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Context.—Pancreatic cancer has a poor prognosis with a 5-year survival of less than 5%. Early detection is at present the only way to improve this outlook. This review focuses on the recent advances in our understanding of pancreatic carcinogenesis, the scientific evidence for a multistaged tumor progression, and the role genetically engineered mouse models can play in recapitulating the natural course and biology of human disease.Objectives.—To illustrate the stepwise tumor progression of pancreatic cancer and genetic alterations within the different stages of progression and to review the findings made with genetically engineered mouse models concerning pancreatic carcinogenesis.Data Sources.—A review of recent literature on pancreatic tumorigenesis and genetically engineered mouse models.Conclusions.—Pancreatic cancer develops through stepwise tumor progression in which preinvasive stages, called pancreatic intraepithelial neoplasia, precede invasive pancreatic cancer. Genetic alterations in oncogenes and tumor suppressor genes underlying pancreatic cancer are also found in pancreatic intraepithelial neoplasia. These mutations accumulate during progression through the consecutive stages of pancreatic intraepithelial neoplasia lesions. Also in genetically engineered mouse models of pancreatic ductal adenocarcinoma, tumorigenesis occurs through stepwise progression via consecutive mouse pancreatic intraepithelial neoplasia, and these models provide important tools for clinical applications. Nevertheless differences between mice and men still remain.

Mutations in the breast cancer susceptibility gene 2 (BRCA2) are commonly found in familial pancreatic cancer. Recently, EMSY (11q13.5) has been described as a BRCA2 interacting protein capable of binding and inactivating the protein domain encoded by exon 3 of the BRCA2 gene. Amplification of EMSY occurs in 13% of sporadic breast cancers and is directly linked to increased expression. Here we investigate the amplification status of this new potential oncogene in 59 sporadic pancreatic cancers using fluorescence in situ hybridization (FISH) and tissue microarray (TMA). Real-time quantitative RT-PCR was performed on 20 pancreatic cancer cell lines and overexpression was calculated using the delta-delta-Ct-method. Amplification of EMSY was found in 8/59 cases (13.6%). 9/20 (45%) cell line samples showed overexpression of EMSY. In conclusion, sporadic pancreatic cancer shows amplification of EMSY at prevalence similar to that found in other cancers.

BACKGROUND & AIMS: There is limited data on the spectrum and risk for cancer associated with germline serine/threonine protein kinase 11 (STK11) mutations that cause Peutz-Jeghers syndrome (PJS).METHODS: We analyzed the incidence of cancer in 240 individuals with PJS possessing germline mutations in STK11.RESULTS: Fifty-four cancers were found among carriers. Overall, the risk for developing cancer at ages 20, 30, 40, 50, 60, and 70 years was 1%, 3%, 19%, 32%, 63%, and 81%, respectively. Kaplan-Meier analysis showed similar cancer risks between missense and truncating mutation carriers (log-rank chi(2) = 2.48; P = 0.12). There was some evidence that mutations in exon 3 of STK11 were associated with a higher cancer risk than mutations within other regions of the gene. We found no difference in overall cancer risk between male and female carriers (log-rank chi(2) = 1.31; P = 0.25) or between familial and sporadic cases (log-rank chi(2) = 1.16, with 1 df; P = 0.28). The most common cancers represented were gastrointestinal in origin--gastroesophageal, small bowel, colorectal, and pancreatic--and the risk for these cancers at ages 30, 40, 50, and 60 years was 1%, 10%, 18%, and 42%, respectively. In women, the risk for breast cancer was substantially increased, being 32% by age 60 years.CONCLUSIONS: These results quantitatively show the spectrum of cancer risk associated with STK11 germline mutations in the context of PJS and provide a valuable reference for defining surveillance regimens.

Background/Aims: Grading gastric mucosal atrophy in antrum biopsy specimens remains a controversial subject because of limitations in interobserver agreement. We previously described a reliable, quantitative method for grading atrophy of the corpus mucosa with excellent reproducibility and good correlation with the Sydney scores. The aims of the present study were to evaluate the applicability of this method for the grading of antral atrophy and to study the effect of Helicobacter pylori eradication on the antral mucosa. Methods: Antrum biopsy specimens were collected from 71 gastroesophageal reflux disease patients at baseline and after 3 and 12 months. After the first endoscopy, all subjects were treated with omeprazole 40 mg daily for 12 months. After randomization, 27 of the 48 H. pylori-positive patients additionally received eradication therapy. In 182 hematoxylin-eosin-stained specimens, which were of sufficient quality, the proportions ( volume percentages) of glands (VPGL), stroma (VPS), infiltrate (VPI), and intestinal metaplasia in the glandular zone of the antrum mucosa were measured using a point-counting method. In these specimens, mucosal atrophy was assessed by two experienced gastrointestinal tract pathologists ( E. B. and J.L.) according to the updated Sydney classification as either nonatrophic mucosa (n = 47) or as mild ( n = 29), moderate ( n = 50), or marked ( n = 56) atrophy. In addition, a group of 23 cases with difficult-to-classify grades of atrophy were included. Results: The mean VPGL decreased with increasing Sydney grades of atrophy ( p

Purpose: The purpose is to document the clinical, pathological, and genetic features of pancreatic carcinoma (PC) in carriers of a specific p16-Leiden mutation (a 19-bp deletion in exon 2 of the CDKN2A gene). Experimental Design: Clinical data and paraffin embedded tissue were obtained from 12 patients of p16-Leiden-positive families with PC. Because of the known 19-bp germline deletion, we could specifically analyze the genotype of the wild-type allele for loss of heterozygosity. K-ras codon 12 mutations were determined and immunohistochemical testing for p16, Tp53, Smad4, and cyclooxygenase 2 was performed. Results: The average age of subjects that developed PC (8 males) was 58 years (range, 43-74 years). Histology was considered as conventional ductal adenocarcinoma in 11 of 12 and neuroendocrine carcinoma (1 of 12). The carcinomas were-located in the head (10 of 12), corpus (1 of 12), and tail (1 of 12) of the pancreas. The specific p16-Leiden mutation was confirmed in the tissue of all subjects. Loss of heterozygosity of the wild-type allele was present in 2 of 7 tumors analyzed. Immunostaining for p16 was negative in 10 of 10. Tp53 mutations were detected in 5 of 12. Smad4 was negative in 5 of 12 and cyclooxygenase 2 was overexpressed in 11 of 12. K-ras codon 12 mutations were present in 9 of 10 and in three precursor lesions even before abrogation of p16 protein expression was seen (one of three). Conclusions: The p16-Leiden deletion was associated with progression toward conventional ductal adenocarcinomas in all cases but one. Our observations might support the feasibility of early diagnosis of PC in p16-Leiden mutation carriers and might also indicate that chemoprevention needs consideration

Purpose: Peutz-Jeghers syndrome (PJS) is a hamartomatous polyposis disorder with a high cancer risk. Debate exists about the premalignant potential of hamartomas. Also, treatment options other than surveillance are not available. Therefore, molecular alterations in hamartomas and PJS carcinomas were studied. The objective was (a) to evaluate expression of cyclooxygenase (COX)-2 as target for chemopreventive treatment and (b) to define the neoplastic potential of hamartomas at the molecular level. Experimental Design: Paraffin-embedded samples of 24 PJS hamartomas, including 2 hamartomas with dysplastic changes, and 11 PJS carcinomas were available. Slides were stained with antibodies against COX-2, beta-catenin, cyclin D1, p21(waf1/cip1), Ki-67, and p53. DNA was studied for loss of heterozygosity (LOH) at 19p (STK11), 5q (APC), and 17p (TP53); mutations in beta-catenin, APC, and K-RAS; and microsatellite instability. Results: Moderate or strong epithelial COX-2 was present in 25% of hamartomas, including two hamartomas with dysplastic changes, and 64% of carcinomas. Several hamartomas showed focal nuclear beta-catenin (18%) and cyclin D1 overexpression (29%), both unrelated to dysplasia at histological examination. Disturbed topographical expression of Ki-67 in relation to p21(waf1/cip1) was focally present in 27% of hamartomas, including those with dysplastic changes. Most carcinomas showed nuclear beta-catenin (71%), cyclin D1 overexpression (71%), and aberrant Ki-67 staining (100%). There was LOH at 19p in 32% of hamartomas and 82% of carcinomas. p53 staining was present in four (36%) carcinomas, one of which showed LOH at 17p. No beta-catenin mutations Were found. APC mutations were present in two carcinomas, but LOH at 5q was not found. Two carcinomas had K-RAS mutations, and one carcinoma had microsatellite instability. Conclusions: The presence of COX-2 expression in PJS carcinomas and dysplastic hamartomas provides a rationale for chemoprevention with nonsteroidal anti-inflammatory drugs or COX-2 inhibitors. Focal immunohistochemical changes, which may indicate a premalignant potential, were present in some nondysplastic PJS hamartomas. Molecular changes in carcinomas and dysplastic hamartomas in PJS are distinct from the usual adenoma-carcinoma sequence

Gastrointestinal carcinomas synthesize elevated levels of prostaglandin E(2) (PGE(2)), which has been mechanistically linked to carcinogenesis. Recently, microsomal prostaglandin E synthase-1 (mPGES-1) was cloned, which seems to be inducible and linked to cyclooxygenase-2 (Cox-2) in the biosynthesis of PGE(2). We examined expression of mPGES-1 in intestinal type gastric adenocarcinomas and in gastric cancer cell lines. The transcript for mPGES-1 was elevated in 57% (4/7) of gastric carcinomas as detected by Northern blot analysis. Moderate to strong mPGES-1 immunoreactivity was observed in 56% (5/9) of the carcinomas as detected by immunohistochemistry. Furthermore, mPGES-1 mRNA, protein and microsomal PGES activity were detected in gastric adenocarcinoma cell lines that originated from intestinal type tumors (MKN-7 and MKN-28). In contrast to Cox-2, however, expression of mPGES-1 mRNA or protein were not induced by phorbol 12-myristate 13-acetate (PMA) or interleukin-1beta (IL-1beta) in any of the gastric cancer cell lines tested (MKN-1, -7, -28, -45 and -74). Two gastric cancer cell lines (MKN-45 and MKN-74) did not express mPGES-1 and lacked microsomal PGES activity, but were still able to synthesize PGE(2). Because all gastric cell lines expressed cPGES as detected by immunoblotting, it is possible that Cox-2 can interact with cPGES or with some other yet unidentified PGES in gastric cancer cells. Furthermore, our data show that regulatory mechanisms that drive expression of mPGES-1 and Cox-2 dissociate in gastric cancer cell lines

The prolonged use of non-steroidal anti-inflammatory drugs (NSAIDs) has been associated with a reduced risk of gastric cancer. The best-known target of these drugs is cyclooxygenase (COX); the COX-2 isoform is frequently up-regulated in gastric adenocarcinomas. Using the post-gastrectomy stomach as a model, the expression of COX-2 mRNA and protein has been investigated during tumour progression in the human stomach. COX-2 expression was comparable in gastric stump carcinomas and conventional gastric carcinomas and localized primarily to the cytoplasm of the neoplastic cells. COX-2 mRNA was elevated in biopsies containing intestinal metaplasia, as determined by reverse transcriptase polymerase chain reaction (RT-PCR). COX-2 immunopositivity became more frequent during progression from reactive epithelium to high-grade dysplasia, both in the epithelial and in the stromal cell compartment. Co-localization of COX-2 positive stromal cells was seen with CD68, alpha-smooth muscle actin (alpha-SMA), vimentin, and HLA-DR, but an as yet unidentified subpopulation of stromal cells remained. Co-localization with the macrophage marker CD68 was only observed in a minority of COX-2-positive cells. These data show that COX-2 expression is a relatively early event during carcinogenesis in the stomach. COX-2 expression increases during tumour progression in the stomach, suggesting a role for COX-2 expression in gastric tumourigenesis. Copyright (C) 2001 John Wiley Sons, Ltd