El-Zaatari M et al (2007) De-regulation of the sonic hedgehog pathway in the InsGas mouse model of gastric carcinogenesis. Br J Cancer 96(12):1855–1861 Eslick GD et al (1999) Association of Helicobacter pylori infection with gastric carcinoma: a meta-analysis. Am J Gastroenterol 94(9):2373–2379 Falchetti M et al (2008) Gastric cancer with high-level microsatellite instability: target gene mutations, clinicopathologic features, and long-term survival. Hum Pathol 39(6):925–932 Farinati F et al (2008) Helicobacter pylori, inXammation, oxidative damage and gastric cancer: a morphological, biological and molecular pathway. Eur J Cancer Prev 17(3):195–200 Ferreira AC et al (2008) Helicobacter and gastric malignancies. Helicobacter 13(Suppl 1):28–34 Figueiredo C et al (2002) Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma. J Natl Cancer Inst 94(22):1680–1687 Fleisher AS et al (1999) Hypermethylation of the hMLH1 gene promoter in human gastric cancers with microsatellite instability. Cancer Res 59(5):1090–1095 Forman D et al (1991) Association between infection with Helicobacter pylori and risk of gastric cancer: evidence from a prospective investigation. BMJ 302(6788):1302–1305 Fox JG, Wang TC (2007) InXammation, atrophy, and gastric cancer. J Clin Invest 117(1):60–69 Freedman ND et al (2009) Polymorphisms in estrogen- and androgenmetabolizing genes and the risk of gastric cancer. Carcinogenesis 30(1):71–77 Friis-Hansen L et al (2006) Gastric inXammation, metaplasia, and tumor development in gastrin-deWcient mice. Gastroenterology 131(1):246–258 Fu S et al (1999) Increased expression and cellular localization of inducible nitric oxide synthase and cyclooxygenase 2 in Helicobacter pylori gastritis. Gastroenterology 116(6):1319–1329 Fukase K et al (2008) EVect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. Lancet 372(9636):392–397 Fukata M, Abreu MT (2008) Role of Toll-like receptors in gastrointestinal malignancies. Oncogene 27(2):234–243 Furukawa H et al (1989) Multifocal gastric cancer in patients younger than 50 years of age. Eur Surg Res 21(6):313–318 Galmiche A et al (2000) The N-terminal 34 kDa fragment of Helicobacter pylori vacuolating cytotoxin targets mitochondria and induces cytochrome c release. EMBO J 19(23):6361–6370 Garcia Rodriguez LA, Lagergren J, Lindblad M (2006) Gastric acid suppression and risk of oesophageal and gastric adenocarcinoma: a nested case control study in the UK. Gut 55(11):1538– 1544 Garcia-Gonzalez MA et al (2007) Gastric cancer susceptibility is not linked to pro-and anti-inXammatory cytokine gene polymorphisms in whites: a Nationwide Multicenter Study in Spain. Am J Gastroenterol 102(9):1878–1892 Giannakis M et al (2008) Helicobacter pylori evolution during progression from chronic atrophic gastritis to gastric cancer and its impact on gastric stem cells. Proc Natl Acad Sci USA 105(11):4358–4363 Gorouhi F et al (2008) Tumour-necrosis factor-A polymorphisms and gastric cancer risk: a meta-analysis. Br J Cancer 98(8):1443–1451 123 626 Grady WM et al (2000) Methylation of the CDH1 promoter as the second genetic hit in hereditary diVuse gastric cancer. Nat Genet 26(1):16–17 Gravalos C, Jimeno A (2008) HER2 in gastric cancer: a new prognostic factor and a novel therapeutic target. Ann Oncol 19(9):1523– 1529 Grunwald GB (1993) The structural and functional analysis of cadherin calcium-dependent cell adhesion molecules. Curr Opin Cell Biol 5(5):797–805 Guilford P et al (1998) E-cadherin germline mutations in familial gastric cancer. Nature 392(6674):402–405 Hahn WC, Weinberg RA (2002) Modelling the molecular circuitry of cancer. Nat Rev Cancer 2(5):331–341 Hall SK et al (2004) Correlation of polymorphic variation in the promoter region of the interleukin-1 beta gene with secretion of interleukin-1 beta protein. Arthritis Rheum 50(6):1976–1983 Hamilton SR, Aaltonen LA (eds) (2000) World Health Organization classiWcation of tumours. Pathology and genetics of tumours of the digestive system. IARC Press, Lyon Hanahan D, Weinberg RA (2000) The hallmarks of cancer. Cell 100(1):57–70 Hatakeyama M (2008) Linking epithelial polarity and carcinogenesis by multitasking Helicobacter pylori virulence factor CagA. Oncogene 27(55):7047–7054 Hayden JD et al (1998) The role of microsatellite instability in gastric carcinoma. Gut 42(2):300–303 Hold GL et al (2007) A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors. Gastroenterology 132(3):905–912 Hou Q et al (2008) Integrative genomics identiWes RAB23 as an invasion mediator gene in diVuse-type gastric cancer. Cancer Res 68(12):4623–4630 Houghton J et al (2004) Gastric cancer originating from bone marrowderived cells. Science 306(5701):1568–1571 Hu PJ et al (2004) Chemoprevention of gastric cancer by celecoxib in rats. Gut 53(2):195–200 Humar B, Guilford P (2008) Hereditary diVuse gastric cancer and lost cell polarity: a short path to cancer. Future Oncol 4(2):229– 239 Humar B et al (2009) E-cadherin deWciency initiates gastric signetring cell carcinoma in mice and man. Cancer Res 69(5):2050– 2056 (1994) Infection with Helicobacter pylori. IARC Monogr Eval Carcinog Risks Hum 61:177–240 Iwano M et al (2002) Evidence that Wbroblasts derive from epithelium during tissue Wbrosis. J Clin Invest 110(3):341–350 Iwata C et al (2007) Inhibition of cyclooxygenase-2 suppresses lymph node metastasis via reduction of lymphangiogenesis. Cancer Res 67(21):10181–10189 Jakubowska A et al (2002) BRCA2 gene mutations in families with aggregations of breast and stomach cancers. Br J Cancer 87(8):888–891 Jemal A et al (2007) Cancer statistics, 2007. CA Cancer J Clin 57(1):43–66 Jenab M et al (2006a) Plasma and dietary carotenoid, retinol and tocopherol levels and the risk of gastric adenocarcinomas in the European prospective investigation into cancer and nutrition. Br J Cancer 95(3):406–415 Jenab M et al (2006b) Plasma and dietary vitamin C levels and risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Carcinogenesis 27(11):2250–2257 Jenab M et al (2008) CDH1 gene polymorphisms, smoking, Helicobacter pylori infection and the risk of gastric cancer in the European Prospective Investigation into Cancer and Nutrition (EPIC-EURGAST). Eur J Cancer 44(6):774–780 123 Hum Genet (2009) 126:615–628 Jin G et al (2007) Variant alleles of TGFB1 and TGFBR2 are associated with a decreased risk of gastric cancer in a Chinese population. Int J Cancer 120(6):1330–1335 Kamangar F et al (2006) Opposing risks of gastric cardia and noncardia gastric adenocarcinomas associated with Helicobacter pylori seropositivity. J Natl Cancer Inst 98(20):1445–1452 Karam R et al (2008) The NMD mRNA surveillance pathway downregulates aberrant E-cadherin transcripts in gastric cancer cells and in CDH1 mutation carriers. Oncogene 27(30):4255–4260 Karnoub AE et al (2007) Mesenchymal stem cells within tumour stroma promote breast cancer metastasis. Nature 449(7162):557–563 Kato S et al (2006) High salt diets dose-dependently promote gastric chemical carcinogenesis in Helicobacter pylori-infected Mongolian gerbils associated with a shift in mucin production from glandular to surface mucous cells. Int J Cancer 119(7):1558–1566 Katoh M (2007) Dysregulation of stem cell signaling network due to germline mutation, SNP, Helicobacter pylori infection, epigenetic change and genetic alteration in gastric cancer. Cancer Biol Ther 6(6):832–839 Kaurah P et al (2007) Founder and recurrent CDH1 mutations in families with hereditary diVuse gastric cancer. JAMA 297(21):2360– 2372 Kim MS et al (2009) Frameshift mutations of Wnt pathway genes AXIN2 and TCF7L2 in gastric carcinomas with high microsatellite instability. Hum Pathol 40(1):58–64 Kokkola A, Sipponen P (2001) Gastric carcinoma in young adults. Hepatogastroenterology 48(42):1552–1555 Krause DS et al (2001) Multi-organ, multi-lineage engraftment by a single bone marrow-derived stem cell. Cell 105(3):369–377 Langman M, Logan R (2007) Risk of cancer and acid suppressant treatment. Gut 56(7):1023 Langman MJ et al (2000) EVect of anti-inXammatory drugs on overall risk of common cancer: case–control study in general practice research database. BMJ 320(7250):1642–1646 Lauren P (1965) The two histological main types of gastric carcinoma: diVuse and so-called intestinal-type carcinoma. An attempt at a histo-clinical classiWcation. Acta Pathol Microbiol Scand 64:31–49 Lee HE et al (2008) Prognostic implications of type and density of tumour-inWltrating lymphocytes in gastric cancer. Br J Cancer 99(10):1704–1711 Leung SY et al (1999) hMLH1 promoter methylation and lack of hMLH1 expression in sporadic gastric carcinomas with highfrequency microsatellite instability. Cancer Res 59(1):159–164 Levidou G et al (2007) Expression of nuclear factor kappaB in human gastric carcinoma: relationship with I kappaB a and prognostic signiWcance. Virchows Arch 450(5):519–527 Li WQ et al (2009) Association between genetic polymorphisms of DNA base excision repair genes and evolution of precancerous gastric lesions in a Chinese population. Carcinogenesis 30(3):500–505 Lim S et al (2003) Alteration of E-cadherin-mediated adhesion protein is common, but microsatellite instability is uncommon in young age gastric cancers. Histopathology 42(2):128–136 Lin WW, Karin M (2007) A cytokine-mediated link between innate immunity, inXammation, and cancer. J Clin Invest 117(5):1175– 1183 Liou JM et al (2008) RANTES-403 polymorphism is associated with reduced risk of gastric cancer in women. J Gastroenterol 43(2):115–123 Liu F et al (2006) Genetic variants in cyclooxygenase-2: expression and risk of gastric cancer and its precursors in a Chinese population. Gastroenterology 130(7):1975–1984 Lynch HT, Smyrk T, Lynch JF (1996) Overview of natural history, pathology, molecular genetics and management of HNPCC (Lynch Syndrome). Int J Cancer 69(1):38–43 Hum Genet (2009) 126:615–628 Lynch HT et al (2008) Hereditary diVuse gastric cancer: diagnosis, genetic counseling, and prophylactic total gastrectomy. Cancer 112(12):2655–2663 Macdonald JS et al (2001) Chemoradiotherapy after surgery compared with surgery alone for adenocarcinoma of the stomach or gastroesophageal junction. N Engl J Med 345(10):725–730 Machado JC et al (1999) E-cadherin gene mutations provide a genetic basis for the phenotypic divergence of mixed gastric carcinomas. Lab Invest 79(4):459–465 Machado JC et al (2003) A proinXammatory genetic proWle increases the risk for chronic atrophic gastritis and gastric carcinoma. Gastroenterology 125(2):364–371 Machado AM et al (2009) Helicobacter pylori infection induces genetic instability of nuclear and mitochondrial DNA in gastric cells. Clin Cancer Res 15(9):2995–3002 Maeda S, Omata M (2008) InXammation and cancer: role of nuclear factor-kappaB activation. Cancer Sci 99(5):836–842 Mannick JB et al (1999) Fas-induced caspase denitrosylation. Science 284(5414):651–654 Marx AH et al (2009) HER-2 ampliWcation is highly homogenous in gastric cancer. Hum Pathol 40(6):769–777 Matley PJ et al (1988) Gastric carcinoma in young adults. Ann Surg 208(5):593–596 Matsumoto Y et al (2007) Helicobacter pylori infection triggers aberrant expression of activation-induced cytidine deaminase in gastric epithelium. Nat Med 13(4):470–476 McColl KE (2006) Acid inhibitory medication and risk of gastric and oesophageal cancer. Gut 55(11):1532–1533 McColl KE, El-Omar E (2002) E-cadherin germline mutations and risk of gastric cancer. Gastroenterology 123(4):1406 (author reply 1406–1407) McDonald SA et al (2008) Mechanisms of Weld cancerization in the human stomach: the expansion and spread of mutated gastric stem cells. Gastroenterology 134(2):500–510 Mendez AM et al (2007) Cereal Wber intake may reduce risk of gastric adenocarcinomas: the EPIC-EURGAST study. Int J Cancer 121(7):1618–23 Merry AH et al (2007) Body mass index, height and risk of adenocarcinoma of the oesophagus and gastric cardia: a prospective cohort study. Gut 56(11):1503–1511 Mihara M et al (2006) Methylation of multiple genes in gastric glands with intestinal metaplasia: a disorder with polyclonal origins. Am J Pathol 169(5):1643–1651 Milne AN et al (2006) Early-onset gastric cancers have a diVerent molecular expression proWle than conventional gastric cancers. Mod Pathol 19(4):564–572 Milne AN et al (2007) Early onset gastric cancer: on the road to unraveling gastric carcinogenesis. Curr Mol Med 7(1):15–28 Mimuro H et al (2002) Grb2 is a key mediator of Helicobacter pylori CagA protein activities. Mol Cell 10(4):745–755 Mizukami Y et al (2008) CCL17 and CCL22 chemokines within tumor microenvironment are related to accumulation of Foxp3+ regulatory T cells in gastric cancer. Int J Cancer 122(10):2286–2293 Mrena J et al (2005) Cyclooxygenase-2 is an independent prognostic factor in gastric cancer and its expression is regulated by the messenger RNA stability factor HuR. Clin Cancer Res 11(20):7362–7368 Murata-Kamiya N et al (2007) Helicobacter pylori CagA interacts with E-cadherin and deregulates the beta-catenin signal that promotes intestinal transdiVerentiation in gastric epithelial cells. Oncogene 26(32):4617–4626 Murphy G et al (2009) Association of gastric disease with polymorphisms in the inXammatory-related genes IL-1B, IL-1RN, IL-10, TNF and TLR4. Eur J Gastroenterol Hepatol 21(6):630–635 Mutoh H et al (2002) Conversion of gastric mucosa to intestinal metaplasia in Cdx2-expressing transgenic mice. Biochem Biophys Res Commun 294(2):470–479 627 Nishimura T (2008) Total number of genome alterations in sporadic gastrointestinal cancer inferred from pooled analyses in the literature. Tumour Biol 29(6):343–350 Noach LA et al (1994) Mucosal tumor necrosis factor-alpha, interleukin-1 beta, and interleukin-8 production in patients with Helicobacter pylori infection. Scand J Gastroenterol 29(5):425–429 Ogiwara H, Graham DY, Yamaoka Y (2008) vacA i-region subtyping. Gastroenterology 134(4):1267 (author reply p 1268) Okamoto R et al (2002) Damaged epithelia regenerated by bone marrow-derived cells in the human gastrointestinal tract. Nat Med 8(9):1011–1017 Oliveira C, Seruca R, Carneiro F (2006) Genetics, pathology, and clinics of familial gastric cancer. Int J Surg Pathol 14(1):21–33 Oliveira C et al (2009a) QuantiWcation of epigenetic and genetic 2nd hits in CDH1 during hereditary diVuse gastric cancer syndrome progression. Gastroenterology 136(7):2137–2148 Oliveira C et al (2009b) Germline CDH1 deletions in hereditary diVuse gastric cancer families. Hum Mol Genet 18(9):1545–1555 Olivier M et al (2003) Li-Fraumeni and related syndromes: correlation between tumor type, family structure, and TP53 genotype. Cancer Res 63(20):6643–6650 Omori Y et al (2009) Alternative lengthening of telomeres frequently occurs in mismatch repair system-deWcient gastric carcinoma. Cancer Sci 100(3):413–418 Park JB et al (1989) AmpliWcation, overexpression, and rearrangement of the erbB-2 protooncogene in primary human stomach carcinomas. Cancer Res 49(23):6605–6609 Park MJ et al (2008) Bile acid induces expression of COX-2 through the homeodomain transcription factor CDX1 and orphan nuclear receptor SHP in human gastric cancer cells. Carcinogenesis 29(12):2385–2393 Park ES et al (2009) Cyclooxygenase-2 is an independent prognostic factor in gastric carcinoma patients receiving adjuvant chemotherapy and is not associated with EBV infection. Clin Cancer Res 15(1):291–298 Parsonnet J et al (1991) Helicobacter pylori infection and the risk of gastric carcinoma. N Engl J Med 325(16):1127–1131 Peltomaki P et al (1993) Microsatellite instability is associated with tumors that characterize the hereditary non-polyposis colorectal carcinoma syndrome. Cancer Res 53(24):5853–5855 Pelucchi C et al (2009) Dietary intake of selected micronutrients and gastric cancer risk: an Italian case–control study. Ann Oncol 20(1):160–165 Persson C et al (2009) Interleukin 1-beta gene polymorphisms and risk of gastric cancer in Sweden. Scand J Gastroenterol 44(3):339–345 Pharoah PD, Guilford P, Caldas C (2001) Incidence of gastric cancer and breast cancer in CDH1 (E-cadherin) mutation carriers from hereditary diVuse gastric cancer families. Gastroenterology 121(6):1348–1353 Piazuelo MB et al (2008) Eosinophils and mast cells in chronic gastritis: possible implications in carcinogenesis. Hum Pathol 39(9):1360–1369 Pinto M et al (2008) Somatic mutations in mismatch repair genes in sporadic gastric carcinomas are not a cause but a consequence of the mutator phenotype. Cancer Genet Cytogenet 180(2):110–114 Qiao XT et al (2007) Prospective identiWcation of a multilineage progenitor in murine stomach epithelium. Gastroenterology 133(6):1989–1998 Rather L (1978) The genesis of cancer; a study in the history of ideas. Johns Hopkins University Press, Baltimore Regalo G et al (2006) C/EBPbeta is over-expressed in gastric carcinogenesis and is associated with COX-2 expression. J Pathol 210(4):398–404 Rhead JL et al (2007) A new Helicobacter pylori vacuolating cytotoxin determinant, the intermediate region, is associated with gastric cancer. Gastroenterology 133(3):926–936 123 628 Ristimaki A et al (1997) Expression of cyclooxygenase-2 in human gastric carcinoma. Cancer Res 57(7):1276–1280 Rogers WM et al (2008) Risk-reducing total gastrectomy for germline mutations in E-cadherin (CDH1): pathologic Wndings with clinical implications. Am J Surg Pathol 32(6):799–809 Sakamoto H et al (2008) Genetic variation in PSCA is associated with susceptibility to diVuse-type gastric cancer. Nat Genet 40(6):730– 740 Sankpal NV et al (2006) Overexpression of CEBPbeta correlates with decreased TFF1 in gastric cancer. Oncogene 25(4):643–649 Saukkonen K et al (2001) Expression of cyclooxygenase-2 in dysplasia of the stomach and in intestinal-type gastric adenocarcinoma. Clin Cancer Res 7(7):1923–1931 Sharma SP (2008) H. pylori and gastric cancer in Asia: enigma, or a play on words? Lancet Oncol 9(9):827 Shikata K et al (2008) Population-based prospective study of the combined inXuence of cigarette smoking and Helicobacter pylori infection on gastric cancer incidence: the Hisayama Study. Am J Epidemiol 168(12):1409–1415 Shiotani A et al (2008) Sonic hedgehog and CDX2 expression in the stomach. J Gastroenterol Hepatol 23(Suppl 2):S161–S166 Silberg DG et al (2002) Cdx2 ectopic expression induces gastric intestinal metaplasia in transgenic mice. Gastroenterology 122(3):689–696 Sitarz R et al (2008a) The COX-2 promoter polymorphism ¡765 G>C is associated with early-onset, conventional and stump gastric cancers. Mod Pathol 21(6):685–690 Sitarz R et al (2008b) IL-1B–31T>C promoter polymorphism is associated with gastric stump cancer but not with early onset or conventional gastric cancers. Virchows Arch 453(3):249–255 Sjodahl K et al (2008) Salt and gastric adenocarcinoma: a populationbased cohort study in Norway. Cancer Epidemiol Biomark Prev 17(8):1997–2001 Sobala GM et al (1993) EVect of eradication of Helicobacter pylori on gastric juice ascorbic acid concentrations. Gut 34(8):1038–1041 SokoloV B (1938) Predisposition to cancer in the Bonaparte family. Am J Surg 40:637–638 Stoicov C et al (2004) Molecular biology of gastric cancer: Helicobacter infection and gastric adenocarcinoma: bacterial and host factors responsible for altered growth signaling. Gene 341:1–17 Suerbaum S, Michetti P (2002) Helicobacter pylori infection. N Engl J Med 347(15):1175–1186 Sun T et al (2007) A six-nucleotide insertion-deletion polymorphism in the CASP8 promoter is associated with susceptibility to multiple cancers. Nat Genet 39(5):605–613 Sun T et al (2008) Functional genetic variations in cytotoxic T-lymphocyte antigen 4 and susceptibility to multiple types of cancer. Cancer Res 68(17):7025–7034 Sung JJ et al (2000) Cyclooxygenase-2 expression in Helicobacter pylori-associated premalignant and malignant gastric lesions. Am J Pathol 157(3):729–735 Takaishi S, Okumura T, Wang TC (2008) Gastric cancer stem cells. J Clin Oncol 26(17):2876–2882 Terres AM et al (1998) H pylori infection is associated with downregulation of E-cadherin, a molecule involved in epithelial cell adhesion and proliferation control. J Clin Pathol 51(5):410– 412 Touati E et al (2003) Chronic Helicobacter pylori infections induce gastric mutations in mice. Gastroenterology 124(5):1408–1419 Tsutsumi R et al (2003) Attenuation of Helicobacter pylori CagA £ SHP-2 signaling by interaction between CagA and Cterminal Src kinase. J Biol Chem 278(6):3664–3670 123 View publication stats Hum Genet (2009) 126:615–628 Tu S et al (2008) Overexpression of interleukin-1beta induces gastric inXammation and cancer and mobilizes myeloid-derived suppressor cells in mice. Cancer Cell 14(5):408–419 van Grieken NC et al (2000) Helicobacter pylori-related and nonrelated gastric cancers do not diVer with respect to chromosomal aberrations. J Pathol 192(3):301–306 van Rees BP et al (2002) Cyclooxygenase-2 expression during carcinogenesis in the human stomach. J Pathol 196(2):171–179 Walch A et al (2008) Combined analysis of Rac1, IQGAP1, Tiam1 and E-cadherin expression in gastric cancer. Mod Pathol 21(5):544–552 Wang TC et al (2000) Synergistic interaction between hypergastrinemia and Helicobacter infection in a mouse model of gastric cancer. Gastroenterology 118(1):36–47 Wang LH et al (2006) Increased expression of sonic hedgehog and altered methylation of its promoter region in gastric cancer and its related lesions. Mod Pathol 19(5):675–683 Wang GY et al (2008) The E-cadherin gene polymorphism 160C!A and cancer risk: a HuGE review and meta-analysis of 26 case– control studies. Am J Epidemiol 167(1):7–14 Watanabe T et al (1998) Helicobacter pylori infection induces gastric cancer in mongolian gerbils. Gastroenterology 115(3):642–648 Watson SA et al (2006) Gastrin—active participant or bystander in gastric carcinogenesis? Nat Rev Cancer 6(12):936–946 Wiggins CL et al (2008) Gastric cancer among American Indians and Alaska Natives in the United States, 1999–2004. Cancer 113(5 Suppl):1225–1233 Wroblewski LE et al (2009) Helicobacter pylori dysregulation of gastric epithelial tight junctions by urease-mediated myosin II activation. Gastroenterology 136(1):236–246 Wu MS et al (1997) Infrequent hMSH2 mutations in sporadic gastric adenocarcinoma with microsatellite instability. Cancer Lett 112(2):161–166 Wu MS et al (2000) Distinct clinicopathologic and genetic proWles in sporadic gastric cancer with diVerent mutator phenotypes. Genes Chromosomes Cancer 27(4):403–411 Wu CW et al (2002) Clinical implications of chromosomal abnormalities in gastric adenocarcinomas. Genes Chromosomes Cancer 35(3):219–231 Yamada H et al (2007) IdentiWcation and characterization of a novel germ line p53 mutation in familial gastric cancer in the Japanese population. Carcinogenesis 28(9):2013–2018 Yokota J et al (1988) Genetic alterations of the c-erbB-2 oncogene occur frequently in tubular adenocarcinoma of the stomach and are often accompanied by ampliWcation of the v-erbA homologue. Oncogene 2(3):283–287 Young GP (2007) Diet and genomic stability. Forum Nutr 60:91–96 Yuasa Y et al (2009) DNA methylation status is inversely correlated with green tea intake and physical activity in gastric cancer patients. Int J Cancer 124(11):2677–2682 Zaky AH et al (2008) Clinicopathologic implications of genetic instability in intestinal-type gastric cancer and intestinal metaplasia as a precancerous lesion: proof of Weld cancerization in the stomach. Am J Clin Pathol 129(4):613–621 Zavros Y et al (2005) Chronic gastritis in the hypochlorhydric gastrindeWcient mouse progresses to adenocarcinoma. Oncogene 24(14):2354–2366 Zhang B et al (2008a) Genetic polymorphisms of the E-cadherin promoter and risk of sporadic gastric carcinoma in Chinese populations. Cancer Epidemiol Biomarkers Prev 17(9):2402–2408 Zhang J et al (2008b) Polymorphisms of tumor necrosis factor-alpha are associated with increased susceptibility to gastric cancer: a meta-analysis. J Hum Genet 53(6):479–489