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sand / or surgery for histological examination and sub-classification of adenocarcinomasaccording to Lauren into diffuse, intestinal or mixed type. Fasting blood samples werecollected preoperatively for determination of serum gastrin by radioimmunoassay (uppernormal range 40 pM) and Helicobacter pylori (H pylori) serology. Tumor localization wasdetermined after macroscopic and histological examination and classified as antrum, corpusand overlapping. Results: Patients with localization of the carcinoma in the gastric corpus(n=45) had significantly higher serum gastrin than patients with carcinoma localized to theantrum (n=32) (100.7±27.5 vs. 17.1±2.6 pM, p=0.004). There was no significant differencein serum gastrin between patients with intestinal type (n=49) carcinoma compared to diffusetype (n=46) carcinoma (49.7±16 vs 58.0±21 pM, p=0.33), while patients with mixed histolog-ical type (n=7) had gastrin 98.7±50.6 pM, (p=0.29 vs. intestinal type). Among patients withtumor localized to the corpus, those with diffuse type carcinoma tended to have higherserum gastrin than patients with intestinal type (131.6±61 vs. 78.4±37 pM, p =0.29). Hpylori positive patients tended to have higher serum gastrin than HP negative patients(69.4±22.4 pM vs. 32.3±11.0 pM, p=0.29), but H pylori status did not differ between diffuseand intestinal type cancers (82.6% vs. 68.7% positive patients, p=0.26). Conclusions: Patientswith adenocarcinomas localized to the gastric corpus had higher serum gastrin that patientwith localization of carcinoma in the antrum. The histological subtype did not seem tobe influenced by serum gastrin concentrations. The findings support the hypothesis thathypergastrinemia, as seen in animal models also promotes carcinogenesis in patients.

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Incidence of Gastric Intestinal Metaplasia in Patients With NegativeHelicobacter pyloriLuis A. Quiel, Juan P. Alderuccio, Aina Adekunle, Itzel Fernandez, Jennifer Harley

Purpose: The aim of this study is to assess the development of gastric cancer precursors,including intestinal metaplasia (IM), despite the treatment for eradication of Helicobacterpylori, in order to determine the need for closer surveillance on this population. Methods:Retrospective study of adult patients who had information on IM status and at least one H.pylori test (stool, biopsy, or CLO) found on EMR were included in this analysis. A compositeH. pylori result was constructed using information from the three individual tests. Variableswith significant IM association status in the bi-variable analysis were included in multivariablelogistic regression analysis. Results: Two hundred twenty eight patients were included. Thepatients were analyzed in two groups (no IM vs. IM). No IM (198 patients): male 79(83.16%); median age: 50 years; race: Hispanic 157 (89.71%), African American 19 (82.61%),White 4 (66.67%), Asian 5 (83.33%), other 10 (66.67%); smoking: 36 (73.47%); PPI use:136 (83.44%); previous treatment for H. pylori: 85 (85%); H. pylori in stool: 23 (92%);H. pylori in biopsy: 45 (84.91%); CLO test+: 45 (90%); composite H. pylori: 82 (87.23%).IM (30 patients): male 16 (16.84%); median age: 61.5 years; race: Hispanic: 18 (10.29%),African American: 4 (17.39%), White: 2 (33.33%), Asian: 1 (16.67%) and other: 5 (33.33%);smoking: 13 (26.53%); PPI use: 27 (16.56%); previous treatment for H. pylori: 15 (15%);H. pylori in stool: 2 (8%); H. pylori in biopsy: 8 (15.09%); CLO test+: 5 (10%); compositeH. pylori: 12 (12.77%). Age (p=0.005), smoking (p=0.02), PPI use (p=0.02), and race othersubgroup (p=0.02) were statically significant. Multivariable analysis: age (OR: 1.05; 95% CI1.02), race other (OR 4.36; 95% CI 1.34), smoking (OR 3.42; 95%CI 1.53), and PPI use(OR 4.10; 95% CI 1.20). Conclusion: Over three-quarters of the participants were Hispanicand age was significant with a higher incidence of IM in older patients. History of smokingand previous use of proton pump inhibitors(PPI) were significant; however, in contrast toexisting knowledge, there was a higher incidence of IM in subjects who had previous useof PPI. There was no statistical difference in the incidence of IM between the groups thatwere positive on H. pylori. In view of lack of studies in the United States, this study willhelp further new guidelines for surveillance of patients with IM despite the treatment forH. pylori, which, as our study showed, does not protect against the development of IM

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The Gastric Precancerous CascadePelayo Correa

The consecutive steps of the gastric precancerous process have been compared to a cascadebecause of their irreversibility in time. Such steps are: chronic gastritis-> multifocal atrophy(gland loss) complete intestinal metaplasia-> incomplete intestinal metaplasia-> dysplasia-> adenocarcinoma. Although gastric cancer rates have been declining for decades, a recentincrease in incidence has been reported in many countries. Helicobacter pylori infection,the presumed cause of the tumor, starts in childhood but cancer itself is generally observedafter the 5th decade. This is probably the most frequent human chronic infection in theworld. The most recent elevation in cancer rates has been observed in many populations,mostly in young patients: 25-39 years of age. Isolates from high risk populations are morevirulent and induce cancer more frequently when administered to Mongolian gerbils whencompared to isolates from low risk populations. Multi-locus sequence typing (MLST) indicatesAfrican ancestry of low risk isolates and European/Amerindian ancestry of high risk isolates.The set of etiologic factors in high risk populations represent a "perfect storm".

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Genetic Polymorphisms of DNMT3A Are Associated With the Aberrant DNAMethylation of CDH1 in Japanese SubjectsTomiyasu Arisawa, Tomoki Fukuyama, Tomomitsu Tahara, Kaho Yamada, Hideto Yamada,Tomoe Nomura, Ranji Hayashi, Kazuhiro Matsunaga, Natsuko Kawada, Toshimi Otsuka,Masakatsu Nakamura, Takeo Shimasaki, Nobuyuki Toshikuni, Hisakazu Shiroeda,Tomoyuki Shibata

[Background] CpG island aberrant methylation is shown to be an important mechanism ingene silencing. E-cadherin (CDH1) is an adhesion molecule involved in tumour invasion/metastasis. Silencing of CDH1 by promoter CpG methylation has also been shown in gastriccancer. There are three active mammalian DNA methyltransferases: DNMT1, 3A and 3B. In

S-318AGA Abstracts

these three methyltransferases, DNMT3A and DNMT3B are considered to be de novo DNAmethyltranferase, which are critical in the dynamic DNA methylation process during embryo-genesis and pathogenesis. Recently, DNMT3A polymorphism is associated with gastric andcolorectal carcinogenesis. Within DNMT3A gene, there are several linkage disequilibriumblocks with above 0.05 of HWE p value and above 0.20 of minor allele frequency. In thisstudy, we investigated an association between CDH1 aberrant methylation in gastric mucosaand two tag polymorphisms of DNMT3A, rs6733868 C>G (linkage with rs7605753,rs13427202, rs7590760, rs6749992 and rs7586294) and rs13428812 A>G (linkage withrs7583409 and rs7578575). [Materials and Methods] Gastric mucosal samples were obtainedfrom 412 subjects without gastric malignancies. Methylation status of CDH1 was determinedby methylation-specific polymerase chain reaction. The genotyping of DNMT3A was per-formed by PCR-SSCP. [Results] Mean age of the subjects was 60.0 years old, male/femaleratio was 235/177 and H. pylori (HP) positive ratio was 249/412. Methylation of CDH1was seen in 150 of 412 subjects. The distribution of rs6733868 and rs13428812 genotypeswere 171CC, 189CG and 51GG (HWE p=1.00), and 254AA, 135AG and 23GG (HWE p=0.39). By a logistic regression analysis after adjustment for age, gender and HP infectionstatus, rs6733868 CG+GG and rs13428812 AG+GG genotypes were significantly associatedwith the reduced risk for CDH1 methylation (OR, 0.483; 95%CI, 0.318-0.734; p=0.0006and OR, 0.380; 95%CI, 0.241-0.599; p<0.0001, respectively). In HP infected subjects, thesesignificant associations were found (rs6733868 CG+GG: OR, 0.376; 95%CI, 0.224-0.631;p=0.0002 and rs13428812 AG+GG: OR, 0.333; 95%CI, 0.188-0.588; p=0.0002), whereasthere was no significant association in HP uninfected subjects. In addition, rs6733868CG+GG were associated with CDH1 methylation in the older subjects and rs13428812AG+GG was associated in the younger subjects. [Conclusions] DNMT3A polymorphismsare significantly associated with the risk for the development of CDH1 mathylation in non-cancerous gastric mucosa. The minor allele of DNMT3A is closely associated with the reducedrisk of CDH1 methylation.

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Methylation of miR-137 Is a Frequent and Early Event in GastricCarcinogenesisAlexander Link, Ruta Steponaitiene, Limas Kupcinskas, Cosima Langner, JurgitaSkieceviciene, Francesc Balaguer, Limas Kupcinskas, Peter Malfertheiner

INTRODUCTION: microRNAs (miRNA) are involved in every cellular process throughposttranscriptional regulation of gene expression and are frequently dysregulated duringcarcinogenesis. miR-137 functions as a tumor-suppressor-miRNA and CpG island methyla-tion of miR-137 is a common event in glioblastoma and colorectal cancer (CRC). However,the role of miR-137 in gastric carcinogenesis remains largely unexplored. In this study wecharacterize the epigenetic alterations of miR-137 in gastric carcinogenesis. METHODS: Wedetermined the methylation status of miR-137 in 266 tissues using bisulfite pyrosequencing.Overall, we analyzed 81 pairs of primary gastric cancer tissues (T-GC) with correspondingadjacent normal gastric mucosa (N-GC), 20 normal gastric tissues from controls (N), 23tissues from patients with chronic/atrophic gastritis ± intestinal metaplasia (CG) and 29pairs of primary CRC tissues (T-CRC) with corresponding adjacent normal colonic mucosa(N-CRC). TaqMan RT-PCR was used to analyze miR-137 expression. Tissue specimens wereprospectively collected in Kaunas, Lithuania and as part of the ERA-Net PathoGenoMicsproject at University of Magdeburg, Germany and informed consent was obtained from allpatients. RESULTS: Methylation of the miR-137 CpG island was more frequent in tumors(T-CRC 75%; T-GC 46.8%) compared to non-tumorous conditions (N-CRC 15.8%; N-GC42.3%) and higher in CRC as in GC. In comparison to N-GC, miR-137 methylation wasvery low in N (5%) and CG (18.2%). Quantitative miR-137 methylation levels were higherin T-CRC (29.83±3.12%) compared to N-CRC (15.37±3.53%, p=0.004) and in similarfashion in T-GC (21.08±1.58%) to N-GC (16.92±1.32%, p=0.045). Gradual increase inmiR-137 methylation was seen in correlation with Correas cascade from N to CG and to N-GC (7.47±0.89%; 10.68±0.97%; 16.92±1.32%, respectively, p<0.0001). miR-137 expressionanalyses showed inverse correlation between miR-137 CpG methylation and miR-137 expres-sion. Tumors with low methylation level showed higher expression compared to tumorswith intermediate or high miR-137 methylation (p=0.0032). Subroup analyses of GC revealhigher miR-137 methylation in tumors localized in antrum compared to cardia and corpus(p=0.07) and higher in intestinal and mixed type compared to diffuse type of GC (p=0.03),while no correlation was found for TNM stage, tumor differentiation or preexisting H.pyloriinfection. CONCLUSIONS: miR-137 is frequently methylated in gastrointestinal cancerssuch as gastric and colorectal cancers. Increasing methylation of miR-137 from normalmucosa, chronic gastritis to cancerous tissues suggests it is an early event in gastric carcinogen-esis. The alterations of miR-137 may play probably a more considerable role in developmentof intestinal type GC; however, the functional role in H.pylori-related carcinogenesis needsfurther evaluation.