Gastritis is an inflammation of the mucosa of the stomach, and has many etiologies. Gastritis can be classified as being acute or chronic. For the purpose of this chapter, we will focus only on chronic gastritis due to its relevance to gastric cancer. Among the causes of chronic gastritis are chronic bile reflux, stress, certain autoimmune disorders and bacterial infection, primarily
2. Histological classification and grading of gastritis
For the purpose of this chapter we decided to divided chronic gastritis in into two main categories, namely non-atrophic and atrophic gastritis . The main purpose of this classification is to individualize high-risk gastritis subgroup that subsequently might develop to gastric cancer. In the gastric mucosa, atrophy is defined as the loss of appropriate glands. Atrophic gastritis, resulting mainly from long-standing
Cross-sectional and long-term follow-up trials conducted in various epidemiologic settings have consistently associated OLGA stages III and IV with a higher risk of gastric cancer vs. low-risk OLGA stages [ie, stages 0, I, and II]] . The latter can be assessed based on whether the metaplastic epithelium phenotype resembles large bowel epithelia [colonic-type intestinal metaplasia] or the small intestinal mucosa [6, 10, 11]. This classification was made by determining the histochemical phenotype of intestinal metaplasia [IM] using high-iron diamine stain. Cross-sectional descriptive studies and follow-up trials have consistently supported a strong association between OLGA stages and IM histochemical phenotypes, where IM of small intestinal type [type I] significantly prevailed in low-risk atrophic stages and high-risk OLGA stages were associated with IM of types II and III . Accordingly, epidemiological studies have shown that degree of severity for non-metaplastic atrophy influences the prevalence of IM and that the severity of IM influences the prevalence of dysplasia . These results support the concept that IM and dysplasia are linked in a sequential cause-effect relationship and confirm a proposed model for the pathogenesis of gastric cancer . However, risk assessment for gastric cancer development has not been well defined for other premalignant conditions .
3. Genetics bases of gastritis
The seminal proposal of a genetic model for tumorigenesis by Fearon & Vogelstein  and, more recently, the categorization of different cancers types into six physiological groups proposed by Hanahan & Weinberg  provide a theoretical framework for understanding the genetic and epigenetic bases of gastritis as well as premalignant conditions of gastric cancer. Thus, gastritis, and gastric cancer premalignant conditions should be understood as a disturbance in the balance between tumor suppressor genes and oncogenes. p53 gene  and the c-erbB2 oncogene [17, 18] were the first tumor suppressor gene and oncogene to be identified in gastric cancer, respectively. From these reports, a growing number of genes have been identified . However, different studies have shown that mutation and/or deletion is an infrequent mechanism of inactivating well stablished tumor suppressor genes such as E-cadherin [20, 21]. Similarly, loss of heterozygosity [LOH] and microsatellite instability [MSI] have been frequently found in gastric cancer [19, 22, 23]. However, mutations of the DNA mismatch repair genes, hMSH2 and hMLH1, responsible for LOH and MSI, are not frequently encountered [19, 24]. Taken together, these observations suggest that genetic alterations do not completely explain the accumulation of genetic damage observed in gastric cancer and premalignant conditions. In this scenario, the recent inactivation of tumor suppressor genes by a novel epigenetic mechanisms, DNA methylation, has been proposed as an alternative mechanism to mutation and/or deletions . The best-documented inactivation by DNA methylation in gastric cancer is the silencing of DNA mismatch repair genes hMSH2 and hMLH1 . This inactivation is responsible for the development of the majority of MSI-related gastric cancers. As such, this inactivation leads to subsequent mutations in simple repetitive sequences within genes that are critical to the neoplastic process .
4. Epigenetic bases of gastritis
Epigenetic processes control the packaging and function of the human genome and contribute to normal development and disease . Epigenetic mechanisms such as DNA methylation, histone modifications and microRNAs  virtually affects all of the pathways in the cellular network, such as DNA repair, cell cycle, and apoptosis . DNA methylation, a process in which cytosines acquire a methyl group in 5' position only if they are followed by a guanine [CpG site]  is an early event in carcinogenesis [29-31]. In addition, DNA metylation has been recently considered as an excellent candidate to explain how certain environmental factors may increase the risk of cancer . Accordingly, an emerging catalog of specific tumor suppressor genes inactivated by DNA methylation in gastrointestinal tumors has been established [33-36]. Most of these studies has been performed by Methylation Specific – Polymerase Chain Reaction [MS-PCR], the most popular assay for DNA methylation . In MSP sodium bisulphite is used to convert cytosine residues to uracil residues in single-stranded DNA under conditions whereby 5-methylcytosine remains non-reactive. The converted DNA is amplified with specific primers and since all the cytosine residues remaining in the sequence represent previously methylated cytosines, MSP approach allows to detect DNA isolated from fewer than 100 cells [38, 39].
5. DNA methylation and gastritis
There are limited reports on DNA methylation analysis in gastritis and premalignant lesions of gastric cancer. Kang et al  tested five genes [p16, hMLH1, DAP-kinase, THBS1, and TIMP-3] in a series of 64 carcinomas and 179 premalignant conditions [69 chronic gastritis, 49 IM and 61 gastric adenomas] to identify two different classes of methylation patterns, preferential methylation of THBS-1 and TIMP-3 in chronic gastritis and IM and preferential methylation of hMLH1 and p16 in intestinal metaplasia, displasia and gastric cancer. These findings suggest that DNA methylation occur early in multistep gastric carcinogenesis and specific patterns of DNA methylation on specific genes ocurr along these steps . A subsequent study identified specific patterns of DNA methylation associated with aging after testing 11 genes in 268 premalignant gastritis . DNA methylation was found in increasingly frequency as a function of aging in five genes [DAP-kinase, E-cadherin, p14, THBS1 and TIMP-3], whereas the other genes [COX-2, GSTP1, MGMT, hMLH1, p16, and RASSF1A] were rarely methylated . Since E-cadherin was methylated at high frequency, a further study demonstrated, for the first time, that DNA methylation of promoter region of E-cadherin was associated with
Recently, our group identified promotor DNA methylation of a novel gene, Reprimo [RPRM], not only in gastric mucosa but also in the plasma of gastric cancer patients . This methylated circulating cell-free DNA offers the opportunity for non-invasive detection of gastric cancer and premalignant gastritis. DNA methylation of promoter region of RPRM was initially identified by high-throughput microarray experiments that analyzed global changes in gene expression in pancreatic cancer cell lines treated with the demethylating agent 5-aza-2-deoxycitidine. Among 11 re-expressed genes, RPRM was highly re-expressed . Following this finding, the analysis of the methylation status of RPRM in clinical samples of pancreatic cancer identified a high frequency of DNA methylation of the promoter of RPRM . Subsequent research focused on different types of tumors [breast, esophagus, lymphoma, etc.] including gastric carcinoma . However, our study, not only looked into the methylation of RPRM in tumor tissues, but also in non-invasive plasma samples from the same patients . Interestingly, methylate circulating cell-free DNA of RPRM was found in over 90% in plasma from gastric cancer patients but less than 10% among asymptomatic controls . Thus, our results were the first to indicate that methylation of promoter region of RPRM might act as a potential biomarker for early detection of gastric cancer. RPRM is a downstream mediator of p53-induced G2 cell cycle arrest . When adenovirus expressing recombinant RPRM cDNA was infected into human colorectal cancer cell line DLD1, cell cycle arrest at the G2 phase was observed . However, it has been suggested that RPRM-induced cell cycle arrest is mediated by an indirect inhibition of Cdc2-CyclinB1 complex translocation to the nucleus . Recently, RPRM has also been proposed to be a tumor suppressor gene through in vitro colony formation assays . After RPRM transfection into the non-expressing renal cell carcinoma cell line SKRC39 there was a signicantly reduced number of G418 resistant colonies compared to the cell lines transfected with an empty vector control. However, it is unknown whether RPRM is a tumor suppressor in gastric cancer. A recent quantitative analysis of promoter DNA methylation of RPRM from Colombian residents from areas with high and low incidence of gastric cancer demonstrated an association with virulence factors cagA [including segments of the 30 end, encoding EPIYA polymorphisms] and vacA s1 and m1 regions of
6. Integration of histological and DNA methylation features of gastritis
Although histological assessment of gastritis to search for premalignant conditions for the development of gastric cancer has been proposed  and epigenetic markers based on DNA methylation are associated with this progression , no integrative approach has been explore up to date for this two disparate fields. Recently, we have integrated histological together with
Interestingly, further work have shown that p73 overexpression might be associated with hypo- or demethylation of the promoter region of p73 . Taken together these findings suggest that DNA methylation might play a role in gastritis and premalignant condition in both ways, inactivating or activating tumor-related genes by hypermethylation or demethylation of promoter region of specific genes, respectively.
In conclusion, specific histological features with increasing risk to progress to gastric cancer can be assessed by OLGA system. Specific DNA methylation changes might play a major role in premalignant gastritis and might be associated with
8. Grant support
Grants-in-Aid for Fondo Nacional de Ciencia y Tecnologia [FONDECYT] #1111014 and Fondo de Fomento al Desarrollo Científico y Tecnológico [FONDEF] #D09i1137 to A.H. Corvalan from the Government of Chile.
We thank Natalia Saez for premium editing and proofreading of the manuscript.