First and second stage genes that have been associated to the development of gastric cancer
1. Introduction
In spite of a decline in incidence and mortality of gastric cancer over the last decades, it is still the fourth most common cancer and the second most common cause of cancer death in the world. The differences in prevalence of gastric cancer have been explained as a multifactorial process with an interaction involving both infection with
2. Epidemiology of gastric cancer
Stomach cancer is the fourth most common cancer worldwide with 930, 000 cases diagnosed in 2002 [1]. Despite a major decline in incidence and mortality over the last decades, stomach cancer is still the fourth most common cancer and the second most common cause of cancer death in the world, accounting for more than 803, 000 deaths each year.
It has been observed that there is a 10-fold variation in incidence between populations with the highest and lowest risk. For instance, the incidence of gastric adenocarcinoma is higher in East Asia, Central America, and South America than in most other parts of the world and is about twice as high among men [2]. This neoplasia is rare before the age of 40, and its incidence peaks in the seventh decade of life [3]. According to the National Cancer Institute, gastric cancer is more common in people over the age of 72 (National Cancer Institute) and the diagnosis of gastric cancers is frequently made based on dyspeptic and alarm symptoms. Unfortunately, sometimes alarm symptoms are not sufficiently sensitive to detect malignancies. Dysphagia, weight loss and a palpable abdominal mass appear to be major independent prognostic factors in gastric cancer, but when these symptoms appear, the patients are usually in advanced stages of cancer [4].
The difference in the prevalence of gastric cancer throughout the world has been described from different points of view. One of the most accepted explanations is that the development of gastric cancer is multifactorial with an interplay involving both infection with
3. Gastric cancer and Helicobacter pylori
In general, countries with a high incidence of stomach cancer have a high prevalence of
The worldwide prevalence of
One of the most prominent differences in gene content among
Despite the overwhelming evidence that
It has been recently proven that
Infection with cagA-positive
4. Host genetic polymorphisms and cancer susceptibility
Host genetic factors play an important role in influencing disease risk, but identifying candidate genes is a major challenge that requires a fundamental understanding of the disease [20]. The best-established risk factors for stomach cancer are
5. Gastric carcinogenesis.
The precancerous process had been the subject of inquiry way before the scientific community was aware of
The discovery of
First stage | |||
Interleukin-1 beta and its receptor antagonist |
High-level expression of IL-1B, reduction of acid output corpus and colonization by |
[25 - 32] | |
Interleukin-8 |
|
High IL-8 levels are found in gastric cancer. |
[33 - 37] |
Nucleotide-binding oligomerization domain containing 2 (NOD2) |
|
NOD2 is upregulated in gastric epithelial cells of patients with chronic infection by H. pylori. NOD2 R702W has been associated to gastric lymphoma. |
[38, 39] |
Cyclooxygenase 2 (COX-2) |
|
COX-2 is over-expressed in gastric cancer and in PTGS2 5939C allele carriers were at increased risk of gastric cancer. |
[40 , 41] |
Toll like receptor 4 | TLR-4 is associated to hyporesponsiveness to LPS and therefore to H. pylori. |
[22 , 42] | |
Interleukin-10 | Low secretion of IL-10 is associated to high inflammation and high risk to gastric cancer. Haplotype ATA is low IL-10 secreting and haplotype GCC is high IL-10 secreting. |
[43] |
|
Selenoprotein S |
|
Selenoprotein S participate in retro-translocation of misfolded proteins from the endoplasmic reticulum to the cytosol for their degradation. Association between the proximal promoter SEPS1 -105G/A polymorphism with circulating levels of pro-inflammatory IL-1β and TNF-α Selenoprotein S (SEPS1) gene -105G"/A promoter polymorphism influences the susceptibility to gastric cancer in the Japanese population. |
[44 - 46] |
Reactive oxygen species (ROS) and reactive nitrogen species (RNS) | Production of ROS and RNS increase gastric inflammation and therefore carcinogenesis. |
[47] | |
Survivin | Survivin downregulation correlate with apoptosis. Infection with |
[48] | |
|
|||
E-cadherin |
|
E-cadherin is a calcium dependent cell-cell adhesion glycoprotein. Heterozygous germline point or small frameshift mutations in the E-cadherin gene ( |
[3, 49] |
p53 | Two alleles encoding either arginine (CGC) or proline (CCC) |
Repair of DNA. When p53 codon 72 polymorphism has been associated with gastric cancer. |
[50 - 53] |
Oncogene RAS | Down regulation of Ras proteins in cancer lead to increased invasion and decreased apoptosis. Mutations in the |
[54] | |
Oncogene MYC | Involved in cell cycle regulation, cell growth arrest, cell adhesion, metabolism, ribosome biogenesis, and protein synthesis | [55] |
6. First stage genes
6.1. Interleukin 1 Family
The association of
The interaction between a host’s immunological defenses, and environmental and
An association between these polymorphisms was not found in some populations [60, 61]; [62-67], suggesting that this divergence may reflect the different genetic background related to ethnicity and the potential confounding variables, such as
6.2. Interleukin 8 and TNFA
Since the watershed publication of El-Omar et al. linking polymorphisms in genes regulating the gastric inflammatory responses to gastric cancer risk due to
Gastric cancer specimens have increased IL-8 protein levels, and many gastric cancer cell lines express high levels of
6.3. NOD1, NOD2, COX2, ROS and RNS
The pathogen-associated intracellular recognition molecules NOD1 and NOD2 are important regulators of chronic inflammation. NOD1 appears to be involved in the activation of a key transcription factor, NF-kB, by the Cag pathogenicity island [39]. Rosenstiel et al. reported that NOD1 and NOD2 were upregulated in the gastric epithelial cells of patients with chronic infection by
Cyclooxygenase2 (COX-2) has long been known to be over-expressed in gastric cancer and in
6.4. Survivin
The expression of the inhibitor-of-apoptosis protein survivin in adults is frequently linked to the development of cancer. Recently, it has been found that infection with
6.5. Toll-like receptor 4
Recognition of pathogens is mediated by a set of germline-encoded receptors that are referred to as pattern-recognition receptors (PRRs). These receptors recognize conserved molecular patterns, which are found in many species of microorganisms. An important PRR is Toll-like receptor 4 (TLR4), a transmembrane receptor that recognizes a range of ligands, including lipopolysaccharide (LPS), which is found in Gram-negative bacteria like
Two single nucleotide polymorphisms (SNPs) in the
Hold et al. addressed the role of TLR with respect to
6.6. Interleukin 10
Interleukin-10 (IL-10) is an anti-inflammatory cytokine that downregulates the production of Th1-derived cytokines [75] and seems to limit and terminate the inflammatory response by the blocking proinflammatory cytokine secretion. Some functional polymorphisms have been described for the IL-10 gene promoter. The single-nucleotide polymorphisms (SNP) at positions -1082 (G/A), −819 (C/T), and −592 (C/A) from the transcriptional start site are in linkage disequilibrium, and are responsible for three different haplotypes formed by the combination of ATA, GCC and ACC. The IL-10 haplotypes and cytokine production have been correlated with counterpointing results [46, 76, 77].
A higher prevalence of gastric cancer in patients with the proinflammatory (low IL-10 secreting) haplotype ATA has been reported, but contrasting results have also reported an association between carcinoma and the anti-inflammatory (high IL-10 secreting) haplotype GCC [43]. The study of Rad et al. showed that this contrastive observation might be explained by the finding that
6.7. Selenoprotein S
Selenoprotein S participates in the retro-translocation of misfolded proteins from the endoplasmic reticulum to the cytosol for their degradation [44]. This membrane protein functions in stress responses to prevent the deleterious consequences of accumulation of misfolded proteins, accumulation that has been linked to immune and inflammatory processes.
A strong association between the proximal promoter SEPS1 polymorphism at -105G/A with circulating levels of pro-inflammatory IL-1β and TNF-α has been reported [45]. A regulatory loop has been recently proposed whereby cytokines stimulate the expression of SEPS1, which in turn diminishes cytokine production [15]. The -105G>A promoter polymorphism of SEPS1 has been associated with the intestinal type of gastric cancer [46]. In another report of stomach biopsies from 268 Japanese gastric cancer and 306 control patients found that carrying the SEPS1-105*A allele was associated with an increased risk of intestinal type gastric cancer (OR: 2.0, 95%CI 1.0–3.9, p < 0.05) as well as of gastric cancer located in the middle third of the stomach (OR: 2.0, 95% CI 1.0–3.9, p < 0.05).
7. Second stage genes
External environmental exposures play an important role. These can give rise to a number of different genetic changes, the most common of which include chromosomal changes such as loss of heterozygosity (LOH), rearrangements, deletions, gains, and translocations; gene mutations such as base substitutions, small insertions and deletions, allelic loss, amplification and rearrangements; and epigenetic events such as alteration in DNA methylation. Loss of tumor suppressor function leads to the initiation and progression of cancer [78, 79]. Inactivation of tumor suppressor genes can result from both genetic mechanisms, such as mutation, and epigenetic mechanisms, such as DNA hypermethylation.
7.1. E-cadherin
E-cadherin is a calcium dependent cell-cell adhesion glycoprotein. Mutations in this gene are associated with gastric, breast, colorectal, thyroid and ovarian cancer [80]. It has been reported that promoter hypermethylation of E-cadherin plays an important role in gastric carcinogenesis [49]. Evidence shows that a heterozygous germline point or small frameshift mutations in the E-cadherin gene (
7.2. P53
The p53 gene has been called the genome guard is critical in maintaining orderly proliferation of cells. Normally, damage to cellular DNA initiates increased expression of
7.3. Oncogenes
Once activated, a proto-oncogene or its product is a tumor-inducing protein [84]. Some of the well-known oncogenes are
The
8. Conclusions
Host genetic susceptibility has been suggested as one of the most important possible explanations for interindividual differences in gastric cancer risk and even to tumor invasion. In the first stage, inflammation seems to play a critical role in the development of many types of cancer, including gastric cancer and genetic changes in gene coding some crucial mediators in the inflammatory response may play an essential role in
In conclusion, there are currently no definitive genetic risk markers for gastric cancer risk that can be applied to all populations. We need to recognize that distal gastric cancer is a multifactorial event. We do not discuss the effect of the environment that may influence both bacteria and the host factors.
References
- 1.
Parkin D. M. Bray F. Ferlay J. Pisani P. 2005 Global cancer statistics, 2002. 55 2 74 108 - 2.
Fuchs C. S. Mayer R. J. 1995 Gastric carcinoma. 333 1 32 41 - 3.
Gore R. M. 1997 Colorectal cancer. 35 2 403 29 - 4.
Maconi G. Manes G. Porro G. B. 2008 Role of symptoms in diagnosis and outcome of gastric cancer 14 8 1149 55 - 5.
Wroblewski L. E. Peek R. M. Wilson K. T. 2010 Helicobacter pylori and gastric cancer: factors that modulate disease risk 23 4 713 39 - 6.
Peek R. M. Blaser M. J. 2002 Helicobacter pylori and gastrointestinal tract adenocarcinomas. 2 1 28 37 - 7.
Suerbaum S. Michetti P. 2002 Helicobacter pylori infection. 347 15 1175 86 - 8.
An international association between Helicobacter pylori infection and gastric cancer. 1993 The EUROGAST Study Group. 341 8857 1359 62 - 9.
Asaka M. Kudo M. Kato M. Sugiyama T. Takeda H. 1998 Review article: Long-term Helicobacter pylori infection--from gastritis to gastric cancer. 1 9 15 - 10.
Yamaoka Y. Kodama T. Gutierrez O. Kim J. G. Kashima K. Graham D. Y. 1999 Relationship between Helicobacter pylori iceA, cagA, and vacA status and clinical outcome: studies in four different countries. 37 7 2274 9 - 11.
Zambon C. F. Basso D. Navaglia F. Germano G. Gallo N. Milazzo M. et al. 2002 Helicobacter pylori virulence genes and host IL-1RN and IL-1beta genes interplay in favouring the development of peptic ulcer and intestinal metaplasia. 18 5 242 51 - 12.
Bourzac K. M. Guillemin K. 2005 Helicobacter pylori-host cell interactions mediated by type IV secretion. 7 7 911 9 - 13.
Censini S. Lange C. Xiang Z. Crabtre,e J. E. Ghiara P. Borodovsky M. et al. 1996 Cag, a pathogenicity island of Helicobacter pylori, encodes type I-specific and disease-associated virulence factors 93 25 14648 53 - 14.
Hatakeyama M. 2009 Helicobacter pylori and gastric carcinogenesis 44 4 239 48 - 15.
Gao Y. Hannan N. R. Wanyonyi S. Konstantopolous N. Pagnon J. Feng H. C. et al. 2006 Activation of the selenoprotein SEPS1 gene expression by pro-inflammatory cytokines in HepG2 cells 33 5 246 51 - 16.
Corley D. A. Kubo A. Levin T. R. Bloc,k G. Habel L. Zhao W. et al. 2008 Helicobacter pylori infection and the risk of Barrett’s oesophagus: a community-based study. 57 6 727 33 - 17.
Whiteman D. C. Parmar P. Fahey P. Moore S. P. Stark M. Zhao Z. Z. et al. 2010 Association of Helicobacter pylori infection with reduced risk for esophageal cancer is independent of environmental and genetic modifiers 139 1 73 83 quiz e11-2. - 18.
Azuma T. Ohtani M. Yamazaki Y. Higashi H. Hatakeyama M. 2004 Meta-analysis of the relationship between CagA seropositivity and gastric cancer. 126 7 1926 7 - 19.
Fukase K. Kato M. Kikuchi S. Inoue K. Uemura N. Okamoto S. et al. 2008 Effect of eradication of Helicobacter pylori on incidence of metachronous gastric carcinoma after endoscopic resection of early gastric cancer: an open-label, randomised controlled trial. 372 9636 392 7 - 20.
El -Omar E. M. Oien K. Murray L. S. El -Nujumi A. Wirz A. Gillen D. et al. 2000 Increased prevalence of precancerous changes in relatives of gastric cancer patients: critical role of H. pylori. 118 1 22 30 - 21.
Brenner H. Rothenbacher D. Arndt V. 2009 Epidemiology of stomach cancer Clifton, N.J.472 467 77 - 22.
Hishida A. Matsuo K. Goto Y. Hamajima N. 2010 Genetic predisposition to Helicobacter pylori-induced gastric precancerous conditions. 2 10 369 79 - 23.
Correa P. 1995 Helicobacter pylori and gastric carcinogenesis. 1 37 43 - 24.
Correa P. Haenszel W. Cuello C. Zavala D. Fontham E. Zarama G. et al. 1990 Gastric precancerous process in a high risk population: cohort follow-up. 50 15 4737 40 - 25.
El -Omar E. M. Carrington M. Chow W. H. Mc Coll K. E. Bream J. H. Young H. A. et al. 2000 Interleukin-1 polymorphisms associated with increased risk of gastric cancer 404 6776 398 402 - 26.
El -Omar E. M. 2001 The importance of interleukin 1beta in Helicobacter pylori associated disease. 48 6 743 7 - 27.
Figueiredo C. Machado J. C. Pharoah P. Seruca R. Sousa S. Carvalho R. et al. 2002 Helicobacter pylori and interleukin 1 genotyping: an opportunity to identify high-risk individuals for gastric carcinoma 94 22 1680 7 - 28.
Furuta T. El -Omar E. M. Xiao F. Shirai N. Takashima M. Sugimura H. et al. 2002 Interleukin 1beta polymorphisms increase risk of hypochlorhydria and atrophic gastritis and reduce risk of duodenal ulcer recurrence in Japan. 123 1 92 105 - 29.
Garza-González E. Bosques-Padilla F. J. El -Omar E. Hold G. Tijerina-Menchaca R. Maldonado-Garza H. J. et al. 2005 Role of the polymorphic IL-1B, IL-1RN and TNF-A genes in distal gastric cancer in Mexico. 114 2 237 41 - 30.
Hwang I. R. Kodama T. Kikuchi S. Sakai K. Peterson L. E. Graham D. Y. et al. 2002 Effect of interleukin 1 polymorphisms on gastric mucosal interleukin 1beta production in Helicobacter pylori infection. 123 6 1793 803 - 31.
Machado J. C. Figueiredo C. Canedo P. Pharoah P. Carvalho R. Nabais S. et al. 2003 A proinflammatory genetic profile increases the risk for chronic atrophic gastritis and gastric carcinoma. 125 2 364 71 - 32.
Rad R. Dossumbekova A. Neu B. Lang R. Bauer S. Saur D. et al. 2004 Cytokine gene polymorphisms influence mucosal cytokine expression, gastric inflammation, and host specific colonisation during Helicobacter pylori infection 53 8 1082 9 - 33.
Garza-Gonzalez E. Bosques-Padilla F. J. Mendoza-Ibarra S. I. Flores-Gutierrez J. P. Maldonado-Garza H. J. Perez-Perez G. I. 2007 Assessment of the toll-like receptor 4 Asp299Gly, Thr399Ile and interleukin-8-251 polymorphisms in the risk for the development of distal gastric cancer. .7 70 - 34.
Kido S. Kitadai Y. Hattori N. Haruma K. Kido T. Ohta M. et al. 2001 Interleukin 8 and vascular endothelial growth factor-- prognostic factors in human gastric carcinomas? 37 12 1482 7 - 35.
Kitadai Y. Haruma K. Mukaida N. Ohmoto Y. Matsutani N. Yasui W. et al. 2000 Regulation of disease-progression genes in human gastric carcinoma cells by interleukin 8. 6 7 2735 40 - 36.
Yamaoka Y. Kodama T. Kita M. Imanishi J. Kashima K. Graham D. Y. 2001 Relation between cytokines and Helicobacter pylori in gastric cancer. 6 2 116 24 - 37.
Song J. H. Kim S. G. Jung S. A. Lee M. K. Jung H. C. Song I. S. 2010 The interleukin-8-251 AA genotype is associated with angiogenesis in gastric carcinogenesis in Helicobacter pylori-infected Koreans 51 2 158 65 - 38.
Rosenstiel P. Hellmig S. Hampe J. Ott S. Till A. Fischbach W. et al. 2006 Influence of polymorphisms in the NOD1/CARD4 and NOD2/CARD15 genes on the clinical outcome of Helicobacter pylori infection 8 7 1188 98 - 39.
Viala J. Chaput C. Boneca I. G. Cardona A. Girardin S. E. Moran A. P. et al. 2004 Nod1 responds to peptidoglycan delivered by the Helicobacter pylori cag pathogenicity island 5 11 1166 74 - 40.
Liu F. Pan K. Zhang X. Zhang Y. Zhang L. Ma J. et al. 2006 Genetic variants in cyclooxygenase-2: Expression and risk of gastric cancer and its precursors in a Chinese population. 130 7 975 84 - 41.
Li Y. He W. Liu T. Zhang Q. 2010 A new cyclo-oxygenase-2 gene variant in the Han Chinese population is associated with an increased risk of gastric carcinoma. 14 6 351 5 - 42.
Schröder N. W. Schumann R. R. 2005 Single nucleotide polymorphisms of Toll-like receptors and susceptibility to infectious disease. 5 3 156 64 - 43.
Wu M. S. Wu C. Y. Chen C. J. Lin M. T. Shun C. T. Lin J. T. 2003 Interleukin-10 genotypes associate with the risk of gastric carcinoma in Taiwanese Chinese. 104 5 617 23 - 44.
Ye Y. Shibata Y. Yun C. Ron D. Rapopor,t T. A. 2004 A membrane protein complex mediates retro-translocation from the ER lumen into the cytosol. 429 6994 841 7 - 45.
Curran J. E. Jowett J. B. Elliott K. S. Gao Y. Gluschenko K. Wang J. et al. 2005 Genetic variation in selenoprotein S influences inflammatory response. 37 11 1234 41 - 46.
Shibata T. Arisawa T. Tahara T. Ohkubo M. Yoshioka D. Maruyama N. et al. 2009 Selenoprotein S (SEPS1) gene-105G>A promoter polymorphism influences the susceptibility to gastric cancer in the Japanese population. .9 2 - 47.
Handa O. Naito Y. Yoshikawa T. 2010 Helicobacter pylori: a ROS-inducing bacterial species in the stomach 59 12 997 1003 - 48.
Valenzuela M. Pérez-Pérez G. Corvalán A. H. Carrasc,o G. Urra H. Bravo D. et al. 2010 Helicobacter pylori-induced loss of the inhibitor-of-apoptosis protein survivin is linked to gastritis and death of human gastric cells 202 7 1021 30 - 49.
Miyazaki T. Murayama Y. Shinomura Y. Yamamoto T. Watabe K. Tsutsui S. et al. 2007 E-cadherin gene promoter hypermethylation in H. pylori-induced enlarged fold gastritis. 12 523 31 - 50.
Lane D. P. 1992 Cancer. p53,guardian of the genome. 358 6381 15 6 - 51.
Hiyama T. Tanaka S. Kitadai Y. Ito M. Sumii M. Yoshihara M. et al. 2002 P53 Codon 72 polymorphism in gastric cancer susceptibility in patients with Helicobacter pylori-associated chronic gastritis. 100 3 304 8 - 52.
Pérez-Pérez G. I. Bosques-Padilla F. J. Crosatti M. L. Tijerina-Menchaca R. Garza-González E. 2005 Role of p53 codon 72 polymorphism in the risk of development of distal gastric cancer. 40 1 56 60 - 53.
Yi S. Y. Lee W. J. 2006 A p53 genetic polymorphism of gastric cancer: difference between early gastric cancer and advanced gastric cancer. 12 40 6536 9 - 54.
Bos J. L. 1989 Ras oncogenes in human cancer: a review. 49 17 4682 9 - 55.
Oster S. K. Ho C. S. Soucie E. L. Penn L. Z. 2002 The myc oncogene: MarvelouslY Complex. 84 81 154 - 56.
Calam J. 1999 Helicobacter pylori modulation of gastric acid. 72 2-3 195 202 - 57.
Chiurillo M. A. Moran Y. Cañas M. Valderrama E. Alvarez A. Armanie E. 2010 Combination of Helicobacter pylori-iceA2 and proinflammatory interleukin-1 polymorphisms is associated with the severity of histological changes in Venezuelan chronic gastritis patients 59 2 170 6 - 58.
Akopyanz N. Bukanov N. O. Westblom T. U. Kresovich S. Berg D. E. 1992 DNA diversity among clinical isolates of Helicobacter pylori detected by PCR-based RAPD fingerprinting. 20 19 5137 42 - 59.
Marshall D. G. Coleman D. C. Sullivan D. J. Xia H. O’Moráin C. A. Smyth C. J. 1996 Genomic DNA fingerprinting of clinical isolates of Helicobacter pylori using short oligonucleotide probes containing repetitive sequences. 81 5 509 17 - 60.
Perri F. Piepoli A. Bonvicini C. Gentile A. Quitadamo M. Di Candia M. et al. 2005 Cytokine gene polymorphisms in gastric cancer patients from two Italian areas at high and low cancer prevalence. 30 5 293 302 - 61.
Kim N. Cho S. I. Yim J. Y. Kim J. M. Lee D. H. Park J. H. et al. 2006 The effects of genetic polymorphisms of IL-1 and TNF-A on Helicobacter pylori-induced gastroduodenal diseases in Korea 11 2 105 12 - 62.
Ruzzo A. Graziano F. Pizzagalli F. Santini D. Battistelli V. Panunzi S. et al. 2005 Interleukin 1B gene (IL-1B) and interleukin 1 receptor antagonist gene (IL-1RN) polymorphisms in Helicobacter pylori-negative gastric cancer of intestinal and diffuse histotype. 16 6 887 92 - 63.
Sakuma K. Uozaki H. Chong J. M. Hironaka M. Sudo M. Ushiku T. et al. 2005 Cancer risk to the gastric corpus in Japanese, its correlation with interleukin-1beta gene polymorphism (+3953*T) and Epstein-Barr virus infection. 115 1 93 7 - 64.
Sicinschi L. A. Lopez-Carrillo L. Camargo M. C. Correa P. Sierra R. A. Henry R. R. et al. 2006 Gastric cancer risk in a Mexican population: role of Helicobacter pylori CagA positive infection and polymorphisms in interleukin-1 and-10 genes. 118 3 649 57 - 65.
Starzyńska T. Ferenc K. Wex T. Kähne T. Lubiński J. Lawniczak M. et al. 2006 The association between the interleukin-1 polymorphisms and gastric cancer risk depends on the family history of gastric carcinoma in the study population. 101 2 248 54 - 66.
Zambon C. F. Basso D. Navaglia F. Belluco C. Falda A. Fogar P. et al. 2005 Pro- and anti-inflammatory cytokines gene polymorphisms and Helicobacter pylori infection: interactions influence outcome. 29 4 141 52 - 67.
Zhang K. Mc Clure J. Elsayed S. Louie T. Conly J. 2005 Novel multiplex PCR assay for characterization and concomitant subtyping of staphylococcal cassette chromosome mec types I to V in methicillin-resistant Staphylococcus aureus. 43 10 5026 33 - 68.
Canedo P. Castanheira-Vale A. J. Lunet N. Pereira F. Figueiredo C. Gioia-Patricola L. et al. 2008 The interleukin-8-251*T/*A polymorphism is not associated with risk for gastric carcinoma development in a Portuguese population. 17 1 28 32 - 69.
Lu W. Pan K. Zhang L. Lin D. Miao X. You W. 2005 Genetic polymorphisms of interleukin (IL)-1B, IL-1RN, IL-8, IL-10 and tumor necrosis factor {alpha} and risk of gastric cancer in a Chinese population. 26 3 631 6 - 70.
Ohyauchi M. Imatani A. Yonechi M. Asano N. Miura A. Iijima K. et al. 2005 The polymorphism interleukin 8-251 A/T influences the susceptibility of Helicobacter pylori related gastric diseases in the Japanese population. 54 3 330 5 - 71.
Kamangar F. Abnet C. C. Hutchinson A. A. Newschaffer C. J. Helzlsouer K. Shugart Y. Y. et al. 2006 Polymorphisms in inflammation-related genes and risk of gastric cancer (Finland). 17 1 117 25 - 72.
Savage S. A. Hou L. Lissowska J. Chow W. H. Zatonski W. Chanock S. J. et al. 2006 Interleukin-8 polymorphisms are not associated with gastric cancer risk in a Polish population. 15 3 589 91 - 73.
Ferrero R. L. 2005 Innate immune recognition of the extracellular mucosal pathogen, Helicobacter pylori 42 8 879 85 - 74.
Hold G. L. Rabkin C. S. Chow W. H. Smith M. G. Gammon M. D. Risch H. A. et al. 2007 A functional polymorphism of toll-like receptor 4 gene increases risk of gastric carcinoma and its precursors 132 3 905 12 - 75.
Podolsky D. K. 2002 Inflammatory bowel disease. 347 6 417 29 - 76.
Crawley E. Kay R. Sillibourne J. Patel P. Hutchinson I. Woo P. 1999 Polymorphic haplotypes of the interleukin-10 5’ flanking region determine variable interleukin-10 transcription and are associated with particular phenotypes of juvenile rheumatoid arthritis. 42 6 1101 8 - 77.
Turner D. M. Williams D. M. Sankaran D. Lazarus M. Sinnott P. J. Hutchinson I. V. 1997 An investigation of polymorphism in the interleukin-10 gene promoter. 24 1 1 8 - 78.
Futreal P. A. Coin L. Marshall M. Down T. Hubbard T. Wooster R. et al. 2004 A census of human cancer genes. 4 3 177 83 - 79.
Vogelstein B. Kinzler K. W. 2004 Cancer genes and the pathways they control. 10 8 789 99 - 80.
Semb H. Christofori G. 1998 The tumor-suppressor function of E-cadherin. 63 6 1588 93 - 81.
Guilford P. Hopkins J. Harraway J. Mc Leod M. Mc Leod N. Harawira P. et al. 1998 E-cadherin germline mutations in familial gastric cancer. 392 6674 402 5 - 82.
Kaurah P. Mac Millan. A. Boyd N. Senz J. De Luca A. Chun N. et al. 2007 Founder and recurrent CDH1 mutations in families with hereditary diffuse gastric cancer. 297 21 2360 72 - 83.
Wynford-Thomas D. Blaydes J. 1998 The influence of cell context on the selection pressure for p53 mutation in human cancer. 19 1 29 36 - 84.
Todd R. Wong D. T. 1999 Oncogenes. 19 6A 4729 46