Genetic alterations of pancreatic intraductal lesions adjacent to invasive ductal carcinoma were investigated. We submitted nine foci of ordinary epithelium, 12 foci of nonpapillary hyperplasia, 12 foci of papillary hyperplasia (pap HP), 66 foci of severe ductal dysplasia, and 27 invasive foci from a total of 10 pancreatic carcinomas for genetic analysis. All foci were individually microdissected and allelic losses of 3p, 4q, 5q, 6q, 8p, 9p, 10q, 11q, 13q, 16q, 17p, and 18q were studied. All invasive and severely dysplastic intraductal foci exhibited loss of heterozygosity (LOH) at more than one chromosomal locus. For each case, allelic loss was frequently observed on 9p (severe ductal dysplasia 90%, invasion 100%), 17p (severe ductal dysplasia 80%, invasion 80%), and 18q (severe ductal dysplasia 88%, invasion 88%). Ninetyfour percent of severe ductal dysplasia and 96% of invasive foci had multiple LOH. Seventeen percent of nonpapillary hyperplasia and 33% of pap HP showed LOH. Only one focus of pap HP showed multiple LOH. The patterns of allelic loss identified in severe ductal dysplasia were generally conserved in synchronous infiltrating tumors, supporting the paradigm that infiltrating tumors are clonally derived from severe ductal dysplasia. In eight of 10 cases, however, we found frequent genetic heterogeneity in the intraductal lesion, suggestive of genetic progression or diversion. These findings indicate that invasive pancreatic carcinoma evolves through successive and divergent genetic changes with selection of aggressive subclones in the intraductal component. Pancreatic ductal carcinoma carries a very poor prognosis because early detection is difficult and effective treatment is not established. The mortality rate of pancreatic carcinoma has been increasing recently in eastern Europe, North America, and in Japan.1,2 A molecular understanding of pancreatic tumorigenesis is critical for developing efficient detection methods and treatment protocols. Molecular studies of pancreatic carcinoma have advanced recently. The oncogene K-ras mutation has been described as its earliest genetic change.3-8 A number of tumor suppressor genes, such as p53, p16, and DPC4, have also been found to play a critical role in the clonal progression of pancreatic tumorigenesis. 9 -20 Using frozen tissue, cell lines, and xenografts, invasive pancreatic carcinoma has been found to have allelic loss on many chromosomal arms.9,21-25 Among these, 1p, 9p, 17p, and 18q have been reported to be deleted in more than 60% of cases, followed by 3p, 6p, 6q, 8p, 10q, 12q, 13q, 21q, and 22q, which have been reported to be deleted in 40 to 60% of pancreatic carcinomas. These chromosomal loci may harbor unidentified tumor suppressor genes critical to the development of pancreatic carcinoma.A diverse spectrum of intraductal epithelial changes, ie, nonpapillary hyperplasia (non-pap HP), papillary hyperplasia (pap HP), atypical hyperplasia/severe dysplasia, and so forth, has been described around invasive pancreatic carcinomas. Mucous cell h...
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