mutation, which tulfilled the Amsterdam criteria or, whmh were strongly- suspicious for ItNPCC. CC specitic survival was calculated Observation time was measured either until the date of death, date ot a second primary CC or until the dosing date of the study, i.e., June 1, 2001. StatisTioal analym was done by Kaplan-Meler survival analysis. A total of 92 subjects with stage lII CC ,,','ere incfilded Of them 28 (17 males) had adjuvant 5-FU chemotherapeutio treatment. The mean follow up was 4 (range: 1-17) years, 8 subjects died of CC. The 5-year survival ``` '̀as 70% (49-90). Sk~:ty-four subjects (36 males) did not have adluvant therapy, mean follow-up: 8 (range: 0-23) years. Of them 20 died of CC The 5- year survival in this group was also 70% (59-83). To date, the selection of patients with CC fbr 5-FU treamlent is based on tbe stage rather than the biology of the turnout. In this study the CC specific five-year sn~,ival of subjects treated with and without adjuvant 5-FU did not diftbr Furtber studies are necessary" to elucidate the exact role of 5-FU in HNPCC.

T1702

Tumor Necrosis Factor-Alpha Gene Polymorphisms Associated with Susceptibility to Enlarged Fold Gastritis and Gastric Carcinoma Itaru Ohyatna, Chikanm~ Niimi, Kennosuke Shirai, A~amu Taguchi, Naoki Ohmiya, Yoshiki Hirooka, Yasumasa Niwa, Hidemi Goto

Background and Aims: Enlarged tblds nl gastric body have been reported to be associated with Hehcob~'ter ~F'lori (Hp) intection, However, the mechanism is still unclear. The aim of this study is to clarity,' the association of tumor necrosis tactor-alpha (TNFA) gene polymor- phisms and smoking with suseept~bility to enlarged told gastritis. We also determined the association of TNFA polynlol~hisms with gastric carcinoma. Materials and Methods: The subjects were 472 subjects (351 men and 121 women, aged 26-81 years) without gastric carcinoma (control group), and 300 patients (218 men and 82 women, aged 32-91 years) wifh gastric carcinoma (GC group). Double contrast imaging oI the upper digestive system was perk~rmed in 396 subjects in the control group and lbe fold width (fw) was determined at the greater curvature of the middle portion of the gastric body" Fasting plasnta gastrin, pepsinogen (PG) 1, PG It, and anti-Hp IgG titers were analyzed in both groups with informed concent. TNFA-857 promoter polymorphisms were distinguished by 5' nuclease PCR assay (TaqMan) and polymerase chain reaction resmction fragmem length polymorphism (PCR- RFLP) using HinclI in the control group, smoking history was obtained by interview, Results: Adjusted odds ratios (OR) of "I]ViFA-857 T/T genotype, Hp seroposinvity, and sex (male) tor enlarged gastric tolds (fw> = 6 0ram) ,,,,'as 11.7 (95% C1 2.0-66, p<O.01), 25.3 (95% C1 57-112, p<0.O001), and 5.6 (95% CI 1,0-31, p<O.05), respectively. Smoking was not a signiIicant nsk factor tbr enlarged fold gastritis. There was no significant difference m any genot),~e or allele frequencies between the total GC group and control group. However, OR of T allele tor PG methodmegative gastric caminoma was 1.4 (95%CJ 1,0-2.0, p<O,05), Conclusion: "LNTA-857 "i/l" genotype, Hp int;ection, and sex (male) were strongly associated with enlarged tbld gastritis, TNFA T allele at position -857 may promote gastric carcinoma without severe atrophy

T1703

Dpc4/Smad4 and TGF Beta-Like Signals in Pancreatic Carcinogenesis Francesco Cetta, Ginseppina Bon, Herve Nounga, Andrea Cariati, Luca Mazzarella

DPC4/SMAD4 (Delected in Pancreatic Carcinoma, locus 4) is a candidate tumor-suppressor gene that has recently been located at chromosoma 18 q 21,1. Biallelic inactivation of DPC4 has been Sbowl~ is 50% of patients with pancreatic carcinonlas. DPC4 is a member of the highly conserved family ot SMAD proteins, that is responsible tbr relaying signals of the large family of TGF beta cyrokmes from the cell membrane to the nucleus. DCP4 seems unique in being the common pathway tPr signalling by" different TGF beta- tamily membels. Potentially' downstream targets which are regulated through the SMAD transcriptional com- plex as well as target genes relevant fi~r hits suppressive function have not yet been identified. 15 patients with ductal cal~inoma of the pancreas (9 males, 6 temales, mean age 65 years, range 53-78) had analysis of gene and protein expression. Six of 15 pts (40%) showed biallefic reactivation of DPC4 A mudel system of tumor cell clones stably reexpressing DPC4/SMAD4 was also developed. This could be a valid approach to identity' genes and proteins invoh'ed m tmnor suppression me&ated through DPC4/SMAD4.

T1704

Gastric Adenomas in the Familial Adenomatous Polyposis Patient: A New Concern? Cori Salvit, Arnold J. Markowltz, Kimberly Wong, Robert C. Knrtz, Jose G. Guifiem

Background: Ahhough upper gastrointestinal (UGI) malignant potential in familial adenoma- tons polypo'~is/PAP) patients has been prmrarily focused on the duodenum/periampuUary region, recent reports have described gastric adenomas in the antrum as well as fundic gland polyps in the fundus and body as potential premalignant lesions. Aim: Report gastric findings in FAP patients enrolled in fhe Memorial Sloan-Kettering Cancer Center (MSKCC) Hereditary Colomcta] Cancer Family Registry. Methods: 48 FAP patients were identified who underwent at least one UGi endoscopy (EGD) at MSKCC since 1991 EGD procedure and pathology reports were reviewed. Results: 33/48 (688%) FAP patients had findings of gastric polyps, or other raised gastric lesions, sampled tbr pathology'. These 33 patients underwent a median of 2 EGDs (range 1-26) 16/33 (48.4%) patients had pathologically confirmed fundic gland pnlyps 5/33 (15.2%) had pathologically contlrmed gastric adenoma/or focal adenomatous change'. These 5 patients included: 1) 59 yo woman with a large l ~ m adenoma in gastric body', that progressed to invasive adenocarcinoma, in addition to other gastric adenomas, fiyperplastic, and fundic gland polyps, and mixed gastric polyps with fundic gland/hyperplas- tic features, aud focal adenomatous change 2) 24 yo woman (daughter ot above patient) with a I cm antral adenoma, 3) 34 yo man with small antral nodules demonstrating adenomatous change and hyperplastic features. 4) 19 yo man w'ith small thndie/body polyps demonstrating local adenomatuus change. 5) 18 yo woman ``vith small ffmdic/body polyps demoustrating fimdie gland polyp with k',cat adenomatous change. Findings ot gastric

adenoma/focal adenomatous change were iintially detected at 360, 22, 98, and 1 month following colecromy in 4/5 patients, and at time of diagnosis of pnlyposis in 1/5 patients who has yet to undergo colectomy. Conclusion: Given the success nl" prophylactic cnlorectal resection, mortality in FAP patients has shifted trom cnlorectal cancer to duodenal/periampui- la D, carcinoma and desmoid disease. Our observation suggests that we may be witnessing a change in the phenotypic expression of the disease that would require an increased awareness of gastric neoplasia, and the potential need for reassessment of UGI screening practices in these high-risk individuals. These preliminary observations wiU require confirma- tion by large collaborative studies including multiple FAP registries.

T1705

Gastrointestinal Cancer in Familial Breast and Ovarian Cancer Syndrome Hildegard Giessauf~ Heinz F. Hammer, Edgar Petru, Alice Dorda

Introduction: Up to 20% of colon cancer is assumed to have a familial background, but only 3 to 5% are attributable to established familial colon cancer syndromes. Aim of the study was to investigate the gastrointestinal cancer history" in families with familial breast and ovarian cancer syndrome Methods: GI cancer history was assessed in 71 families, which fit the entry' criteria for analysis of BRCA1 gene mutation (>2 cases of breast cancer < 50 yrs among one kindredship, and/or > 1 case of breast cancer before age of 35 yrs, and/or > 2 cases of ovarian cancer irrespective of age) and was related to BRCA 1 status, age, sex and organ distribution of the GI cancer Results: Out of 71 ta.milies 22 (32%) had a positive GI cancer history. Six of 22 families (27%) with and 11 of 49 families (22%) without GI cancer history' had the BRCA 1 mutation, in the 6 tamifies with positive GI cancer history, and BRCA 1 mutation 8 GI cancers were observed (4 colon, 1 stomach, 1 gallbladder, 1 pancreas, 1 liver). In the 16 lamifies with positive Gl cancer history" without BRCA 1 mutation 20 GI cancers were observed (12 colon, 2 pancreas, 4 stomach, 1 liver, 1 esophagus) with one of the patients having a stomach and a colon cancer. In families with GI cancer and positwe BRCA1 G1 cancers affected 4 temale and 4 male patients, whereas in the BRCA 1 negative G1 cancer positive lamihes GI cancers atf;ected 6 female and 13 male patients. Age range of patients affected by G1 cancer was between 45 and 75 years in the BRCA 1 pnsin``'e lamilies and between 50 and 79 years in the BRCA 1 negative families. Only in two families in both the BRCA 1 positive and BRCa~ 1 negative cancer families G1 cancers occurred in at least two different lamdy members. Summary: G1 cancers occur in i of 3 families with lamilial breast and ovarian cancer syndrome. In the majority of these families GI cancers affect only one family member. The cnlon is the most frequently involved organ. Whereas in BRCA 1 positive families GI cancers have an equal sex distribution, in BRC4. 1 negative families there is a 2:1 male preponderance of GI cancers. Age distribution ot GI cancer patterns is similar in BRCA 1 positive and negative families. Conclusion: In the care of patients with familial breast and ovarian cancer syndrome attention also should be given to the possible occurrence of GI cancers.

T1706

Predisposing Individual and Familial Factors to Synchronous Colorectal Neoplasms in Patients with Colorectal Cancer: A Multicenter, Prospective, Nation-Wide Study Vlrgima Pinol, Antoni Castells

Background: Patients with colorectal cancer (CRC) have an increased risk for developing synchronous and metachmnons neoplasms. However, besides those cases with inherited disorders predisposing to tumor mnltieemricity, it is unknown which individuals are prone to this condition, a fact with noteworthy clinical implications. Aim: To identi(v individual and familial characteristics associated with the development of synchronous colorectal neo- plasms in patients with CRC Patients and methods: During one-year period, all patients with CRC attended in 25 Spanish hospitals were included. Exclusion criteria were patients in whom CRC developed m the context of tamifial adenomatous polyposis or inflammatory bowel disease, refusal to participate m the study, incomplete family history', and partial study of the colon and rectum. In addition to demographic, clinical, tumor-related, and familial characteristics, presence of synchronous colorectal neoplasms (adenoma or carci- noma) was evaluated. Univanate (Student t and chi-sqnare tests) and multivariate (logistic regression) analyses were performed. Results: A total of 1522 patients were included in tbe study'. Synchronous colorectal neoplasms were documented in 505 (33.2%) patients, ade- noma (n=411), carcinoma (n=27), or both (n=67). Development of these lesions was associated with re.ale gender (OR: 1.90; IC95%: 1.49-2.42), personal history of colorectal adenoma (OR: 2.73; 1C95%: 1.41-5.23), proximal location of primary tumor (OR: 1.40; IC95%: 1.08-1.79), less advanced TNM stage (OR: 1.52; fC95%: 1.20-I.91), signet-ring cell-type mirrors (OR: 1.54; 1C95%: 1.0892.19), and family history of CRC (OR: 1.79; IC95%: 1.01-3.16) or gastric cancer (OR: 2.19; 1C95%: 1.20-3.98). Predictive modeling disclosed that the risk of' developing synchronous colorectal neoplasms was notably higher when patients fulfilled more than three independent predictive variables (OR 4.46; IC95% 2.73-7.28). Conclusions: Based on individual and familial characteristics ~ i a t e d with s)mchrortous cnlorectal neoplasms, it has been possible to identify" a subgroup of patients with CRC prone to tumor mnlucentricity. Confirmation that this risk correlates with a higher probability of metachronous lesions would justify the use of these easily available parameters to select those patients who may" benefit from preventive strategies, mainly" intensive endo- seoptc surveillance and chemopmvention.

T1707

Lack of Association Between The Calcium-Sensing Receptor (CaSR) A986S Polymorphism and Colorectal Cancer Peter Fuszek, Gabor Speer, Zsoh Nagy, Janus Papp, Peter L. Lakatos, Peter I~katos

in Hungary the second most frequent cause of death is colorectal cancer (CC). Evidence showed the protective role of calcimn supplementation against CC. Serum calcimn concentra- tion is determined by genetic factors, such as G-protein-coupled cell-surlace receptor (CaSR)

A-551 AGA Abstracts