IL-1beta and IL-10 genotypes in a high gastric cancer risk province in China

shown that chronic H. pylori infection is associatedwith decreasedp27K% Recently, altered expression of p16~"k'~, a member of another group of CDIs, has been reported in gastric cancer. The aim of the current study was to examinewhether H. pyloriinfluences the expression of p16~"4ain the gastric mucosa. Methods: p16=n~expressionwas evaluatedin gastric antral biopsies by immunohistochemistry using a polyclonal antibody (Pharmingen) at a 1:400 titre in 50 patients with non-ulcer dyspepsia undergoing endoscopy. 19 patients were N. py/orinegative, 23 carded cagA+ strains and 8 carried cagA-strains. H. pylori was diagnosed by rapid urease test, histology and serology, and H. py/ori cagA status was determined by serology. Sectionswere designatedpositive if at least 25% of the epithelial cells were stained. Adjacent sections were stained for proliferating epithelial cells (by Ki67) and for apoptotic cells (by TUNEL assay), and proliferative and apoptotics indices were calculated. Results: Both in uninfected controls and in N. pylorhpositive patients, the expression of p16~°k'~was higher in the neck and base of the gland compared to the foveolar area. Epithelial staining for p16~"k'~wasincreased in H. pylori infection (32% of cases positive in H. pylori-infected patients vs 11% in controls in the foveolar region, 76% vs 41% in the neck, and 77% vs 58% in the glandular base, p = 0.4 for the neck). Both proliferation and apoptosis were increased in association with H. pylori but there was no correlation betweenthe expression of 16~nk'aand the proliferation index. However, a significant positive correlation was found between the apoptotic index and p16~"k~immunostaining in the foveolar and neck regions. No significant differences in p16~"k'~expressionwere seen betweencagA-positive and negative cases. Conclusions: The tumor suppressor gene p16~nk4ais paradoxically over expressed in the epithelial cells of H. pylori-infected patients. The increasedexpressionof p16tnk'~induced by N. pylori correlates with increasedapoptosis, suggesting a possible role for this cell cycle regulator in increasedgastric cell turnover induced by N. py/ori.

p = 0.27 respectively).However,inthe Hp positive group 71.1% of the patientswere genotype NA and 26.7% were NC compared to 51.4% NA and 42.9% NC in the Hp negativegroup (p=0.07). This is very close to formal significance. CONCLUSION:Our results at present would suggestthat there is no significant relationshipbetweenthis IL-12 markerand histological tumour type. However the trend to significance at this locus implicates a probable role for the IL-12p40 C allelein Helicobacterpylorii negativegastric cancer.This exciting observation will now be pursued in a larger patient cohort. 3993 Interleukin-1 PolymorphismsIn Patients With Gastric Cancer And In An Apparently Healthy Population Without Gastric Cancer In Japan Naoki Ohmiya, NagoyaUniv Sch of Medicine, NagoyaJapan; Hidemi Goto, Nagoya,Japan Background: Helicobacter pylori (H. pylon) infects the stomach in more than 90% of gastric cancer cases. Recently it was reported that inturluukin-l(IL-1) gene cluster polymorphisms in Caucasian populations are associated with an increased risk of both hypochlorhydria induced by H. pylori and gastric cancer. Here we investigatethe relationship between those polymorphisms and atrophic gastritis status in a healthy population and clinicopathologic features of gastric cancer in Japan. Methods: Allelic polymorphisms at positions -31, -511, and +3954 in IL-1B gene; 86-bp tandem repeat in intron 2 in IL-1Rli gene; fasting plasma gastrin; pepsinogen (PG) I and II levels; and anti-H, pylori IgG titers were analyzedin 427 individuals (control group) who received multiphasic health testing (gastric cancer was ruled out by high-quality barium X-ray and/or endoscopy)and in 143 patientssuffering from gastric cancer (GC group) with informed consent. Results: Frequenciesof polymorphisms were as follows: 20.3% (C/C), 51.3% (C/T), 28.4% (T/T) at -31; 28.9% (C/C), 50.8% (C/T), 20.3% (T/T) at -511; 91.0% (C/C), 9.0% (C/T) at +3954; 87.2% (1/1), 8.3% (1/2), 3.8% (1/3-5), 0.5% (2/2), and 0.2% (2/3) in IL-1RN in the control group, and 24.7% (C/C), 51.4% (C/T), 23.9% (T/T) at -31; 25.3% (C/C), 50.0% (C/T), 24.7% (T/T) at -511; 90.9% (C/C), 9.1% (C/ T) at +3954; 90.2% (1/1), 5.6% (1/2), 3.5% (1/3-5), 0.7% (2/2) in IL-1RN in the GC group. Gastrin levels were 87.0-+7.6 (C/C), 135.9-+18.3 (C/T), 152.4-+31 (T/T) pg/ml at -31 in the H. pylori-positJve control group aged50s and 60s. Therewere more H. pylori-positivu atrophic gastritis cases diagnosed by the PG method in C/T and T/T than in C/C at -31 (odds ratios [OR] 2.1 and 2.0) in the H. pylorkpositive control group. Cancers with C/C at -31 position were located in the proximal stomach and those with T/T in the distal stomach (OR 2.1). More cancers with T/T were PG positive than those with C/C at -31(0R 1.7). There was no significant difference in genotype distribution regarding cancer differentiation, vascular invasion, lymph node metastasis, or TNM stage. Conclusion: There was a marked difference in IL-1 B + 3954 and IL-1Rli polymorphisms between Caucasiansand Japanese.T allele at IL1B-31 may induce strong gastric inflammation under N. pylori infection followed by atrophic gastritis and be eventually associatedwith carcinogenesisin the distal stomach.

3996 Seroreactivity to 35-kDa Antigen is Associated with a Lower Risk of Gastric Adenocarcinoma Tju-Siang Chua, Kwong-Ming Fock, Changi Gen Hosp, Singapore Singapore; Yiong-Huak Chart, Ctin Trials and Epidemiology Research Unit, Singapore Singapore; Suppiah Dhamodaran, Tay-Meng Ng, Jen-Lock Khor, Changi Gen Hosp, Singapore Singapore; EngKiong Teo Introduction: Helicobacterpylori (HP) infection is associatedwith an increasedrisk of gastric adenocarcinoma. However, only a minority of those infected with HP will develop gastric cancer. Stratification of HP strains based on carcinogenic potential will provide a basis for selective surveillanceand eradicationtherapy. Aims: (1) To study the anti-HP antibody profile in Chinese with gastric adenocarcinoma. (2) To identify any HP antigen which may be associated with an increased or decreasedrisk of gastric carcinoma. Patients and Methods: This was a case-control study comparing the seroprevalenceof antibodies to various lip antigens in Chinesewith gastric carcinomaand the normal Chinesepopulation. Blood samples were obtained from Chinese patients with gastric carcinoma. The control population was drawn from subjectswho had beenrandomly invitedto participatein a nationwidehealthsurvey. The HP status of all study subjectswere determinedby an enzyme-linkedimmunosorbentassay (ELISA) developedusing local antigens. Western blotting immunoassay,which can detect six HP antigens (CagA, VacA, 19.5, 26.5, 30 and 35 kDa), was carried out on all ELISA-positive samples. Results: 41 patients with gastric carcinoma (73.2% males, mean age 44.6-+15,5 years) and 190 control subjects (49.5% males, mean age 67.4-+12.8 years) were included. 37 (27 males, 10 females) in the gastric carcinoma group and 88 (44 males, 44 females) in the control population were ELISA positive for HP. HP seropositivity was significantly higher in patients with gastric carcinoma compared to controls (90.2% vs 46.3%, p
3994 IL-lbeta and IL-IO Genotypesin a High Gastric Cancer Risk Province in China Emad M. El-Omar, Univ of Aberdeen,Aberdeen United Kingdom; Wei-Cheng You, WongHo Chow, Joseph F. Fraumeni Jr, Charles S. Rabkin, National Cancer Institute, Bethesda, MD Background: Linqu County, Shandong, China, has one of the world's highest mortality rates from gastric cancer (GC)and 98 % of the adult population >35 years old has chronic atrophic gastritis (CAG), intestinal metaplasia(IM) or dysplasia (DYS). We recently reported that proinflammatory genotypesof the IL-1 genecluster were associatedwith increasedrisk of gastric cancer and its precursors in Caucasians(Nature, 2000; 404: 398-402). Aims: To determine the prevalenceof pro-inflammatory genotypes of the IL-1B and IL-IO genes in this Chinese population and comparethem to a healthyCaucasianpopulation from Polandthat has a lower risk of GC and a lower prevalence of atrophy. We also examined associations of these genotypes with rates of progression or regression from one histological type to another. Subjects & Methods: The two populationsstudied were: (1) 921 Shandongresidentscomprising equal numbers of GAG, IM or DYS in 1989 who were re-endoscopedfive years later, and (2) 429 healthy Caucasiansfrom Poland. We used 5' nuclease assays to detect two IL-1,8enhancing alleles (IL-1 B-511T & IL-1B-31T) and three IL-10-attenuatingalleles (IL-10-1082A, IL-10-819T & IL-10-592A). Results: The prevalence of IL-lfl-enhancing IL-1B-511T+/ -31T+ genotypes was 72% in the Shandong population compared to 49% in the Polish population (p<0.001). Similarly, the Shandong population had a high prevalence(42%) of the low IL-10 ATNATA genotype and correspondingly a low prevalence(16%) of the IL-10enhancing GCC/GCCgenotype comparedto the Polish population (6% and 67%, respectively; p<0.O01). There was no association of the IL-1B or IL-IO genofypes with either baseline histology (GAG, IM, or DYS) nor with rates of progression or regressionamong these stages. Conclusions: The high prevalenceof pro-inflammatory genotypes of IL-1B and IL-IO in the Chinese population may contribute to their high propensity for developing gastric atrophy in response to H. pylori infection. While this genetic predisposition to atrophy may lead to increased risk of GC, other factors (genetic or environmental) may accentuate or attenuate this risk. Geographicdifferences in GC incidence may be partly explainedby ethnic variation in prevalenceof these cytokinu gone polymorphisms.

3997 Coexpression of Cyclooxygenase-2 (COX-2), Hepatocyte Growth Factor (HGF) and Gactrin in Gastric Cancer Before and After Eradication of Helicobacter pylori (Hp) Peter C. Konturek, First Dept of Medicine, Univ Erlangen-Nuremberg,Erlangen Germany; Stanislaw J. Konturek, Aleksandra Duda, Institute of Physiology, Univ Sch of Medicine, Cracow Poland; Holger Meixner, First Dept of Medicine, Univ Erlangen-Nuremberg, Erlangen Germany; Wladyslaw 8ielanski, Institute of Physiology, Cracow Poland; Artur Hartwich, Monika Zuchowicz, District Hosp Cracow, Cracow Poland; Eckhart G. Hahn, First Dept of Medicine, Erlangun Germany Background: Hp has been implicated in the pathogenesis of gastric cancer (GC), but the mechanims of gastric carcinogenesis remain still unclear. There is an evidencethat mucosal growth factors and prostaglandins(PG) produced by COX-2 may be involved in this process,,. In the present study we examinedthe genu and protein expressionof HGF, gastrin and COX1 and COX-2 in GC. Patient and Methods: Twenty five stage I or II GC patients and 20 ageand gender-matchedcontrol subjects hospitalized with non-ulcer dyspepsia were included into this study. The Hp status was determined by serology and histology. The gene and protein expression of HGF, COX-l, COX-2 and gastrin were determined in large biopsies by RT-PCRand Western blot, respectively.In addition, PGE2generationand gastrin content were measured in biopsy specimensby specific RIA. Ten GC patients were investigatedbefore and four weeks after successful eradication of Hp. The biopsies were obtained during endoscopy from GC tumor and surrounding antral mucosa. Results:An overall seropositivity for Hp was 76% in GC and was significantly higher than in the control group (64%). The gene expression of HGF was detected in 52%, gastrin in 84 % and COX-2 in 80% of biospies from GC. The

3995 p16~"="Is Overexpressedin N. pylori-associated Gastritis and Is Correlated with Increased Epithelial Apoptosis Chitin Raim, Wolfson Medical Ctr, Holon Israel; Hanina Hibshoosh, Columbia Univ, New York, NY; Yuichi Kawabata, I. B. Weinstein, Herbert Irving Comprehensivecancer Ctr, Columbia Univ, New York, NY; Steven F. Moss, Brown University/RhodeIsland Hosp, Providence, RI Recent studies implicate cell cycle regulatoryproteins as critical targets during carcinogenesis. Loss of expression of the cyclin dependent kinase inhibitor (CDI) p27K'~ is an independent poor prognostic factor in severalcancers,including gastric carcinoma,and we have previously

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