This is an application to develop new methods to detect mutations in the CDKN2 tumor suppressor gene to investigate the sensitivity, reliability and specificity of CDKN2 mutation analysis in identifying neoplastic cells in biopsy specimens from patients at high risk for pancreatic cancer. Earlier detection of these cancers will allow for earlier surgical resection and as a consequence will positively influence patient outcome. Pancreatic carcinoma has a particularly poor prognosis and is considered to be one of the deadliest malignancies. Less than 20 percent of pancreatic cancer patients survive one year after diagnosis, and the overall five-year survival rate is only three percent. Early detection and curative surgery for patients with stage I or H disease increases five-year survival to up to 50 percent. At present the detection of early-stage tumors, followed by surgical resection, is the cornerstone of pancreatic cancer therapy. Diagnostic markers are urgently needed for earlier detection of this aggressive cancer. Several lines of evidence suggest that the CDKN2 gene is a good candidate for the development of DNA-based tests to distinguish pancreatic cancers from other pancreatic masses and to identify neoplasms earlier than is currently possible. In order to determine the effectiveness of the detection of CDKN2 mutations in pancreatic cancers we propose the following: (1) development of sensitive and reliable methods for the detection of CDKN2 mutations in clinical specimens (detection of specific mutations will be accomplished by dot blot hybridization with oligonucleotides specific for mutations, polymerase chain reaction (PCR) amplification and restriction digestion assays and by testing for premature protein truncation (PTT). The sensitivity and specificity of each of these assays will be carefully investigated. (2) We will determine whether CDKN2 mutations are present in chronic pancreatitis through the evaluation of a collection of DNAs prepared from fresh and archivel specimens. DNA prepared from specimens from patients with simple chronic pancreatitis and from patients with co-existing pancreatitis and adenocarcinoma will be investigated for CDKN2 mutation. (3) We will apply newly devised CDKN2 mutation detection systems to the study of prospectively acquired biopsy specimens from patients at high risk for the development of pancreatic adenocarcinomas. Fresh biopsy specimens will be evaluated for CDKN2 mutations, using what are determined to be the most sensitive and reliable methods based on our investigations of archival and fresh pancreatitis specimens.
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