H. pylori genotyping may be useful for the identification of patients at high risk of progression of gastric preneoplastic lesions and who need more intensive surveillance.

There are no established criteria to classify patients into high or low risk of progressing to gastric cancer (GC). The aim of the study was to identify predictors of GC occurrence among patients with gastric preneoplastic lesions. A prospective and retrospective follow-up study was carried out in a province in Spain with one of the highest risk of GC. The study included 478 patients who underwent gastric biopsy in 1988-1994 with diagnoses of normal mucosa, nonatrophic gastritis (NAG), non-metaplastic multifocal atrophic gastritis (MAG) and complete or incomplete intestinal metaplasia (IM) and who accepted to undergo a new biopsy during [2005][2006][2007] or had an event during follow up. Inter-and intra-observer variability of histological diagnosis was assessed. Analysis was done using Cox proportional hazards risk (HR) models. The mean age of the patients was 50 years, 47% were males and the mean follow-up time was 12.8 years. During follow-up, 23 GC (4.8%) were diagnosed (21 adenocarcinomas and 2 lymphomas) with an incidence of 3.77 per 1,000 person per year. The incidence rate of GC for those with incomplete IM was 16.5 per 1,000 person years. Out the 21 adenocarcinomas, 16 had an incomplete IM in the baseline diagnosis. Incomplete IM (HR 11.3; 95% CI 3.8-33.9) and a family history of GC (HR 6.1; 95% CI 1.7-22.4) were the strongest risk factors for gastric adenocarcinoma. Subtyping of IM and family history of GC may be useful for the identification of high-risk patients who need more intensive surveillance.Experimental and epidemiological evidence indicates that gastric cancer (GC) is the result of a long multistep and multifactorial process. 1 An inflammatory process in the antrum, usually associated with Helicobacter pylori (Hp) infection, is considered to be the cause of the initial lesion, which may progress toward a multifocal chronic atrophic gastritis in the corpus, intestinal metaplasia (IM), dysplasia and finally the invasive carcinoma. 2 This seems to be the sequence of the intestinal type of gastric adenocarcinoma, which is the predominant type of GC in many countries, and these lesions are considered as precursors of this type of cancer. IM is usually subclassified as ''complete'' (small intestinal type or Type I) or ''incomplete'' (colonic type or Types II and III), which is thought to be the most advanced stage of IM. 3 The diffuse type of GC, on the contrary, lacks well-defined precursors, although many studies have observed that it is also associated with intestinal metaplasia. 3 Symptoms are often absent or nonspecific in patients suffering this long multistep process, and, therefore, GC is usually diagnosed at an advanced stage when curative options are very limited. 4,5 Five-year relative survival rates of GC in European patients are very low (less than 23%) 6 ; therefore, better control of risk factors and identification of high-risk patients at an early stage of disease represent the most effective ways for reducing the burden of this tumor.The need to reevaluate premalignant gastric le...

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BackgroundIntestinal metaplasia (IM) is a precursor lesion that precedes gastric cancer (GC). There are two IM histological subtypes, complete (CIM) and incomplete (IIM), the latter having higher progression rates to GC. This study was aimed at analysing gene expression and molecular processes involved in the progression from normal mucosa to IM, and also from IM subtypes to GC.MethodologyWe used expression data to compare the transcriptome of healthy gastric mucosa to that of IM not progressing to GC, and the transcriptome of IM subtypes that had progressed to GC to those that did not progress. Some deregulated genes were validated and pathway analyses were performed.ResultsComparison of IM subtypes that had progressed to GC with those that did not progress showed smaller differences in the expression profiles than the comparison of IM that did not progress with healthy mucosa. New transcripts identified in IM not progressing to GC included TRIM, TMEM, homeobox and transporter genes and SNORD116. Comparison to normal mucosa identified non tumoral Warburg effect and melatonin degradation as previously unreported processes involved in IM. Overexpressed antigen processing is common to both IM-subtypes progressing to GC, but IIM showed more over-expressed oncogenic genes and molecular processes than CIM.ConclusionsThere are greater differences in gene expression and molecular processes involved in the progression from normal healthy mucosa to IM than from IM to gastric cancer. While antigen processing is common in both IM-subtypes progressing to GC, more oncogenic processes are observed in the progression of IIM.

Background Intestinal metaplasia (IM) is a gastric cancer precursor lesion (GCPL), with the highest risk to progress to gastric cancer (GC). Clinical guidelines recommend gastroscopy every 3 years for extensive IM. Unfortunately, studies on protein biomarkers indicating a transition from IM to GC are lacking. We have recently found that the IFNα-responsive gene Schlafen 4 (Slfn4) present in immune cells correlates with metaplastic changes in Helicobacter-infected mice. Therefore we tested the hypothesis that a human homolog of Slfn4, which is Schlafen 5 (SLFN5) correlates with progression of GCPL to GC. Methods Jurkat T-lymphoid and HL-60 myeloid cell lines were treated with IFNα and SLFN5 mRNA was quantified by qPCR. SLFN5 protein expression in the inflamed gastric mucosa was co-localized to specific immune cell types by immunohistochemistry using CD20, CD2 and MAC2 antibodies. SLFN5 expression was also determined by immunohistochemistry in FFPE samples from individuals with non-atrophic, atrophic gastritis, complete and incomplete IM as well as GC. Results We demonstrated that IFNα treatment of Jurkat and HL-60 cells induced SLFN5 mRNA. SLFN5 protein was expressed mainly by T lymphocytes in inflamed gastric mucosa. The highest level of SLFN5 expression was observed in subjects with IM that progressed to GC. ROC curves demonstrated that combining SLFN5 expression with the histological diagnosis of IM significantly increased the probability of identifying patients that might progress to GC. Conclusion Elevated SLFN5 protein expression in subjects with IM correlated with progression to gastric cancer.

method design for H. pylori genotyping, sample typing, manuscript draft , and fi nal version: R.M. Ferreira and C. Figueiredo; gastroscopies: P. Alonso; statistical analyses: C. Bonet; pathology reviews: M.L. Pardo, J.M. Ruiz Liso, and J.M. Sanz-Anquela; result interpretation and fi nal approval of the manuscript: all authors.

In order to assess whether inherited genetic variability in the mucin genes associates with the evolution of gastric cancer precursor lesions (GCPLs), we genotyped 22 tagSNPs in MUC1, MUC6 and MUC2 genes of 387 patients with GCPLs that had been followed up for 12.8 years. According to the diagnosis at recruitment and at the end of follow-up, the lesions did not change in 43.1% of the patients, regressed in 28.7% and progressed in 28.2%. Three SNPs in the 3'-moiety of MUC2 were significantly associated with a decreased risk of progression of the lesions, whereas another four SNPs, located at the 5'-moiety, were found to be significantly associated either with increased [one single-nucleotide polymorphism (SNP)] or decreased (three SNPs) probability of regression. Stratified analysis indicated that significance was maintained only in those subjects positive for Helicobacter pylori infection and in those not consuming non-steroidal anti-inflammatory drugs, which were found protective against lesion progression. Haplotype analyses indicated the presence of two haplotypes, one in each moiety of the gene, that were significantly associated with decreased risk of progression of the lesions [odds ratio (OR) = 0.49 and 0.46; 95% confidence interval (CI) = 0.28-0.85 and 0.25-0.86, respectively]. The 5'-end haplotype was also associated with increased probability of regression (OR = 1.67; 95% CI = 1.02-2.73), altogether suggesting a protective role against progression of the precancerous lesions. No significant association was found with variants in MUC1 and MUC6 genes. These results indicate, for the first time, that genetic variability in MUC2 is associated with evolution of GCPLs, especially in H.pylori infected patients, suggesting a role of this secreted mucin in gastric carcinogenesis.

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