Abstract

1. Pancreatic ductal adenocarcinoma is the fifth leading cause of cancer death in the United States. It is estimated that approximately 27,600 Americans were diagnosed with pancreatic cancer in 1997. It is a nearly uniformly fatal disease, and the mortality rate closely follows that of the incidence. Pancreatic cancer presents clinically with pain, with symptoms related to obstruction of the biliary or pancreatic ducts, or with protean symptoms such as weight loss and cachexia.

   
   

2. Although most carcinomas of the pancreas appear to be sporadic, a number of anecdotal case reports and case-control studies suggest that as many as 10 percent of all cases of pancreatic carcinoma are hereditary. The gene or genes responsible for the familial aggregation of pancreatic cancer largely are unknown, but germ-line mutations in the BRCA2 gene and, less commonly, in the p16 gene, have been shown to predispose to pancreatic cancer, although with incomplete penetrance.

   
   

3. The profile of genetic mutations in pancreatic cancer is distinct from other neoplasms. The K-ras oncogene is commonly activated by somatic mutations in pancreatic cancer, whereas three tumor-suppressor genes are commonly inactivated. Ninety percent or more of pancreatic cancers harbor activating point mutations in codon 12 of K-ras. The p16 tumor-suppressor gene is inactivated in 90 to 100 percent of pancreatic cancers, p53 in 50 to 75 percent, and DPC4 in 50 percent. In addition, occasional somatic mutations of the RB1, MKK4, LKB1, and TGFβ receptor genes also have been reported. Various gene amplifications affect a minority of carcinomas.

   
   

4. Inactivation of the DPC4 gene may be rather specific for pancreatic neoplasia. DPC4 is inactivated in as few as 15 percent of colorectal cancers and in less than 10 percent of other major cancer types. Dpc4 belongs to a class of proteins that mediate signals of the TGFβ superfamily.

   
   

5. Microsatellite instability (RER+) is seen in a small minority (∼4 percent) of pancreatic cancers. These RER+ cancers have a characteristic histologic appearance and frequently have wild-type K-ras genes.

   
   

6. Pancreatic cancer is likely to harbor changes in additional yet uncharacterized genes. Chromosome arms with unexplained losses of heterozygosity at frequencies of greater than 40 percent in pancreatic cancer include 1p, 6p, 8p, 12q, 13q, 21q, and 22q.

   
   

7. A large number of pancreatic cancers have been karyotyped. Double minute chromosomes, possibly representing gene amplification, were identified in 8 percent of pancreatic cancers in one study. These karyotyping studies also provide an understanding of the structural basis for genetic losses identified at the molecular level. Sites having loss of heterozygosity tend to correspond to sites of karyotypic abnormalities in individual tumors.

   
   

8. The diagnosis of pancreatic cancer is suspected based on clinical findings and often can be confirmed with radiologic and endoscopic techniques. Effective screening tests are not available yet.

   
   

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