Cell-of-Origin Patterns Dominate the Molecular Classification of 10,000 Tumors from 33 Types of Cancer.

We conducted comprehensive integrative molecular analyses of the complete set of tumors in The Cancer Genome Atlas (TCGA), consisting of approximately 10,000 specimens and representing 33 types of cancer. We performed molecular clustering using data on chromosome-arm-level aneuploidy, DNA hypermethylation, mRNA, and miRNA expression levels and reverse-phase protein arrays, of which all, except for aneuploidy, revealed clustering primarily organized by histology, tissue type, or anatomic origin. The influence of cell type was evident in DNA-methylation-based clustering, even after excluding sites with known preexisting tissue-type-specific methylation. Integrative clustering further emphasized the dominant role of cell-of-origin patterns. Molecular similarities among histologically or anatomically related cancer types provide a basis for focused pan-cancer analyses, such as pan-gastrointestinal, pan-gynecological, pan-kidney, and pan-squamous cancers, and those related by stemness features, which in turn may inform strategies for future therapeutic development.

Carcinogenic Helicobacter pylori Strains Selectively Dysregulate the In Vivo Gastric Proteome, Which May Be Associated with Stomach Cancer Progression.

Helicobacter pylori is the strongest risk factor for gastric cancer. Initial interactions between H. pylori and its host originate at the microbial-gastric epithelial cell interface, and contact between H. pylori and gastric epithelium activates signaling pathways that drive oncogenesis. One microbial constituent that increases gastric cancer risk is the cag pathogenicity island, which encodes a type IV secretion system that translocates the effector protein, CagA, into host cells. We previously demonstrated that infection of Mongolian gerbils with a carcinogenic cag+H. pylori strain, 7.13, recapitulates many features of H. pylori-induced gastric cancer in humans. Therefore, we sought to define gastric proteomic changes induced by H. pylori that are critical for initiation of the gastric carcinogenic cascade. Gastric cell scrapings were harvested from H. pylori-infected and uninfected gerbils for quantitative proteomic analyses using isobaric tags for relative and absolute quantitation (iTRAQ). Quantitative proteomic analysis of samples from two biological replicate experiments quantified a total of 2764 proteins, 166 of which were significantly altered in abundance by H. pylori infection. Pathway mapping identified significantly altered inflammatory and cancer-signaling pathways that included Rab/Ras signaling proteins. Consistent with the iTRAQ results, RABEP2 and G3BP2 were significantly up-regulated in vitro, ex vivo in primary human gastric monolayers, and in vivo in gerbil gastric epithelium following infection with H. pylori strain 7.13 in a cag-dependent manner. Within human stomachs, RABEP2 and G3BP2 expression in gastric epithelium increased in parallel with the severity of premalignant and malignant lesions and was significantly elevated in intestinal metaplasia and dysplasia, as well as gastric adenocarcinoma, compared with gastritis alone. These results indicate that carcinogenic strains of H. pylori induce dramatic and specific changes within the gastric proteome in vivo and that a subset of altered proteins within pathways with oncogenic potential may facilitate the progression of gastric carcinogenesis in humans.

Dynamics of Helicobacter pylori infection as a determinant of progression of gastric precancerous lesions: 16-year follow-up of an eradication trial.

OBJECTIVE: To evaluate the long-term effect of cumulative time exposed to Helicobacter pylori infection on the progression of gastric lesions. DESIGN: 795 adults with precancerous gastric lesions were randomised to receive anti-H. pylori treatment at baseline. Gastric biopsies were obtained at baseline and at 3, 6, 12 and 16 years. A total of 456 individuals attended the 16-year visit. Cumulative time of H. pylori exposure was calculated as the number of years infected during follow-up. Multivariable logistic regression models were used to estimate the risk of progression to a more advanced diagnosis (versus no change/regression) as well as gastric cancer risk by intestinal metaplasia (IM) subtype. For a more detailed analysis of progression, we also used a histopathology score assessing both severity and extension of the gastric lesions (range 1-6). The score difference between baseline and 16 years was modelled by generalised linear models. RESULTS: Individuals who were continuously infected with H. pylori for 16 years had a higher probability of progression to a more advanced diagnosis than those who cleared the infection and remained negative after baseline (p=0.001). Incomplete-type IM was associated with higher risk of progression to cancer than complete-type (OR, 11.3; 95% CI 1.4 to 91.4). The average histopathology score increased by 0.20 units/year (95% CI 0.12 to 0.28) among individuals continuously infected with H. pylori. The effect of cumulative time of infection on progression in the histopathology score was significantly higher for individuals with atrophy (without IM) than for individuals with IM (p<0.001). CONCLUSIONS: Long-term exposure to H. pylori infection was associated with progression of precancerous lesions. Individuals infected with H. pylori with these lesions may benefit from eradication, particularly those with atrophic gastritis without IM. Incomplete-type IM may be a useful marker for the identification of individuals at higher risk for cancer.

Human and Helicobacter pylori coevolution shapes the risk of gastric disease.

Helicobacter pylori is the principal cause of gastric cancer, the second leading cause of cancer mortality worldwide. However, H. pylori prevalence generally does not predict cancer incidence. To determine whether coevolution between host and pathogen influences disease risk, we examined the association between the severity of gastric lesions and patterns of genomic variation in matched human and H. pylori samples. Patients were recruited from two geographically distinct Colombian populations with significantly different incidences of gastric cancer, but virtually identical prevalence of H. pylori infection. All H. pylori isolates contained the genetic signatures of multiple ancestries, with an ancestral African cluster predominating in a low-risk, coastal population and a European cluster in a high-risk, mountain population. The human ancestry of the biopsied individuals also varied with geography, with mostly African ancestry in the coastal region (58%), and mostly Amerindian ancestry in the mountain region (67%). The interaction between the host and pathogen ancestries completely accounted for the difference in the severity of gastric lesions in the two regions of Colombia. In particular, African H. pylori ancestry was relatively benign in humans of African ancestry but was deleterious in individuals with substantial Amerindian ancestry. Thus, coevolution likely modulated disease risk, and the disruption of coevolved human and H. pylori genomes can explain the high incidence of gastric disease in the mountain population.

Epigenetic and genetic variation in GATA5 is associated with gastric disease risk.

Gastric cancer incidence varies considerably among populations, even those with comparable rates of Helicobacter pylori infection. To test the hypothesis that genetic variation plays a role in gastric disease, we assessed the relationship between genotypes and gastric histopathology in a Colombian study population, using a genotyping array of immune-related single nucleotide polymorphisms (SNPs). Two synonymous SNPs (rs6061243 and rs6587239) were associated with progression of premalignant gastric lesions in a dominant-effects model after correction for multiple comparisons (p = 2.63E-07 and p = 7.97E-07, respectively); effect sizes were ß = -0.863 and ß = -0.815, respectively, where ß is an estimate of effect on histopathology scores, which ranged from 1 (normal) to 5 (dysplasia). In our replication cohort, a second Colombian population, both SNPs were associated with histopathology when additively modeled (ß = -0.256, 95 % CI = -0.47, -0.039; and ß = -0.239, 95 % CI = -0.45, -0.024), and rs6587239 was significantly associated in a dominant-effects model (ß = -0.330, 95 % CI = -0.66, 0.00). Because promoter methylation of GATA5 has previously been associated with gastric cancer, we also tested for the association of methylation status with more advanced histopathology scores in our samples and found a significant relationship (p = 0.001). A multivariate regression model revealed that the effects of both the promoter methylation and the exonic SNPs in GATA5 were independent. A SNP-by-methylation interaction term was also significant. This interaction between GATA5 variants and GATA5 promoter methylation indicates that the association of either factor with gastric disease progression is modified by the other.

Use of the noninvasive entero-test in the detection of Helicobacter pylori in children in an endemic area in Colombia.

BACKGROUND AND OBJECTIVE: Gastric infection with Helicobacter pylori (H pylori), a strong risk factor for gastric cancer, is highly prevalent in children residing in the Colombian Andes. We aimed to validate the use of the Entero-test to culture and genotype H pylori strains from asymptomatic Colombian children. METHODS: Children (ages 10-15 years, n = 110, 80 of which were H pylori positive by the urea breath test [UBT]) were subjected to the Entero-test, and strings were cultured and/or used for DNA extraction for polymerase chain reaction (PCR). These children had been treated for H pylori in 2007. A second population of children (ages 10-15 years, n = 95),which had not been previously treated, was also subjected to the Entero-test. RESULTS: Of UBT-positive children in the treated group, 29 of 80 (36%) Entero-test samples were H pylori culture positive; 29 additional string extracts were tested by PCR for the H pylori virulence factors cagA and vacA. PCR from cultures and extracts yielded a sensitivity of 74% and specificity of 87%. In the untreated group, 16 of 94 UBT-positive children (17%) produced Entero-tests that were culture positive. Fifty-eight of 94 (62%) string extracts were PCR positive for cagA and/or vacA. In previously treated children, H pylori strains were more often the less virulent vacA s2 (P = 0.001), m2 (P = 0.006), and i2 genotypes (P = 0.039). CONCLUSIONS: The Entero-test may be used as a noninvasive test to detect H pylori in asymptomatic children residing in high-risk areas for gastric cancer. Treatment of H pylori in children was associated with less virulent genotypes.

Non-invasive genotyping of Helicobacter pylori cagA, vacA, and hopQ from asymptomatic children.

BACKGROUND: Helicobacter pylori infection is usually acquired in childhood, but little is known about its natural history in asymptomatic children, primarily due to the paucity of non-invasive diagnostic methods. H. pylori strains harboring cagA and specific alleles of hopQ and vacA are associated with increased risk for gastric cancer. Many studies of H. pylori virulence markers in children have the bias that symptomatic subjects are selected for endoscopy, and these children may harbor the most virulent strains. Our aim is to genotype cagA, hopQ, and vacA alleles in stool DNA samples of healthy Colombian children residing in an area with high incidence of gastric cancer, to avoid selection bias resulting from endoscopy. METHODS: H. pylori status of 86 asymptomatic children was assessed by (13) C-urea breath test (UBT) and PCR. H. pylori 16S rRNA, cagA, hopQ, and vacA genes were amplified from stool DNA samples and sequenced. RESULTS: UBT was positive in 69 (80.2%) of 86 children; in stool DNA analysis, 78.3% were positive by 16S rRNA PCR. cagA, vacA, and hopQ were detected in 66.1%, 84.6%, and 72.3% of stool DNA samples from 16S rRNA-positive children. Of the children's DNA samples, which revealed vacA and hopQ alleles, 91.7% showed vacA s1 and 73.7% showed type I hopQ. Type I hopQ alleles were associated with cagA positivity and vacA s1 genotypes (p < 0.0001). CONCLUSIONS: Using stool DNA samples, virulence markers of H. pylori were successfully genotyped in a high percentage of the asymptomatic infected children, revealing a high prevalence of genotypes associated with virulence. Type I hopQ alleles were associated with the presence of cagA and the vacA s1 genotype.

Phylogeographic origin of Helicobacter pylori is a determinant of gastric cancer risk.

BACKGROUND AND AIMS: Helicobacter pylori colonises the stomach in half of all humans, and is the principal cause of gastric cancer, the second leading cause of cancer death worldwide. While gastric cancer rates correlate with H pylori prevalence in some areas, there are regions where infection is nearly universal, but rates of gastric cancer are low. In the case of Colombia, there is a 25-fold increase in gastric cancer rate in the Andean mountain (high risk) region compared to the coastal (low risk) region, despite similarly high (∼90%) prevalence of H pylori in the two locations. Our aim was to investigate the ancestral origin of H pylori strains isolated from subjects in these high- and low-risk regions and to determine whether this is a predictive determinant of precancerous lesions. METHODS: Multi-locus sequence typing was used to investigate phylogeographic origins of infecting H pylori strains isolated from subjects in the Pacific coast and Andes Mountains in the state of Nariño, Colombia. We analysed 64 subjects infected with cagA+ vacA s1m1 strains. Gastric biopsy slides from each individual were scored for histological lesions and evaluated for DNA damage by immunohistochemistry. RESULTS: We show that strains from the high-risk region were all of European phylogeographic origin, whereas those from the low risk region were of either European (34%) or African origin (66%). European strain origin was strongly predictive of increased premalignant histological lesions and epithelial DNA damage, even in the low-risk region; African strain origin was associated with reduced severity of these parameters. CONCLUSION: The phylogeographic origin of H pylori strains provides an explanation for geographic differences in cancer risk deriving from this infection.

Association of haplotypes of inflammation-related genes with gastric preneoplastic lesions in African Americans and Caucasians.

Identification of biomarkers is needed for development of screening programs to prevent gastric cancer. Because racial differences exist in cancer rates, we aimed to evaluate the association between polymorphisms in inflammation-related genes and gastric preneoplastic lesions in African Americans and Caucasians from Louisiana, USA. Gastric biopsies from 569 adults (361 African Americans and 208 Caucasians) undergoing diagnostic endoscopy were used for histological diagnosis and genomic DNA extraction. Polymorphisms within eight genes (IL1B, IL8, IL6, TNF, PTGS2, ARG1, IL10 and TGFB1) were investigated by TaqMan. The cagA status of Helicobacter pylori infection was assessed by PCR. Haplotype logistic regression models were used to identify variables associated with intestinal metaplasia or dysplasia. African Americans carrying the haplotype IL1B-511T/-31C/+3954T, which includes the three risk-associated alleles at the IL1B locus, were more likely to being diagnosed with intestinal metaplasia or dysplasia than those carrying the most common haplotype T-C-C (adjusted OR: 2.51, 95% CI: 1.1-5.5). None of the polymorphisms were associated with intestinal metaplasia and dysplasia in Caucasians. Age and cagA-positive status were independent factors associated with these lesions. Haplotypes at the IL1B locus may participate in mediating the susceptibility to gastric carcinogenesis and might be useful as markers of advanced premalignant lesions in African Americans. Interestingly, carriage of IL1B+3954T allele seems to be the key factor, even though the role played by other polymorphisms cannot be excluded.

Promoter DNA hypermethylation in gastric biopsies from subjects at high and low risk for gastric cancer.

Gene promoter CpG island hypermethylation is associated with Helicobacter pylori (H. pylori) infection and may be an important initiator of gastric carcinogenesis. To examine factors influencing methylation, we utilized bisulfite Pyrosequencing® technology for quantitative analysis of promoter DNA methylation in RPRM, APC, MGMT and TWIST1 genes using DNA from 86 gastric biopsies from Colombian residents of areas with high and low incidence of gastric cancer. H. pylori colonies were cultured from the same subjects, and gastric pathology was evaluated. Virulence factors cagA (including segments of the 3' end, encoding EPIYA polymorphisms) and vacA s and m regions were characterized in the H. pylori strains. Using univariate analysis, we found significantly elevated levels of RPRM and TWIST1 promoter DNA methylation in biopsies from residents of the high-risk region compared to those from residents of the low-risk region. The presence of cagA and vacA s1m1 alleles were independently associated with elevated levels of promoter DNA methylation of RPRM and MGMT. Using multivariate analysis, DNA methylation of RPRM was associated with location of residence, cagA and vacA s1m1 status and methylation of TWIST1. We conclude that cagA and vacA virulence determinants are significantly associated with quantitative differences in promoter DNA methylation in these populations, but that other as yet undefined factors that differ between the populations may also contribute to variation in methylation status.

Helicobacter pylori genotyping and sequencing using paraffin-embedded biopsies from residents of colombian areas with contrasting gastric cancer risks.

BACKGROUND: cagA-positive and vacA s1 and m1 genotypes of Helicobacter pylori are associated with an elevated risk of gastric cancer (GC). We determined these genotypes using paraffin-embedded gastric biopsy specimens harvested from infected individuals and compared genotype distributions in two Colombian populations residing in geographic regions with a high and low incidence of GC. METHODS: DNA from paraffin-embedded gastric biopsies from 107 adults was amplified using primers specific for cagA, for the cag'empty site', for the s and m alleles of vacA, and for H. pylori 16S rRNA. RESULTS: H. pylori infection was detected by molecular assays in 97 (90.7%) biopsies. Complete genotyping of cagA and vacA was achieved in 94 (96.9%) cases. The presence of cagA was detected in 78 of 97 cases (80.4%); when considered separately, cagA and vacA s regions were not significantly associated with a particular geographic area. The vacA m1 allele and s1m1 genotypes were more common in the area of high risk for GC (p = .037 and p = .044, respectively), while the vacA m2 allele and s2m2 genotypes were more prevalent in the low-risk area. The prevalence of the combination of cagA-positive, vacA s1m1 genotypes was 84.3% and 60.5% for high and low risk areas, respectively (p = .011). CONCLUSIONS: H. pylori cagA and vacA genotyping from paraffin-embedded gastric biopsies permitted reliable typability and discrimination. The more virulent cagA-positive s1m1 strains, as well as vacA m1 genotype, were more prevalent in high risk than in low risk areas, which may contribute to the difference in GC risk between those two regions.

Plasma selenium measurements in subjects from areas with contrasting gastric cancer risks in Colombia.

BACKGROUND: An inverse association between selenium status and incidence of different neoplasias including gastric cancer has been reported. This pilot study aimed to determine and compare selenium status in two Colombian populations with different gastric cancer risks: a high-risk area in the volcanic region of the Andes Mountains and a low-risk area on the Pacific coast. METHODS: Eighty nine adult males were recruited in the outpatient clinics of two public hospitals (44 and 45 from high- and low-risk areas, respectively) and provided a blood sample. Seventy one (79.8%) participants underwent upper gastrointestinal endoscopy. Plasma selenium was assayed using a fluorometric method, selenoprotein-P by ELISA, and glutathione peroxidase activity by a spectrophometric method. Histological diagnosis and Helicobacter pylori infection were evaluated in gastric biopsy samples. Unpaired samples t-test and linear regression analyses were used for statistical analyses. RESULTS: Although none of the subjects in either of the two geographic areas was selenium deficient, the level of plasma selenium was significantly lower in men from the high-risk area compared with those from the low-risk area. Levels of selenoprotein-P and glutathione peroxidase activity were similar between groups after adjustment for confounders. Selenium measurements were not associated with histopathological diagnosis. CONCLUSIONS: The high incidence of gastric cancer in the Andean region of Colombia is unlikely to be explained by selenium deficiency. We cannot exclude, however, that suboptimal selenium levels may exist in the gastric mucosa of subjects in the high-risk area. Therefore, the benefit of selenium supplementation in gastric cancer prevention cannot be dismissed.

Helicobacter pylori pathogen regulates p14ARF tumor suppressor and autophagy in gastric epithelial cells.

Infection with Helicobacter pylori is one of the strongest risk factors for development of gastric cancer. Although these bacteria infect approximately half of the world's population, only a small fraction of infected individuals develops gastric malignancies. Interactions between host and bacterial virulence factors are complex and interrelated, making it difficult to elucidate specific processes associated with H. pylori-induced tumorigenesis. In this study, we found that H. pylori inhibits p14ARF tumor suppressor by inducing its degradation. This effect was found to be strain-specific. Downregulation of p14ARF induced by H. pylori leads to inhibition of autophagy in a p53-independent manner in infected cells. We identified TRIP12 protein as E3 ubiquitin ligase that is upregulated by H. pylori, inducing ubiquitination and subsequent degradation of p14ARF protein. Using isogenic H. pylori mutants, we found that induction of TRIP12 is mediated by bacterial virulence factor CagA. Increased expression of TRIP12 protein was found in infected gastric epithelial cells in vitro and human gastric mucosa of H. pylori-infected individuals. In conclusion, our data demonstrate a new mechanism of ARF inhibition that may affect host-bacteria interactions and facilitate tumorigenic transformation in the stomach.

Comparative Molecular Analysis of Gastrointestinal Adenocarcinomas.

We analyzed 921 adenocarcinomas of the esophagus, stomach, colon, and rectum to examine shared and distinguishing molecular characteristics of gastrointestinal tract adenocarcinomas (GIACs). Hypermutated tumors were distinct regardless of cancer type and comprised those enriched for insertions/deletions, representing microsatellite instability cases with epigenetic silencing of MLH1 in the context of CpG island methylator phenotype, plus tumors with elevated single-nucleotide variants associated with mutations in POLE. Tumors with chromosomal instability were diverse, with gastroesophageal adenocarcinomas harboring fragmented genomes associated with genomic doubling and distinct mutational signatures. We identified a group of tumors in the colon and rectum lacking hypermutation and aneuploidy termed genome stable and enriched in DNA hypermethylation and mutations in KRAS, SOX9, and PCBP1.

MLH1 and MSH2 expression in pterygia.

PURPOSE: Pterygia have been reported to share some of the genetic defects seen in cancers, including microsatellite instability (MSI). We examined pterygia for the presence of proteins typically missing or defective in adenocarcinomas with MSI. We also performed microsatellite analysis on DNA from pterygia to test for instability in the size of the microsatellites, using markers conventionally used to characterize MSI in tumors (Bethesda convention markers). METHODS: We examined 13 pterygia by immunohistochemistry for MLH1 and MSH2, 2 proteins involved in DNA mismatch repair. In addition, we amplified the pterygial DNA with primers specific for 5 Bethesda markers (BAT25, BAT26, D2S123, D5S346, and D17S250). RESULTS: MLH1 staining was present at low levels in the basal cells of the cornea and migrating limbal cells of the pterygia. MSH2 staining was present in basal and in maturing epithelial cells of the cornea and migrating limbal cells of pterygia. We observed no reproducible examples of MSI or loss of heterozygosity (LOH). CONCLUSIONS: We were unable to confirm the presence of MSI and LOH by using the markers we examined. MSH2 staining appeared to be normal in pterygia. MLH1 staining was present but in reduced amounts compared with that seen in the conjunctiva.

Draft Genome Sequences of 13 Colombian Helicobacter pylori Strains Isolated from Pacific Coast and Andean Residents.

We present here the draft genomes of 13 Helicobacter pylori strains isolated from Colombian residents on the Pacific coast (n = 6) and in the Andes mountains (n = 7), locations that differ in gastric cancer risk. These 13 strains were obtained from individuals with diagnosed gastric lesions.

Increased expression of deleted in malignant brain tumors (DMBT1) gene in precancerous gastric lesions: Findings from human and animal studies.

Helicobacter pylori infection triggers a cascade of inflammatory stages that may lead to the appearance of non-atrophic gastritis, multifocal atrophic, intestinal metaplasia, dysplasia, and cancer. Deleted in malignant brain tumors 1 (DMBT1) belongs to the group of secreted scavenger receptor cysteine-rich proteins and is considered to be involved in host defense by binding to pathogens. Initial studies showed its deletion and loss of expression in a variety of tumors but the role of this gene in tumor development is not completely understood. Here, we examined the role of DMBT1 in gastric precancerous lesions in Caucasian, African American and Hispanic individuals as well as in the development of gastric pathology in a mouse model of H. pylori infection. We found that in 3 different populations, mucosal DMBT1 expression was significantly increased (2.5 fold) in individuals with dysplasia compared to multifocal atrophic gastritis without intestinal metaplasia; the increase was also observed in individuals with advanced gastritis and positive H. pylori infection. In our animal model, H. pylori infection of Dmbt1-/- mice resulted in significantly higher levels of gastritis, more extensive mucous metaplasia and reduced Il33 expression levels in the gastric mucosa compared to H. pylori-infected wild type mice. Our data in the animal model suggest that in response to H. pylori infection DMBT1 may mediate mucosal protection reducing the risk of developing gastric precancerous lesions. However, the increased expression in human gastric precancerous lesions points to a more complex role of DMBT1 in gastric carcinogenesis.

Interleukin-1beta and interleukin-1 receptor antagonist gene polymorphisms and gastric cancer: a meta-analysis.

BACKGROUND: Polymorphisms of interleukin-1B (IL1B) and its receptor antagonist (IL1RN) genes have been inconsistently associated with gastric cancer risk. We examined these associations by performing meta-analyses. MATERIALS AND METHODS: Twenty-five studies testing the association between IL1B and/or IL1RN gene polymorphisms and gastric cancer were examined: 14 studies of IL1B-511, 14 studies of IL1B-31, 8 studies of IL1B+3954, and 23 studies of IL1RN. Overall and ethnicity-specific summary odds ratios and corresponding 95% confidence intervals for gastric cancer associated with these polymorphisms were estimated using fixed- and random-effects models. Heterogeneity and publication bias were evaluated. RESULTS: IL1B-511T and IL1RN*2 were associated with gastric cancer risk in Caucasians, but not in Asians. For IL1B-511T, the association in Caucasians was stronger when intestinal-subtype and noncardia gastric cancer cases were examined. A nonsignificant trend was observed between IL1B-31C and gastric cancer in Caucasians. No significant association of IL1B+3954T and gastric cancer risk was detected. Studies with better methodologic characteristics reported stronger effects. There was no evidence of publication bias. CONCLUSION: IL1B-511T is associated with gastric cancer susceptibility in Caucasians. The meta-analyses suggest that the conflicting results among studies may be explained by variation in allele frequencies among the ethnic groups and variation in tumor types, as well as by the methodologic quality of the studies.

The homing receptor CD44 is involved in the progression of precancerous gastric lesions in patients infected with Helicobacter pylori and in development of mucous metaplasia in mice.

Infection with Helicobacter pylori (H. pylori) leads to inflammatory events that can promote gastric cancer development. Immune cells transition from the circulation into the infected mucosa through the interaction of their receptors and ligands in the endothelial compartment. CD44 expression is increased in advanced gastric lesions. However, the association of this molecule with the progression of these lesions over time has not been investigated. In addition, there is a lack of understanding of the CD44-dependent cellular processes that lead to gastritis, and possibly to gastric cancer. Here we studied H. pylori-positive subjects with gastric lesions that ranged from multifocal atrophic gastritis to dysplasia to determine gene expression changes associated with disease progression over a period of 6 years. We report that CD44 expression is significantly increased in individuals whose gastric lesions progressed along the gastric precancerous cascade. We also show that CD44-/- mice develop less severe and less extensive H. pylori-induced metaplasia, and show fewer infiltrating Gr1+ cells compared to wild type mice. We present data suggesting that CD44 is associated with disease progression. Mechanisms associated with these effects include induction of interferon gamma responses.